Conditions: Respiratory Disorders
Keywords: Immunogenicity Observer-blind Reactogenicity Chronic Obstructive Pulmonary Disease Safety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 145
Healthy volunteers: no

Brief summary:
The purpose of this Phase II study is to assess the safety, reactogenicity and immunogenicity of the investigational Non-typeable Haemophilus influenzae (NTHi) vaccine in patients with moderate and severe persistent airflow obstruction.

Detailed description:

Arms:
arm 1: Subjects in this group will receive the investigational NTHi vaccine. arm 2: Subjects in this group will receive placebo.

Interventions: intervention 1: NTHi-10-AS01E intervention 2: NaCl Placebo
Intervention descriptions: intervention 1: Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule. intervention 2: Intramuscular vaccination in the deltoid region of the non-dominant arm according to protocol schedule.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals 
Rue de l’institut 89, 
1330 Rixensart, Belgium 
Primary Study vaccine 
GlaxoSmithKline (GSK) Biologicals’ investigational 
Non-typeable Haemophilus influenzae (NTHi) 
vaccine, containing 10 µg of PD, 10 µg of PE-PilA 
and the adjuvant AS01E (GSK2838504A) 
Other Study vaccine 
Placebo control 
 
eTrack study number and 
Abbreviated Title 
200157 (NTHI-004) 
 
EudraCT number 
2013-003062-13 
Date of protocol 
Final Version 2: 28 October 2013 
Date of protocol 
amendment 
 
Amendment 1 Final: 27 March 2014 
Amendment 2 Final: 15 December 2014 
Amendment 3 Final: 15 April 2016 
Title 
An observer-blind study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A 
when administered to COPD patients 
 
Detailed Title 
A Phase II, randomised, observer-blind, placebo- 
controlled, multi-centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A, 
when administered intramuscularly according to a 0, 2 
month schedule to COPD patients aged 40 to 80 years 
 
Co-ordinating author 
(Amended 15 April 2016) 
, 
(XPE Pharma & 
Science for GSK Biologicals) 


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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
, PPD 
, PPD
and PPD 
, PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
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eTrack study number and 
Abbreviated Title 
200157 (NTHI-004) 
 
EudraCT number 
2013-003062-13 
Detailed Title 
A Phase II, randomised, observer-blind, placebo- 
controlled, multi-centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A, 
when administered intramuscularly according to a 0, 2 
month schedule to COPD patients aged 40 to 80 years 
Contributing authors 
(Amended 15 April 2016) 
 
• 
, PPD 
Research & Development Lead 
• 
, PPD 
Biostatistician 
 
, Clinical 
 
, Lead 
• 
, Project Biostatistician 
• 
, Study Delivery Lead 
• 
(Novellas Healthcare 
for GSK Biologicals), 
, Study 
Delivery Manager 
• 
, CLS Clinical Read-Out 
Team Leader 
• 
and PPD 
Laboratory Study Managers 
, CLS 
•

Safety Representatives 
• 
(Aixial Pharma for GSK 
Biologicals) and 
, Study Data 
Manager 
• 
, Project Data Manager 
•
Regulatory Lead 
, Global 
 
GSK Biologicals’ Protocol DS v 14.0 
 
Copyright 2013-2016 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited. 
, 


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Protocol Amendment 3 Sponsor Signatory Approval 
 
eTrack study number and 
Abbreviated Title 
200157 (NTHI-004) 
 
EudraCT number 
2013-003062-13 
Date of protocol 
amendment 
Amendment 3 Final:15 April 2016 
Detailed Title 
A Phase II, randomised, observer-blind, placebo- 
controlled, multi-centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A, 
when administered intramuscularly according to a 0, 2 
month schedule to COPD patients aged 40 to 80 years 
Sponsor signatory 
(Amended 15 April 2016) 
Signature 
Ashwani Kumar Arora, 
Clinical and Epidemiology Project Lead 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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Protocol Amendment 3 Rationale 
Amendment number: 
Amendment 3 
 
Rationale/background for changes: 
• 
In compliance with ICH requirements, the protocol mentions that all results will be 
presented in an integrated report at the end of the study. 
• 
Following re-development and re-validation of the anti-PD ELISA, a new cut-off 
was defined. 
• 
Reference to the GSK Biologicals’ Laval laboratory was removed, as this 
laboratory will not be used in the study. In addition, this laboratory is no longer 
part of GSK Biologicals’ laboratories. 
• 
Internal assay qualification procedures were revised and it was decided that the 
level of characterisation of the ELISA assays can be minimal (set-up level) for this 
study as immunogenicity data are descriptive. In consequence, the assays will be 
standardized but not qualified as stated in the original version.This change will not 
impact the validity of the results. 
• 
A tertiary endpoint was added as the presence of viral pathogens in sputum will be 
examined as part of microbiome analysis. 
• 
In order to see early effects of the vaccine on the microbiome, analysis on fresh 
sputum samples (culture results) will be done on all available data up to the data 
lock point of the interim analysis. 
• 
In order to have a first look whether or not the investigational vaccine has an 
impact on AECOPD, AECOPD analyses will be done up to the data lock point of 
the interim analysis. 
• 
Wording was added to clarify process for collection of sputum H. influenzae 
sweeps. 
• 
Wording was updated in order to be aligned with the Statistical Ananlysis Plan. 
• 
In addition, minor edits in other sections were made for clarification purposes. 


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I agree: 
Protocol Amendment 3 Investigator Agreement 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ investigational vaccine and other study-related duties and 
functions as described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-site or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative. 
• 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s). 
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements. 
 
Hence I: 
• 
Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during the 
course of the study and for one year following completion of the study. 
• 
Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities. 
• 
Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study. 


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eTrack study number and 
Abbreviated Title 
200157 (NTHI-004) 
EudraCT number 
2013-003062-13 
Date of protocol 
amendment 
Investigator name 
Amendment 3 Final:15 April 2016 
Signature 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For internal use only 
 
 
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1. Sponsor 
Sponsor Information 
GlaxoSmithKline Biologicals 
Rue de l’institut 89, 1330 Rixensart, Belgium 
 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 9.4.3.1. 
 
5. GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency unblinding 
GSK Biologicals’ Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 9.8. 


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SYNOPSIS 
Detailed Title 
A Phase II, randomised, observer-blind, placebo-controlled, 
multi-centre study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals’ investigational vaccine 
GSK2838504A, when administered intramuscularly according 
to a 0, 2 month schedule to COPD patients aged 40 to 80 years 
 
Indication 
Active immunisation to reduce the frequency of Non-typeable 
Haemophilus influenzae (NTHi)-associated moderate and 
severe acute exacerbations (AECOPD) in COPD patients with a 
previous history of AECOPD 
 
Rationale for the 
study and study 
design 
Rationale for the study 
The purpose of this Phase II study, in which the investigational 
NTHi vaccine will be administered for the first time to 
moderate and severe COPD patients (i.e. GOLD grade 2 and 3), 
is to assess the vaccine’s safety, reactogenicity and 
immunogenicity in this population, and to evaluate in an 
exploratory manner whether an NTHi vaccine can reduce the 
frequency of moderate and severe AECOPD associated with 
NTHi. Placebo will be used as a control. Both the 
investigational NTHi vaccine and the placebo will be given on 
top of the standard of care. 
 
Rationale for the study design 
• 
Scheduled study visits, during which the effect of 
immunisation against NTHi will be evaluated, will take 
place at pre-defined timepoints. In addition, ad-hoc 
AECOPD-driven study visit(s) and/ or phone contact(s) 
will take place for each AECOPD occurring from first 
vaccination up to study conclusion. Besides evaluating the 
effect of vaccination against NTHi on AECOPD, the 
information obtained during these AECOPD-driven study 
contacts will help refining the case definition of AECOPD 
and of NTHi-associated AECOPD. 
• 
As the investigational vaccine will be administered for the 
first time to moderate and severe COPD patients, an 
internal Safety Review Committee (iSRC) will be 
appointed next to the existing project’s Safety Review 
Team (SRT) and safety holding rules have been defined. 
Administration vaccine Dose 1 will follow a staggered 
design, starting with vaccination of GOLD 2 subjects only. 
Administration of vaccine Dose 1 to GOLD 3 subjects will 
depend on the favourable outcome of an iSRC evaluation 
of safety data up to at least day 6 after vaccination from 


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about 20 GOLD 2 subjects (i.e. approximately 10 subjects/ 
group). 
In addition, starting administration of vaccine Dose 2 will 
for each GOLD grade depend on the favourable outcome 
of an iSRC evaluation of all available safety data. 
 
Rationale for the use of placebo 
There is currently no established vaccine with recognised 
efficacy in reducing the frequency of NTHi-associated 
AECOPD. Placebo will therefore be used as a control. 
 
Objectives 
Primary 
• 
To describe the safety and reactogenicity of the 
investigational vaccine. 
 
Secondary 
• 
To describe the humoral and cellular immunogenicity of 
the investigational vaccine. 
 
Tertiary 
• 
To explore the impact of the investigational vaccine on 
AECOPD. 
• 
To explore the impact of the investigational vaccine on 
NTHi presence in sputum. 
• 
To explore the impact of the investigational vaccine on 
health-related quality of life (HRQOL). 
• 
To explore the impact of the investigational vaccine on 
lung function. 
• 
To explore the impact of the investigational NTHi vaccine 
on exercise capacity. 
• 
To describe selected biomarkers in stable COPD and 
during AECOPD. 
• 
To collect blood and sputum samples for assay 
development, for disease diagnostic purpose, for lung 
microbiome analysis and/ or for additional evaluation of 
the immune responses to the investigational vaccine and to 
other potential pathogens involved in AECOPD. 


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Study design 
• 
Experimental design: Phase II randomised, observer- 
blind, placebo-controlled, multi-centre study with 2 
parallel groups. 
• 
Duration of the study: for each subject enrolled, the study 
will last approximately 16 months from Visit 1 up to study 
end: 
 
Epoch 001: starting at Screening and ending at study 
conclusion. 
• 
Study groups: 
 
Group 10-AS01E: approximately 70 subjects 
receiving 2 doses of the investigational NTHi vaccine. 
 
Group Control: approximately 70 subjects receiving 
2 doses of placebo. 
 
Synopsis Table 1 
Study groups and epoch foreseen in the study 
 
Study groups 
Number of subjects 
Age (Min/Max) 
Epoch 
Epoch 001 
10-AS01E 
70 
40 - 80 years 
X 
Control 
70 
40 - 80 years 
X 
• Control: placebo control. 
• 
Vaccination schedule: 0, 2 months (i.e. at Visit 1 
[Day 0 and Visit 4 [Day 60). 
 
Synopsis Table 2 
Study groups and treatments foreseen in the study 
 
Treatment name 
Vaccine/ 
product name 
Study groups 
10-AS01E 
Control 
10µgAg/ AS01E 
NTHi-10 
X 
AS01E 
Placebo 
NaCl 
X 
 
• 
Treatment allocation: subjects will be minimised by: 
 
Age (40 - 59 years or 60 - 80 years). 
 
Number of moderate/ severe AECOPD in the 
previous year (< 2 or  2). 
 
GOLD grade (GOLD 2 or GOLD 3). 
All factors will have equal weight in the minimisation 
algorithm. 


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• 
Blinding: observer-blind. 
Synopsis Table 3 
Blinding of study epochs 
 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
 
• 
Sampling schedule: 
 
Blood samples for safety assessment (haematology/ 
biochemistry parameters) will be collected from all 
subjects at the Screening Visit (pre-Day 0), Visit 1 
(Day 0), Visit 2 (Day 7), Visit 3 (Day 30), Visit 4 
(Day 60), Visit 5 (Day 67), Visit 6 (Day 90), Visit 8 
(Day 270) and at Visit 10 (Day 450). 
 
Blood samples for assessment of humoral 
immunogenicity will be collected from all subjects at 
Visit 1 (Day 0), Visit 3 (Day 30), Visit 4 (Day 60), 
Visit 6 (Day 90), Visit 8 (Day 270) and at Visit 10 
(Day 450). 
 
Blood samples for assessment of cell-mediated 
immunogenicity (CMI) will be collected from all 
subjects in the CMI sub-cohort at Visit 1 (Day 0), Visit 
6 (Day 90), Visit 8 (Day 270) and at Visit 10 (Day 
450). 
 
Blood samples for biomarkers will be collected from 
all subjects at Visit 1 (Day 0), Visit 10 (Day 450) and 
at each AECOPD visit from first vaccination to study 
conclusion. 
 
Blood samples for assessment of haematology 
parameters will be collected at each AECOPD visit. 
 
Sputum samples will be collected from all subjects at 
the Screening Visit (pre-Day 0), Visit 6 (Day 90), 
Visit 7 (Day 180), Visit 8 (Day 270), Visit 9 
(Day 360), Visit 10 (Day 450) and at each AECOPD 
visit from first vaccination to study conclusion. 
• 
COPD symptoms: All subjects will be asked to record 
COPD symptoms in their electronic Diary Card: 
 
Daily in the morning throughout the study (including 
during AECOPD): morning symptoms. 
 
Daily at bedtime throughout the study (including 
during AECOPD): EXACT-PRO. 


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• 
HRQOL assessments: 
 
All subjects will be asked to complete the COPD 
assessment test (CAT) at the Screening Visit (pre- 
Day 0), Visit 8 (Day 270), Visit 10 (Day 450) and at 
each AECOPD visit from first vaccination to study 
conclusion. 
 
All subjects will be asked to complete St. George's 
Respiratory Questionnaire for COPD patients 
(SGRQ-C) at the Screening Visit (pre-Day 0), Visit 8 
(Day 270) and at Visit 10 (Day 450). 
 
All subjects will be asked to complete the Medical 
Research Council Dyspnoea (mMRC) scale at the 
Screening Visit (pre-Day 0), Visit 8 (Day 270), 
Visit 10 (Day 450) and at each AECOPD visit from 
first vaccination to study conclusion. 
• 
Pre- and post-bronchodilator spirometry assessments 
will be done for all subjects at the Screening Visit 
(pre-Day 0), Visit 8 (Day 270) and at Visit 10 (Day 450). 
• 
Exercise capacity: all subjects will be asked to perform the 
6-Minute Walk Test (6MWT) at the Screening Visit 
(pre-Day 0) and at Visit 10 (Day 450). 
• 
Type of study: self-contained. 
• 
Data collection: electronic Case Report Form (eCRF), 
electronic Diary Cards and SITEpro tablets. 
• 
Safety monitoring: safety evaluations by the SRT 
(blinded) and by an iSRC (unblinded) will be performed. 
 
Number of subjects The targeted sample size is 70 subjects/ group (i.e. 140 
subjects in total). 
 
Endpoints 
(Amended 15 April 
2016) 
Primary 
• 
Occurrence of each solicited local adverse event (AE), 
during the 7-day follow-up period (i.e. day 0 - 6) following 
each vaccination, in all subjects. 
• 
Occurrence of each solicited general AE, during the 7-day 
follow-up period (i.e. day 0 - 6) following each 
vaccination, in all subjects. 
• 
Occurrence of any unsolicited AE, during the 30-day 
follow-up period (i.e. day 0 - 29) following each 
vaccination, in all subjects. 


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• 
Occurrence of each haematological/ biochemical laboratory 
abnormality at Day 0, Day 7, Day 30, Day 60, Day 67, Day 
90, Day 270 and Day 450, in all subjects. 
• 
Occurrence of any potential immune-mediated disease 
(pIMD) from first vaccination up to study conclusion, in all 
subjects. 
• 
Occurrence of any serious adverse event (SAE) from first 
vaccination up to study conclusion, in all subjects. 
 
Secondary 
• 
Anti-PD, anti-PE and anti-PilA total IgG antibody 
concentrations as measured by ELISA, at Day 0, Day 30, 
Day 60, Day 90, Day 270 and at Day 450, in all subjects. 
• 
NTHi-specific cell-mediated immune responses as 
measured by flow cytometry intracellular cytokine staining 
(ICS) (frequency of specific CD4+/CD8+ T-cells expressing 
two or more markers, such as IL-2, IL-13, IL-17, IFN-γ, 
TNF-α and CD40L), at Day 0, Day 90, Day 270 and at Day 
450, in a sub-cohort of subjects. 
 
Tertiary 
• 
Number of cases of NTHi-associated moderate and severe 
AECOPD, over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Number of cases of NTHi-associated AECOPD (any 
severity), over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Number of cases of moderate and severe AECOPD (any 
cause), over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Number of cases of AECOPD (any cause, any severity), 
over a period starting 1 month post-Dose 2 and lasting for 1 
year, in all subjects. 
• 
Time to first AECOPD, in all subjects. 
• 
Assessment of EXACT-PRO score, daily at bedtime 
throughout the study, in all subjects. 
• 
NTHi presence in sputum, at Screening, Day 90, Day 180, 
Day 270, Day 360 and Day 450, and from first vaccination 
to study conclusion for each AECOPD, in all subjects. 


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• 
Assessment of CAT score, at Screening, Day 270 and Day 
450, and from first vaccination to study conclusion for each 
AECOPD, in all subjects. 
• 
Assessment of SGRQ-C score, at Screening, Day 270 and 
Day 450, in all subjects. 
• 
Assessment of mMRC scale, at Screening, Day 270 and 
Day 450, and from first vaccination to study conclusion for 
each AECOPD, in all subjects. 
• 
Occurrence of rescue medication use, over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Occurrence of healthcare use for AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all 
subjects. 
• 
Assessment of FEV1% of predicted normal value at 
Screening, Day 270 and Day 450, in all subjects. 
• 
Assessment of 6MWT score, at Screening and Day 450, in 
all subjects. 
• 
Occurrence of selected biomarkers in a subset of blood 
samples, at Day 0 and Day 450, and from first vaccination 
to study conclusion for each AECOPD, in all subjects. 
• 
Presence of respiratory viral pathogens in sputum 
(including respiratory syncytial virus, parainfluenza 
virus, enterovirus/ rhinovirus, metapneumovirus, 
influenza virus, adenovirus, bocavirus and coronavirus) 
at Screening, Day 90, Day 180, Day 270, Visit Day 360 
and Day 450 and at each AECOPD visit from first 
vaccination to study conclusion, in all subjects. 


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TABLE OF CONTENTS 
 
PAGE 
 
SPONSOR INFORMATION ............................................................................................ 7 
SYNOPSIS ...................................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................... 24 
GLOSSARY OF TERMS ............................................................................................... 27 
1. 
INTRODUCTION .................................................................................................... 32 
1.1. 
Background ................................................................................................ 32 
1.1.1. 
Chronic obstructive pulmonary disease and acute 
exacerbations .............................................................................. 32 
1.1.2. 
Current management of AECOPD ............................................... 33 
1.1.3. 
GSK Biologicals’ investigational NTHi vaccine ............................. 33 
1.2. 
Rationale for the study and study design .................................................... 33 
1.2.1. 
Rationale for the study ................................................................. 33 
1.2.2. 
Rationale for the study design ...................................................... 34 
1.2.2.1. 
Scheduled study visits and AECOPD-driven 
study contacts ............................................................ 34 
1.2.2.2. 
Safety overview and staggered vaccination ................ 34 
1.2.3. 
Rationale for the use of placebo ................................................... 35 
1.3. 
Benefit: Risk assessment ............................................................................ 35 
1.3.1. 
Risk Assessment ......................................................................... 35 
1.3.2. 
Benefit Assessment ..................................................................... 35 
1.3.3. 
Overall Benefit : Risk Conclusion ................................................. 35 
2. 
OBJECTIVES ......................................................................................................... 36 
2.1. 
Primary objective ........................................................................................ 36 
2.2. 
Secondary objective ................................................................................... 36 
2.3. 
Tertiary objectives ....................................................................................... 36 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 37 
4. 
AECOPD ................................................................................................................ 40 
4.1. 
Detection of AECOPD ................................................................................. 40 
4.1.1. 
Date of onset and end date of AECOPD ...................................... 41 
4.1.2. 
Guideline for assessing AECOPD that increase in severity .......... 41 
4.2. 
Treatment of AECOPD ............................................................................... 41 
4.2.1. 
Guidelines for treatment with antibiotics ....................................... 41 
4.2.2. 
Guidelines for treatment with systemic corticosteroids ................. 41 
4.3. 
Case definition NTHi-associated AECOPD ................................................. 42 
5. 
STUDY COHORT ................................................................................................... 42 
5.1. 
Number of subjects ..................................................................................... 42 
5.2. 
Inclusion criteria for enrolment .................................................................... 42 
5.3. 
Exclusion criteria for enrolment ................................................................... 43 
6. 
CONDUCT OF THE STUDY .................................................................................. 45 


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6.1. 
Regulatory and ethical considerations, including the informed 
consent process .......................................................................................... 45 
6.2. 
Subject identification and randomisation of treatment.................................. 46 
6.2.1. 
Subject identification .................................................................... 46 
6.2.2. 
Randomisation of treatment ......................................................... 46 
6.2.2.1. 
Randomisation of supplies .......................................... 46 
6.2.2.2. 
Treatment allocation to the subject ............................. 47 
6.2.2.2.1.       
Study group and treatment 
number allocation ................................... 47 
6.2.2.2.2.       ..................................................... Tr
eatment number allocation for subsequent 
doses ...................................................... 47 
6.3. 
Method of blinding ...................................................................................... 47 
6.4. 
General study aspects ................................................................................ 48 
6.5. 
Outline of study procedures ........................................................................ 49 
6.5.1. 
Lists of study procedures during scheduled study visits ............... 49 
6.5.2. 
List of study procedures during AECOPD-driven study 
visits and phone contacts ............................................................. 51 
6.5.3. 
Concurrence of AECOPD-driven study visits and 
scheduled study visits .................................................................. 52 
6.5.4. 
Intervals between study visits....................................................... 52 
6.6. 
Detailed description of study procedures ..................................................... 53 
6.6.1. 
Informed consent ......................................................................... 53 
6.6.2. 
Check inclusion/ exclusion criteria ................................................ 53 
6.6.3. 
Record history of moderate and severe AECOPD within 
the previous year ......................................................................... 53 
6.6.4. 
Check subject’s COPD status ...................................................... 53 
6.6.5. 
Record demographic data ............................................................ 53 
6.6.6. 
Medical history, including significant comorbidities ....................... 53 
6.6.7. 
Vaccination history ....................................................................... 53 
6.6.8. 
Smoking exposure history ............................................................ 54 
6.6.9. 
Smoking status ............................................................................ 54 
6.6.10. 
Physical examination ................................................................... 54 
6.6.11. 
Measure/ record height and weight .............................................. 54 
6.6.12. 
Pre- and post-bronchodilator spirometry ...................................... 54 
6.6.13. 
Chest X-ray .................................................................................. 55 
6.6.14. 
Urine pregnancy test .................................................................... 55 
6.6.15. 
Sampling...................................................................................... 55 
6.6.15.1. Blood samples ............................................................ 55 
6.6.15.2. Sputum samples ......................................................... 56 
6.6.16. 
Check contraindications to vaccination ........................................ 57 
6.6.17. 
Record pre-vaccination body temperature .................................... 57 
6.6.18. 
Treatment number allocation ....................................................... 57 
6.6.19. 
Vaccination .................................................................................. 57 
6.6.20. 
Recording of adverse events, serious adverse events and 
pregnancies ................................................................................. 57 
6.6.21. 
Record    concomitant    medications/    products    and 
vaccinations ................................................................................. 58 
6.6.22. 
Record intercurrent medical  conditions  requiring  medical 
attention ....................................................................................... 59 
6.6.23. 
Train subjects on the use of electronic Diary Card and 
assign electronic Diary Card to subject ........................................ 59 
6.6.24. 
6-minute walk test ........................................................................ 59 


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6.6.25. 
HRQOL questionnaires ................................................................ 59 
6.6.26. 
Record healthcare use for AECOPD ............................................ 60 
6.6.27. 
Confirm AECOPD and record its start date .................................. 60 
6.6.28. 
Document AECOPD severity and end date .................................. 60 
6.6.29. 
Screening conclusion ................................................................... 60 
6.6.30. 
Study conclusion .......................................................................... 60 
6.7. 
Biological sample handling and analysis ..................................................... 60 
6.7.1. 
Use of specified study materials .................................................. 61 
6.7.2. 
Biological samples ....................................................................... 62 
6.7.3. 
Laboratory assays ....................................................................... 63 
6.7.4. 
Immunological correlates of protection ......................................... 66 
7. 
STUDY VACCINES AND ADMINISTRATION ........................................................ 66 
7.1. 
Description of study vaccines ...................................................................... 66 
7.2. 
Storage and handling of study vaccines ...................................................... 67 
7.3. 
Dosage and administration of study vaccines ............................................. 68 
7.4. 
Replacement of unusable vaccine doses .................................................... 68 
7.5. 
Contraindications to subsequent vaccination .............................................. 68 
7.6. 
Concomitant medications/products and concomitant vaccination ................ 69 
7.6.1. 
Recording of concomitant medications/products and 
concomitant vaccination ............................................................... 69 
7.6.2. 
Concomitant medications/products and vaccines that may 
lead to the elimination of a subject from ATP analysis for 
immunogenicity ............................................................................ 69 
7.6.3. 
Concomitant medications/ products that may lead to the 
elimination of a subject from the ATP analysis for efficacy ........... 70 
7.7. 
Intercurrent medical conditions that may lead to elimination of a 
subject from ATP analyses for immunogenicity ........................................... 70 
8. 
HEALTH ECONOMICS .......................................................................................... 70 
9. 
SAFETY ................................................................................................................. 70 
9.1. 
Safety definitions ........................................................................................ 71 
9.1.1. 
Definition of an adverse event ...................................................... 71 
9.1.2. 
Definition of a serious adverse event ........................................... 72 
9.1.3. 
Solicited adverse events .............................................................. 72 
9.1.3.1. 
Solicited local (injection-site) adverse events .............. 73 
9.1.3.2. 
Solicited general adverse events ................................ 73 
9.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 73 
9.1.5. 
Adverse events of specific interest (potential immune- 
mediated diseases) ...................................................................... 73 
9.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ........................................................................................... 76 
9.2.1. 
AECOPD ..................................................................................... 76 
9.2.2. 
Pregnancy ................................................................................... 76 
9.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 77 
9.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 77 
9.3.2. 
Post-Study adverse events and serious adverse events .............. 78 


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9.3.3. 
Evaluation of adverse events and serious adverse events ........... 79 
9.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 79 
9.3.3.2. 
Assessment of adverse events ................................... 80 
9.3.3.2.1.       ..................................................... Ass
essment of intensity ................................ 80 
9.3.3.2.2.       ..................................................... Ass
essment of causality ............................... 81 
9.3.3.3. 
Assessment of outcomes ............................................ 82 
9.3.3.4. 
Medically attended visits ............................................. 82 
9.4. 
Reporting of serious adverse events, pregnancies, and other events .......... 83 
9.4.1. 
Prompt reporting of potential immune-mediated diseases, 
serious adverse events and pregnancies to GSK 
Biologicals ................................................................................... 83 
9.4.2. 
Reporting of pIMDs to GSK Biologicals ........................................ 83 
9.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 84 
9.4.3.1. 
Back-up system in case the electronic SAE 
reporting system does not work .................................. 84 
9.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................... 84 
9.4.5. 
Updating of pIMD, SAE and pregnancy information after 
freezing of the subject’s eCRF ..................................................... 85 
9.4.6. 
Regulatory   reporting   requirements   for   serious   adverse 
events .......................................................................................... 85 
9.5. 
Follow-up  of  adverse  events,  serious   adverse   events,   and 
pregnancies ................................................................................................ 85 
9.5.1. 
Follow-up of adverse events and serious adverse events ............ 85 
9.5.1.1. 
Follow-up during the study .......................................... 85 
9.5.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 85 
9.5.2. 
Follow-up of pregnancies ............................................................. 86 
9.6. 
Treatment of adverse events....................................................................... 86 
9.7. 
Unblinding ................................................................................................... 86 
9.8. 
Emergency unblinding ................................................................................ 86 
9.9. 
Subject card ................................................................................................ 87 
9.10. Safety monitoring ........................................................................................ 87 
9.10.1. 
Safety Review Team .................................................................... 87 
9.10.2. 
Internal Safety Review Committee ............................................... 88 
9.10.3. 
Study holding rules ...................................................................... 89 
10. SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 92 
10.1. Subject completion...................................................................................... 92 
10.2. Subject withdrawal ...................................................................................... 92 
10.2.1. 
Subject withdrawal from the study ................................................ 92 
10.2.2. 
Subject withdrawal from investigational vaccine ........................... 93 
10.3. Screening failures ....................................................................................... 93 
11. STATISTICAL METHODS ...................................................................................... 93 
11.1. Primary endpoints ....................................................................................... 93 
11.2. Secondary endpoints .................................................................................. 94 
11.3. Tertiary endpoints (Amended 15 April 2016) ............................................... 94 
11.4. Determination of sample size ...................................................................... 95 
11.5. Study cohorts to be analysed ...................................................................... 96 


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11.5.1. 
Total vaccinated cohort ................................................................ 96 
11.5.2. 
ATP cohort for analysis of immunogenicity ................................... 96 
11.5.3. 
ATP cohort for analysis of persistence of immunogenicity ............ 96 
11.5.4. 
ATP cohort for analysis of efficacy ............................................... 97 
11.6. Derived and transformed data ..................................................................... 97 
11.7. Analysis of demographics ........................................................................... 98 
11.8. Analysis of safety ........................................................................................ 99 
11.8.1. 
iSRC safety evaluations ............................................................. 100 
11.9. Analysis of immunogenicity ....................................................................... 100 
11.10. Analysis of impact of the investigational vaccine on AECOPD .................. 101 
11.11. Analysis of HRQOL, lung capacity and exercise capacity .......................... 102 
11.12. Analysis of selected biomarkers ................................................................ 102 
11.13. Interpretation of analyses .......................................................................... 103 
11.14. Conduct of analyses ................................................................................. 103 
11.14.1. Sequence of analyses (Amended 15 April 2016) ........................ 103 
11.14.2. Statistical considerations for interim analyses ............................ 104 
12. ADMINISTRATIVE MATTERS ............................................................................. 104 
12.1. Case Report Form/Remote Data Entry instructions ................................... 104 
12.2. Study Monitoring by GSK Biologicals ........................................................ 104 
12.3. Record retention ....................................................................................... 105 
12.4. Quality assurance ..................................................................................... 105 
12.5. Posting of information on publicly available clinical trial registers and 
publication policy ...................................................................................... 106 
12.6. Provision of study results to investigators .................................................. 106 
13. COUNTRY SPECIFIC REQUIREMENTS ............................................................. 106 
14. REFERENCES ..................................................................................................... 107 


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LIST OF TABLES 
 
PAGE 
 
Table 1 
Classification of severity of airflow limitation in COPD (based on 
post-bronchodilator FEV1) ...................................................................... 32 
Table 2 
Classification of severity of AECOPD ..................................................... 33 
Table 3 
Study groups and epoch foreseen in the study ....................................... 38 
Table 4 
Study groups and treatments foreseen in the study ................................ 38 
Table 5 
Blinding of study epoch .......................................................................... 38 
Table 6 
Sub-cohort for CMI ................................................................................. 42 
Table 7 
List of study procedures during scheduled study visits ........................... 49 
Table 8 
List of study procedures during AECOPD-driven study visits and 
phone contacts ....................................................................................... 51 
Table 9 
Intervals between study visits ................................................................. 52 
Table 10 
Biological samples ................................................................................. 62 
Table 11 
Haematology and biochemistry .............................................................. 63 
Table 12 
Humoral  Immunity  (Antibody  determination)  (Amended   15   April 
2016) ...................................................................................................... 63 
Table 13 
Cell-Mediated Immunity .......................................................................... 64 
Table 14 
Microbiology (Amended 15 April 2016) ................................................... 65 
Table 15 
Biomarkers ............................................................................................. 66 
Table 16 
Study vaccines ....................................................................................... 67 
Table 17 
Dosage and administration ..................................................................... 68 
Table 18 
Solicited local adverse events ................................................................ 73 
Table 19 
Solicited general adverse events ............................................................ 73 
Table 20 
List of potential immune-mediated diseases ........................................... 75 
Table 21 
Reporting periods for adverse events, serious adverse events 
and pregnancies ..................................................................................... 78 
Table 22 
Intensity scales for solicited symptoms ................................................... 80 


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Table 23 
Timeframes for submitting potential immune-meditated disease, 
serious adverse event and pregnancy reports to GSK Biologicals .......... 83 
Table 24 
List of holding rules ................................................................................ 90 
Table 25 
GSK Biologicals’ laboratories (Amended 15 April 2016) ....................... 110 
Table 26 
Outsourced laboratories (Amended 15 April 2016) ............................... 110 
Table 27 
FDA  toxicity  grading  scales   for   hematology/   biochemistry 
parameters ........................................................................................... 114 


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LIST OF FIGURES 
 
PAGE 
 
Figure 1 
Study design overview ........................................................................... 37 
Figure 2 
Overview of iSRC evaluation .................................................................. 89 
Figure 3 
Risk assessment curves for safety holding rules 1 and 2 for 
treatment arms of 10 or 20 subjects (no adjustment for 
multiplicity) ............................................................................................. 91 
Figure 4 
Probability not  to  observe  an  AE  for  60,  70  or  80  subjects  per 
group ...................................................................................................... 95 


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LIST OF APPENDICES 
 
PAGE 
 
APPENDIX A LABORATORY ASSAYS ...................................................................... 109 
APPENDIX B CLINICAL LABORATORIES ................................................................. 110 
APPENDIX C FDA Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (September 2007) .......................................................... 111 
APPENDIX D AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ......................................................................................... 116 


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LIST OF ABBREVIATIONS 
6MWT 
6-Minute Walk Test 
AE 
Adverse event 
AECOPD 
Acute exacerbation of COPD 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATP 
According-to-protocol 
CAT 
COPD assessment test 
CI 
Confidence interval 
CLS 
(Amended 15 
April 2016) 
Clinical Laboratory Sciences 
CMI 
Cell-mediated immunity 
COPD 
Chronic obstructive pulmonary disease 
CRDL 
Clinical Research & Development Lead 
eCRF 
Electronic case report form 
EDD 
Estimated date of delivery 
EGA 
Estimated gestational age 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
eTDF 
Electronic temperature excursion decision form 
EU 
European Union 
EXACT-PRO 
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome 
FDA 
Food and Drug Administration, United States 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
GMC 
Geometric mean concentrations 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
H. influenzae 
Haemophilus influenzae 
HRQOL 
Health-Related Quality of Life 
ICF 
Informed consent form 


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ICS 
Intracellular cytokine staining 
IEC 
Independent ethics committee 
IFN- 
Interferon gamma 
IgG 
Immunoglobulin G 
IHC 
International Conference on Harmonisation 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
iSRC 
Internal safety review committee 
LMP 
Last menstrual period 
MATEX 
MATerial EXcellence 
M. catarrhalis 
Moraxella catarrhalis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Millilitre 
mMRC scale 
Modified Medical Research Council Dyspnoea scale 
MPL 
Monophosphoryl Lipid A 
NTHi 
Non-Typeable Haemophilus influenzae 
PA 
Posterior to anterior 
P. aeruginosa 
Pseudomonas aeruginosa 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Protein D 
PE 
Protein E 
PI 
Prescribing information 
pIMD 
Potential immune-mediated disease 
PT 
Preferred term 
qPCR 
Quantitative polymerase chain reaction 
RDE 
Remote data entry 
SAE 
Serious adverse event 
S. aureus 
Staphylococcus aureus 
SBIR 
Randomisation system on internet 
SDV 
Source document verification 
SGRQ-C 
St. George’s Respiratory Questionnaire for COPD patients 
SmPC 
Summary of product characteristics 
SPM 
Study procedures manual 


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S. pneumoniae 
Streptococcus pneumoniae 
S. pyogenes 
Streptococcus pyogenes 
SRT 
Safety review team 
STGG 
Skim milk, tryptone, glucose, and glycerin transport medium 
TNF- 
Tumour necrosis factor alpha 
TVC 
Total vaccinated cohort 
UK 
United Kingdom 
ULN 
Upper limit of the normal range 
USA 
United States of America 
VE 
Vaccine efficacy 
VSMB 
Vaccine safety monitoring board 
WBC 
white blood cells 
WHO-ICD 
World Health Organisation - international classification of 
diseases 


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GLOSSARY OF TERMS 
Adequate contraception: 
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly and when applicable, in 
accordance with the product label for example: 
• 
Abstinence from penile-vaginal intercourse, when 
this is their preferred and usual lifestyle. 
• 
Oral contraceptives, either combined or progestogen 
alone. 
• 
Injectable progestogen. 
• 
Implants of etenogestrel or levonorgestrel. 
• 
Estrogenic vaginal ring. 
• 
Percutaneous contraceptive patches. 
• 
Intrauterine device or intrauterine system. 
• 
Male partner sterilisation prior to the female 
subject’s entry into the study, and this male is the 
sole partner for that subject. 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her medical 
history. 
• 
Male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository). 
• 
Male condom combined with a female diaphragm, 
either with or without a vaginal spermicide (foam, 
gel, film, cream, or suppository). 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, when this 
is their preferred and usual lifestyle. 
 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product. 
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. 


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Alcoholism: 
Alcoholism, also known as dependency on alcohol or 
alcohol addiction, is a chronic disease. The signs and 
symptoms of alcoholism include: 
• 
A strong craving for alcohol. 
• 
Continued use despite repeated physical, 
psychological, or interpersonal problems. 
• 
The inability to limit drinking. 
Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the trial, 
and only when the data are cleaned to an acceptable level 
of quality will appropriate personnel be unblinded or 
when required in case of a serious adverse event. In an 
observer-blind study, the subject and the site and sponsor 
personnel involved in the clinical evaluation of the 
subjects are blinded while other study personnel may be 
aware of the treatment assignment (see Section 6.3 for 
details on observer-blinded studies). 
 
Current smoker: 
A person who is currently smoking or who stopped 
smoking within the past 6 months. 
 
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
 
Epoch: 
An epoch is a self-contained set of consecutive 
timepoints or a single timepoint from a single protocol. 
Self-contained means that data collected for all subjects 
at all timepoints within that epoch allows to draw a 
complete conclusion to define or precise the targeted 
label of the product. Typical examples of epochs are 
primary vaccinations, boosters, yearly immunogenicity 
follow-ups, and surveillance periods for efficacy or 
safety. 
 
eTrack: 
GSK’s tracking tool for clinical trials. 
 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 7.6.2, 7.6.3 and 11.5 for details on criteria for 
evaluability). 
 
Former smoker: 
A person who stopped smoking for at least 6 months. 


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Immunological correlate 
of protection: 
 
 
Investigational 
vaccine/product: 
(Synonym of 
Investigational Medicinal 
Product) 
The defined humoral antibody response above which 
there is a high likelihood of protection in the absence of 
any host factors that might increase susceptibility to the 
infectious agent. 
 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorisation when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
 
Menopause: 
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years. 
 
Pack-years of smoking: 
Pack-years is a quantification of cigarette smoking, a way 
to measure the total amount a person has smoked in the 
course of his/ her lifetime. The number of pack-years is 
calculated as follows: 
(average number of cigarettes smoked per day x 
number of years smoked)/ 20 
E.g. a smoking history of 10 pack-years means having 
smoked 20 cigarettes per day for 10 years, or having 
smoked 10 cigarettes per day for 20 years. 
Note: For the purpose of this study, pipe and/or cigar use 
should not be used to calculate pack year history. 
 
Potential Immune- 
Mediated Disease: 
 
 
Primary completion 
date: 
Potential immune-mediated diseases (pIMDs) are a subset 
of AEs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. 
 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for the primary outcome, whether the clinical trial 
concluded according to the pre-specified protocol or was 
terminated. 


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Protocol amendment: 
The International Conference on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK Biologicals further details this to include a change 
to an approved protocol that affects the safety of subjects, 
scope of the investigation, study design, or scientific 
integrity of the study. 
 
Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study. 
Note: Any change that falls under the definition of a 
protocol amendment (e.g. a change that affects the safety 
of subjects, scope of the investigation, study design, or 
scientific integrity of the study) MUST be prepared as an 
amendment to the protocol. 
Randomisation: 
Process of random attribution of treatment to subjects in 
order to reduce bias of selection. 
 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
 
Site Monitor: 
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites. 
 
Solicited adverse event: 
AEs to be recorded as endpoints in the clinical study. The 
presence/occurrence/intensity of these events is actively 
solicited from the subject or an observer during a 
specified post-vaccination follow-up period. 
 
Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects. 
 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the vaccine(s)/product(s) or as a control. 
 
Subject number: 
A unique number identifying a subject, assigned to each 
subject consenting to participate in the study. 
 
Treatment: 
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject, 
identified by a unique number, according to the study 
randomisation or treatment allocation. 


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Treatment number: 
A number identifying a treatment to a subject, according 
to the study randomisation or treatment allocation. 
 
Unsolicited adverse 
event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Chronic obstructive pulmonary disease and acute exacerbations 
 
Chronic obstructive pulmonary disease (COPD) is a disease characterised by persistent 
airflow obstruction which is not fully reversible and which is usually progressive in the 
long term. The airflow limitation in COPD patients can be classified into GOLD grades 
as shown in Table 1 [GOLD, 2013]. 
 
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 
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. COPD results from 
a gene-environment interaction. The most important environmental risk factor for COPD 
is tobacco smoking, even though other factors, such as occupational exposure, may also 
contribute to the development of the disease [GOLD, 2013]. The prevalence and burden 
of COPD are projected to increase in the coming decades due to continued exposure to 
risk factors and the changing age structure of the world’s population. 
 
The morbidity and mortality of COPD is substantially contributed to by acute 
exacerbation of COPD (AECOPD), which are events during which the patient’s 
respiratory symptoms acutely worsen beyond normal day-to-day variations and which 
require a change in maintenance treatment. Higher exacerbation rates have been related 
to a faster decline in lung function and are known to have a negative effect on the 
patient’s quality of life. Moreover, frequent exacerbations are associated with significant 
mortality, particularly if they require hospitalisation. Between 40 - 60% of medical 
expenditure for COPD is a direct consequence of AECOPD Cazzola, 2008. 
The lungs are known to be colonised with different strains of bacteria [Erb-Downward, 
2011]. In COPD patients, acquisition of new bacterial strains is believed to be an 
important cause of AECOPD [Sethi, 2002]. Although estimates vary widely, Non- 
typeable Haemophilus influenzae (NTHi) appears to be the main bacterial pathogen 
associated with AECOPD (11-38%), followed by Moraxella catarrhalis (M. catarrhalis) 
(3-25%) and Streptococcus pneumoniae (S. pneumoniae) (4-9%) [Alamoudi, 2007; 
Bandi, 2003; Hutchinson, 2007; Ko, 2007; Larsen, 2009; Murphy, 2005; Papi, 2006; 
Sethi, 2002; Sethi, 2008]. 


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Reducing the frequency and severity of AECOPD is one of the main goals of COPD 
maintenance treatment. The severity of AECOPD can be graded according to the 
intensity of medical intervention required (see Table 2) [Wedzicha, 2007. 
Table 2 
Classification of severity of AECOPD 
 
Grade 
Intensity of medical intervention 
Mild 
Can be controlled with an increase in dosage of regular medications 
Moderate 
Requires treatment with systemic corticosteroids and/ or antibiotics 
Severe 
Requires hospitalisation 
 
1.1.2. 
Current management of AECOPD 
 
A wide range of pharmacologic (such as inhaled corticosteroids, bronchodilators, 
phosphodiesterase inhibitors, theophyllines, long-term antibiotics and mucolytics) and 
non-pharmacologic (such as lung volume reduction surgery, home oxygen, ventilatory 
support and pulmonary rehabilitation) interventions exist to reduce AECOPD and 
hospitalisation rates. However, a need for further novel interventions remains because 
current approaches are not completely effective, even when targeted and used optimally. 
 
No vaccine is currently indicated for the prevention of AECOPD, even though flu and 
pneumococcal vaccines are routinely recommended to COPD patients. The availability of 
a vaccine for the prevention of bacterial AECOPD could contribute significantly to the 
management of COPD. 
 
1.1.3. 
GSK Biologicals’ investigational NTHi vaccine 
 
GlaxoSmithKline (GSK) Biologicals is developing a vaccine targeting NTHi in order to 
reduce the frequency of moderate and severe AECOPD in COPD patients with a previous 
history of AECOPD. The vaccine is intended to be administered on top of standard of 
care. The selected investigational vaccine consists out of 3 conserved surface proteins 
(protein D [PD, protein E [PE and PilA; the latter 2 are included in the vaccine as a 
fusion protein named PE-PilA) adjuvanted with GSK’s proprietary Adjuvant System 
AS01E. 
Refer to the current Investigator Brochure and its supplement for information regarding 
the pre-clinical and clinical studies and the potential risks and benefits of the 
investigational NTHi vaccine. 
 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
 
The purpose of this Phase II study, in which the investigational NTHi vaccine will be 
administered for the first time to moderate and severe COPD patients, is to assess the 
vaccine’s safety, reactogenicity and immunogenicity in this population, and to evaluate in 
an exploratory manner whether an NTHi vaccine can reduce the frequency of moderate 


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and severe AECOPD associated with NTHi. Placebo will be used as a control. Both the 
investigational NTHi vaccine and the placebo will be given on top of the standard of care. 
 
1.2.2. 
Rationale for the study design 
 
1.2.2.1. 
Scheduled study visits and AECOPD-driven study contacts 
 
Scheduled study visits, during which the effect of immunisation against NTHi will be 
evaluated, will take place at pre-defined timepoints (see Figure 1). 
 
In addition to the scheduled study visits, ad-hoc AECOPD-driven study visit(s) and/ or 
phone contact(s) will take place for each AECOPD occurring from first vaccination up 
to study conclusion: 
• 
An AECOPD visit will be scheduled as soon as possible after the onset of AECOPD 
symptoms (maximum 96 hours after and, if applicable, preferably before starting 
treatment with antibiotics). 
• 
Follow-up phone call(s) and/ or visits will take place to determine the end of the 
AECOPD. These contacts will take place at least every 2 weeks, until the AECOPD 
has resolved. 
Besides evaluating the effect of vaccination against NTHi on AECOPD, the information 
obtained during these AECOPD-driven study contacts will help refining the case 
definition of AECOPD and of NTHi-associated AECOPD. 
 
1.2.2.2. 
Safety overview and staggered vaccination 
 
As the investigational vaccine will be administered for the first time to moderate and 
severe COPD patients, an internal Safety Review Committee (iSRC) will be appointed 
next to the existing project’s Safety Review Team (SRT) and safety holding rules have 
been defined. 
 
The iSRC will conduct unblinded reviews of all available safety data from the present 
study, including data on AECOPD (frequency, intensity and duration). Each safety 
evaluation by the iSRC will be preceded by a blinded safety review of the same safety 
data by the SRT. 
 
Administration of vaccine Dose 1 will follow a staggered design, starting with 
vaccination of GOLD 2 subjects only. Administration of vaccine Dose 1 to GOLD 3 
subjects will depend on the favourable outcome of an iSRC evaluation of safety data up 
to at least day 6 after vaccination from about 20 GOLD 2 subjects (i.e. approximately 10 
subjects/ group). 
 
In addition, starting administration of vaccine Dose 2 will for each GOLD grade depend 
on the favourable outcome of an iSRC evaluation of all available safety data. 
 
Refer to Section 9.10 for more detailed information on safety monitoring and escalation 
of safety signals to GSK Biologicals’ Vaccine Monitoring Board (VSMB). 


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1.2.3. 
Rationale for the use of placebo 
 
There is currently no established vaccine with recognised efficacy in reducing the 
frequency of NTHi-associated AECOPD. Placebo will therefore be used as a control. 
 
1.3. 
Benefit: Risk assessment 
Please refer to the current IB for the summary of potential risks and benefits of the NTHi 
investigational vaccine. 
 
The following section outlines the risk assessment and mitigation strategy for the study 
protocol: 
 
1.3.1. 
Risk Assessment 
 
Important 
Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
NTHi investigational vaccine 
Theoretical risk of acquiring 
a vaccine-induced 
autoimmune disease after 
vaccination 
No confirmed signals related to 
this potential risk have been 
identified during the preclinical 
and clinical programs so far 
(data from two studies using 
NTHi vaccines: NTHI-002 (non- 
adjuvanted formulations) and 
NTHI-003 (adjuvanted and 
non-adjuvanted formulations). 
Close monitoring of potential 
immune-mediated diseases in 
clinical development programs 
using adjuvants systems. The 
potential risk of events of 
possible autoimmune aetiology 
to occur is mentioned in the 
Informed Consent Form (ICF). 
 
1.3.2. 
Benefit Assessment 
 
Benefits considerations include: 
 
• 
Contribution to the process of developing of a vaccine against AECOPD. 
• 
Medical evaluations/assessments associated with this study (i.e. physical 
examination, blood testing [haematology and biochemistry data], spirometry). 
 
1.3.3. 
Overall Benefit : Risk Conclusion 
 
Taking into account the measures taken to minimize risks to subjects participating in this 
study, the potential and/or known risks identified in association with the candidate NTHi 
vaccine are justified by the anticipated benefits that may be afforded to patients for the 
prevention of AECOPD. 


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2. 
OBJECTIVES 
2.1. 
Primary objective 
• 
To describe the safety and reactogenicity of the investigational vaccine. 
Refer to Section 11.1 for the definition of the primary endpoints. 
2.2. 
Secondary objective 
• 
To describe the humoral and cellular immunogenicity of the investigational vaccine. 
Refer to Section 11.2 for the definition of the secondary endpoints. 
2.3. 
Tertiary objectives 
• 
To explore the impact of the investigational vaccine on AECOPD. 
• 
To explore the impact of the investigational vaccine on NTHi presence in sputum. 
• 
To explore the impact of the investigational vaccine on health-related quality of life 
(HRQOL). 
• 
To explore the impact of the investigational vaccine on lung function. 
• 
To explore the impact of the investigational NTHi vaccine on exercise capacity. 
• 
To describe selected biomarkers in stable COPD and during AECOPD. 
• 
To collect blood and sputum samples for assay development, for disease diagnostic 
purpose, for lung microbiome analysis and/ or for additional evaluation of the 
immune responses to the investigational vaccine and to other potential pathogens 
involved in AECOPD. 
 
Refer to Section 11.3 for the definition of the tertiary endpoints. 


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3. 
STUDY DESIGN OVERVIEW 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the outline of study procedures (Section 6.5), are essential and required for 
study conduct. 
 
Figure 1 
Study design overview 
 
 
• 
Experimental design: Phase II randomised, observer-blind, placebo-controlled, 
multi-centre study with 2 parallel groups. 
 
• 
Duration of the study: for each subject enrolled, the study will last approximately 
16 months from Visit 1 up to study end: 
 
Epoch 001: starting at Screening and ending at study conclusion. 
• 
Study groups: 
 
Group 10-AS01E: approximately 70 subjects receiving 2 doses of the 
investigational NTHi vaccine. 
 
Group Control: approximately 70 subjects receiving 2 doses of placebo. 


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Table 3 
Study groups and epoch foreseen in the study 
 
Study groups 
Number of 
subjects 
Age (Min/Max) 
Epoch 
Epoch 001 
10-AS01E 
70 
40 - 80 years 
X 
Control 
70 
40 - 80 years 
X 
 
• 
Control: placebo control. 
• 
Vaccination schedule: 0, 2 months (i.e. at Visit 1 [Day 0 and Visit 4 [Day 60). 
Table 4 
Study groups and treatments foreseen in the study 
 
Treatment name 
Vaccine/ 
product name 
Study groups 
10-AS01E 
Control 
10µgAg/ AS01E 
NTHi-10 
X 
AS01E 
Placebo 
NaCl 
X 
 
• 
Treatment allocation: subjects will be minimised by: 
 
Age (40 - 59 years or 60 - 80 years). 
 
Number of moderate/ severe AECOPD in the previous year (< 2 or  2). 
 
GOLD grade (GOLD 2 or GOLD 3). 
All factors will have equal weight in the minimisation algorithm. 
Subjects will be randomised using a centralised randomisation system on internet 
(SBIR) at first dose. Treatment number allocation (without randomisation) will also 
occur at Dose 2 using SBIR. 
 
• 
Blinding: observer-blind 
Table 5 
Blinding of study epoch 
 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
 
• 
Sampling schedule. 
 
Blood samples for safety assessment * (haematology/ biochemistry 
parameters) will be collected from all subjects at the Screening Visit (pre-Day 
0), Visit 1 (Day 0), Visit 2 (Day 7), Visit 3 (Day 30), Visit 4 (Day 60), Visit 5 
(Day 67), Visit 6 (Day 90), Visit 8 (Day 270) and at Visit 10 (Day 450). 
* Additional blood sample(s) for safety assessment may be taken at the 
discretion of the investigator if deemed necessary. 
 
Blood samples for assessment of humoral immunogenicity will be collected 
from all subjects at Visit 1 (Day 0), Visit 3 (Day 30), Visit 4 (Day 60), Visit 6 
(Day 90), Visit 8 (Day 270) and at Visit 10 (Day 450). 


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 
Blood samples for assessment of cell-mediated immunogenicity (CMI) will 
be collected from all subjects in the CMI sub-cohort at Visit 1 (Day 0), Visit 6 
(Day 90), Visit 8 (Day 270) and at Visit 10 (Day 450). 
 
Blood samples for biomarkers will be collected from all subjects at Visit 1 
(Day 0), Visit 10 (Day 450) and at each AECOPD visit from first vaccination to 
study conclusion. 
 
Blood samples for assessment of haematology parameters will be collected at 
each AECOPD visit. 
 
Sputum samples will be collected from all subjects at the Screening Visit 
(pre-Day 0), Visit 6 (Day 90), Visit 7 (Day 180), Visit 8 (Day 270), Visit 9 
(Day 360), Visit 10 (Day 450) and at each AECOPD visit from first vaccination 
to study conclusion. 
 
• 
COPD symptoms: All subjects will be asked to record COPD symptoms in their 
electronic Diary Card: 
 
Daily in the morning throughout the study (including during AECOPD): 
morning symptoms. 
 
Daily at bedtime throughout the study (including during AECOPD): 
EXACT-PRO. 
 
• 
HRQOL assessments: 
 
All subjects will be asked to complete the COPD assessment test (CAT) at the 
Screening Visit (pre-Day 0), Visit 8 (Day 270), Visit 10 (Day 450) and at each 
AECOPD visit from first vaccination to study conclusion. 
 
All subjects will be asked to complete St. George's Respiratory Questionnaire 
for COPD patients (SGRQ-C) at the Screening Visit (pre-Day 0), Visit 8 (Day 
270) and at Visit 10 (Day 450). 
 
All subjects will be asked to complete the Medical Research Council 
Dyspnoea (mMRC) scale at the Screening Visit (pre-Day 0), Visit 8 (Day 270), 
Visit 10 (Day 450) and at each AECOPD visit from first vaccination to study 
conclusion. 
 
• 
Pre- and post-bronchodilator spirometry assessments will be done for all subjects 
at the Screening Visit (pre-Day 0), Visit 8 (Day 270) and at Visit 10 (Day 450). 
 
• 
Exercise capacity: all subjects will be asked to perform the 6-Minute Walk Test 
(6MWT) at the Screening Visit (pre-Day 0) and at Visit 10 (Day 450). 
 
• 
Type of study: self-contained. 
• 
Data collection: electronic Case Report Form (eCRF), electronic Diary Cards and 
SITEpro tablets. 


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• 
Safety monitoring: safety evaluations by the SRT (blinded) and by an iSRC 
(unblinded) will be performed. Refer to Section 9.10 for more detailed information 
on safety monitoring. 
 
4. 
AECOPD 
4.1. 
Detection of AECOPD 
Occurrence of each 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 each 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 one major symptom together with any one 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. 
• 
Any symptom occurring on at least 5 consecutive days prior to a potential 
exacerbation will be discounted from the symptoms that 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 check whether an AECOPD visit is 
warranted. In addition, the site should pro-actively 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). 
For all potential AECOPD detected between first vaccination and study conclusion: 
• 
If the site concludes that the subject is not experiencing an AECOPD, this should be 
documented/ reported. 
• 
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 and, if applicable, preferably before starting treatment with antibiotics) *. 
* In case of AECOPD occurring before Visit 1, subjects should be treated outside the 
study according to standard practice. These subjects can only continue in the study if 
the entire Screening Visit is repeated after they are stable for at least 30 days. 


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During the AECOPD visit, the investigator will confirm the occurrence of the AECOPD 
based on clinical and medical judgement, and will record its date of onset. The end date 
of the AECOPD and its severity will be determined/ confirmed during follow-up phone 
call(s) and/ or study visit(s), which will take place at least every 2 weeks until the 
AECOPD has resolved. 
 
4.1.1. 
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. 
 
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. 
 
Both start and end date of each confirmed AECOPD occurring from Visit 1 to study 
conclusion will be recorded in the eCRF. 
 
4.1.2. 
Guideline for assessing AECOPD that increase in severity 
 
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity. 
 
4.2. 
Treatment of AECOPD 
As the treatment given for an AECOPD might have an impact on relapse/ recurrence or 
time until the next AECOPD, guidance on how to preferably treat AECOPD is provided 
in Sections 4.2.1 and 4.2.2. 
 
4.2.1. 
Guidelines for treatment with antibiotics 
 
If there is evidence of respiratory infection that in the opinion of the investigator warrants 
the need for antibiotics the following guidelines are recommended: 
• 
It is suggested to use an aminopenicillin, a macrolide or a tetracycline as initial 
empirical treatment for 7 days (taking into account guidance issued locally by 
infectious disease specialists or other relevant medical function). 
 
• 
If first line antibiotic treatment fails and additional antibiotics are used, the total 
duration of antibiotic treatment should ideally be  30 days. 
4.2.2. 
Guidelines for treatment with systemic corticosteroids 
 
If in the opinion of the investigator the AECOPD is severe enough to warrant the need for 
systemic corticosteroids (with or without antibiotics) the following guidelines are 
recommended: 
• 
It is suggested to use prednisolone 30 mg as initial empirical treatment for 7 days. 
• 
The duration of treatment with systemic corticosteroids should ideally be  14 days. 


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4.3. 
Case definition NTHi-associated AECOPD 
The case definition of NTHi-associated AECOPD has not been established yet. 
NTHi-association will be determined using sputum samples taken during AECOPD and 
could for instance be based on the presence of (NT)Hi (any), on (NT)Hi bacterial load or 
on the acquisition of a new strain of NTHi. The final case definition to be used in the 
analysis of this study will be built based on the data obtained in the on-going GSK 
Biologicals’ study EPI-HIP-001 (114378) “An epidemiology study to assess the 
contribution of bacterial and viral pathogens to AECOPD in adults and elderly between 
40 and 85 years of age in the UK”. 
 
An endpoint assessment/ adjudication committee may be appointed to review AECOPD. 
 
5. 
STUDY COHORT 
5.1. 
Number of subjects 
The target is to enrol approximately 70 eligible COPD patients aged 40 to 80 years per 
study group (i.e. 140 subjects in total). Refer to Section 11.4 for a detailed description of 
the criteria used in the estimation of the sample size. 
 
Approximately 40 subjects will be part of a sub-cohort for CMI analysis (20 subjects/ 
group). An additional blood sample will be taken from these subjects at specified 
timepoints. 
 
Table 6 
Sub-cohort for CMI 
 
Sub-cohort name 
Description 
Estimated number of subjects 
Sub-cohort for CMI 
At specific timepoints, an additional blood sample will 
be taken from these subjects for evaluation of the 
vaccine component-specific CMI responses. 
40 subjects ( 20 subjects in 
each group) 
 
5.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. electronic Diary Card completion, number of 
blood draws, sputum sampling, pre- and post-bronchodilator spirometry, return for 
follow-up visits). 
• 
A male or female between, and including, 40 and 80 years of age at the time of the 
first vaccination. 
• 
Written informed consent obtained from the subject. 


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• 
Confirmed diagnosis of COPD (based on post-bronchodilator spirometry) with 
forced expiratory volume in 1 second (FEV1) over forced vital capacity (FVC) ratio 
(FEV1/FVC) < 0.7, AND FEV1 < 80% and  30% predicted (GOLD 2 and 3). 
• 
Current or former smoker with a cigarette smoking history of ≥ 10 pack-years. 
Refer to the glossary of terms for the definitions of pack-years and of current and 
former smoker. 
• 
Stable COPD patient* with documented history (e.g. medical record verification) of 
at least 1 moderate or severe AECOPD within the 12 months before Screening. 
* Patient for whom the last episode of AECOPD is resolved for at least 30 days at 
the time of Screening. 
Refer to the Study Procedures Manual (SPM) for details on what is accepted as 
documented history of AECOPD. Refer to Table 2 for the definitions of moderate 
and severe AECOPD. 
• 
Regular sputum producer. 
• 
Capable to comply with the daily electronic Diary Card completion throughout the 
study period, according to investigator’s judgement at Visit 1. 
Refer to the SPM for recommendations on what is considered adequate compliance 
by Visit 1. 
• 
Female subjects of non-childbearing potential may be enrolled in the study. 
 
Non-childbearing potential is defined as current tubal ligation, hysterectomy, 
ovariectomy or post-menopause. 
Refer to the glossary of terms for the definition of menopause. 
• 
Female subjects of childbearing potential may be enrolled in the study, if the subject: 
 
has practiced adequate contraception for 30 days prior to vaccination, and 
 
has a negative pregnancy test on the day of vaccination, and 
 
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Refer to the glossary of terms for the definition of adequate contraception. 
 
5.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
• 
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). 


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• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine within 30 days preceding the first dose of study vaccine, or planned 
use during the study period. 
• 
Planned administration/ administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of vaccine, with the exception of any influenza or pneumococcal 
vaccine which may be administered ≥ 15 days preceding or following any study 
vaccine dose. 
• 
Previous vaccination with any vaccine containing NTHi antigens. 
• 
Administration of immunoglobulins or any blood products within the 3 months 
preceding the first dose of study vaccine or planned administration during the study 
period. 
• 
Chronic administration (defined as more than 14 days in total) of non-steroid 
immunosuppressants or other immune-modifying drugs within 6 months prior to the 
first vaccine dose (e.g. methotrexate). 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
• 
History of immune-mediated disease other than COPD. 
Refer to Table 20 for a non-exhaustive list of potential immune-mediated diseases 
(pIMDs). 
• 
Administration of systemic corticosteroids (prednisone  10 mg/day, or equivalent) 
within the 30 days before Screening. 
 Subjects who received systemic corticosteroids within this period may be 
enrolled at a later date if enrolment is still open. 
• 
Administration of systemic antibiotics within the 30 days before Screening. 
 Subjects who received systemic antibiotics within this period may be enrolled at 
a later date if enrolment is still open. 
• 
Chronic use of antibiotics for prevention of AECOPD (e.g. azithromycin). 
• 
Receiving oxygen therapy. 
• 
Planned lung transplantation. 
• 
Planned/ underwent lung resection surgery (e.g. lung volume reduction surgery or 
lobectomy). 
• 
Diagnosis of α-1 antitrypsin deficiency as the underlying cause of COPD. 
• 
Diagnosed with a respiratory disorder other than COPD (such as sarcoidosis, active 
tuberculosis, clinically significant bronchiectasis, lung fibrosis, pulmonary 
embolism, pneumothorax, current diagnosis of asthma in the opinion of the 
investigator), or chest X-ray/ CT scan revealing evidence of clinically significant 
abnormalities not believed to be due to the presence of COPD. Subjects with allergic 


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rhinitis do not need to be excluded and may be enrolled at the discretion of the 
investigator. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccines and/ or the bronchodilator used for spirometry assessment 
during the study. 
• 
Contraindication for spirometry testing (such as recent eye surgery, recent thoracic 
or abdominal surgery procedures, unstable cardiovascular status, recent myocardial 
infection or pulmonary embolism). 
• 
Clinically significant* abnormality in haematology (haemoglobin, platelets or WBC) 
or biochemistry parameter (ALT, AST or creatinine), as per the judgement of the 
investigator. 
* As the study participants are COPD patients, various pre-existing haematological/ 
biochemical abnormalities might be detected. The investigator should use his/ her 
clinical judgement to decide which ones are clinically significant. 
• 
Acute cardiac insufficiency. 
• 
Malignancies within the previous 5 years (excluding non-melanotic skin cancer and 
carcinoma in situ of the cervix, if considered cured) or lymphoproliferative disorder. 
• 
Any known disease or condition likely to cause death during the study period. 
• 
Acute disease and/ or fever at the time of Screening. 
 
Fever is defined as oral or axillary temperature  37.5°C. The preferred route for 
recording temperature in this study will be oral. 
 Subjects with acute disease and/ or fever at the time of Screening may be 
enrolled at a later date if enrolment is still open. Subjects with a minor illness 
without fever may be enrolled at the discretion of the investigator. 
• 
Pregnant or lactating female. 
• 
Current alcoholism and/or drug abuse. 
Refer to the glossary of terms for the definition of alcoholism. 
• 
Other condition which the investigator judges may put the safety of the subject at 
risk through study participation or which may interfere with the study findings (e.g. 
anaemia, patient on dialysis). 
• 
Planned move to a location that will complicate participation in the trial through 
study end. 
 
6. 
CONDUCT OF THE STUDY 
6.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 


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The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), all applicable subject 
privacy requirements and the guiding principles of the Declaration of Helsinki. 
 
GSK will obtain favourable opinion/ approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject informed consent. 
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
 
Freely given and written informed consent must be obtained from each subject prior to 
participation in the study. 
 
GSK Biologicals will prepare a model ICF which will embody the ICH GCP and GSK 
Biologicals required elements. While it is strongly recommended that this model ICF is to 
be followed as closely as possible, the informed consent requirements given in this 
document are not intended to pre-empt any local regulations which require additional 
information to be disclosed for informed consent to be legally effective. Clinical 
judgement, local regulations and requirements should guide the final structure and 
content of the local version of the ICF. 
 
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/ IEC. 
 
6.2. 
Subject identification and randomisation of treatment 
6.2.1. 
Subject identification 
 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre. 
 
6.2.2. 
Randomisation of treatment 
 
6.2.2.1. 
Randomisation of supplies 
 
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a programme developed for use in Statistical Analysis 


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System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the drug depot. 
 
6.2.2.2. 
Treatment allocation to the subject 
 
The treatment numbers will be allocated by dose. 
 
6.2.2.2.1.       Study group and treatment number allocation 
 
The target will be to enrol approximately 140 eligible subjects who will be randomly 
assigned to the 2 study groups in a (1:1) ratio (approximately 70 subjects in each group). 
 
Allocation of a subject to a study group at the investigator site will be performed using a 
centralised randomisation system on the internet (SBIR). The randomisation algorithm 
will use a minimisation procedure accounting for age (40 - 59 years or 60 - 80 years), 
number of moderate/ severe AECOPD in the previous year (< 2 or  2) and GOLD grade 
(GOLD 2 or GOLD 3). All factors will have equal weight in the minimisation algorithm. 
 
At Visit 1, before administration of vaccine Dose 1 to eligible subjects who signed and 
dated the ICF at the Screening Visit, the dedicated site staff will access SBIR. Upon 
providing the subject’s age category (40 - 59 years or 60 - 80 years), number of 
moderate/ severe AECOPD in the previous year and his/ her GOLD grade, the 
randomisation system will determine the study group and will provide the treatment 
number to be used for the first dose. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, refer to the SBIR user guide or the SPM for specific 
instructions. 
 
6.2.2.2.2.       Treatment number allocation for subsequent doses 
 
For each dose subsequent to the first dose, the dedicated study staff will access SBIR. 
Upon providing the subject identification number, the system will provide a treatment 
number consistent with the allocated study group. 
 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
 
When SBIR is not available, refer to the SBIR user guide or the SPM for specific 
instructions. 
 
6.3. 
Method of blinding 
As the vaccines in this study are of different appearance and the investigational NTHi 
vaccine will have to be reconstituted whereas the placebo does not, double-blinding is not 
feasible and data will be collected in an observer-blind manner. By observer-blind, it is 
meant that during the course of the study, the vaccine recipient and those responsible for 


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the evaluation of any study endpoint will all be unaware of which vaccine was 
administered. 
 
Study site 
Each study site is responsible for having a blinding plan. To work in an observer-blind 
manner, vaccine preparation and administration will be done by authorised medical 
personnel who will not participate in any of the study clinical evaluation assays. Two 
teams of study personnel will hence be set up: 
• 
A team of unblinded personnel (responsible for the preparation and the 
administration of the vaccines) 
• 
A team of blinded personnel (responsible for the clinical evaluation of the subjects). 
Refer to the SPM for guidance on vaccine preparation and administration while 
maintaining the blind. 
 
Laboratory testing 
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample. 
 
Analysis 
An analysis of immunogenicity and safety data up to Visit 6 (Day 90) will be done on as 
cleaned as possible data (please refer to Section 11.14.1 for more information). At this 
point, the GSK statistician (or delegates) of the project will be unblinded (i.e. will have 
access to the individual subject treatment assignment). The remaining GSK study 
personnel (excluding the iSRC members and their back-ups) will remain blinded (i.e. will 
not have access to the individual subject treatment assignment) until study end. It is 
possible however, due to the limited sample size, that unblinding occurs for a few 
subjects having a specific adverse event (AE) or serious adverse event (SAE) (e.g. an AE/ 
SAE occurring only in a single group). Therefore anyone having access to the analysis up 
to Day 90 could become unblinded regarding those specific cases. 
 
6.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
 
Refer to Section 9.10 for more information on safety monitoring and holding rules. 


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6.5. 
Outline of study procedures 
6.5.1. 
Lists of study procedures during scheduled study visits 
Table 7 
List of study procedures during scheduled study visits 
 
Epoch 
Epoch 001 
Type of contact 
Screening (a b) 
Visit 1 Visit 2 Visit 3 
Visit 4 
Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 
Timepoint 
pre-D0 
D0 
D7 
D30 
D60 
D67 
D90 
D180 
D270 D360 
D450 
Sampling timepoint 
Screening 
Pre-Vacc Post-Vac 1 
Pre-Vacc 2 
Post-Vacc 2 
Informed consent 
● 
Check inclusion/exclusion criteria 
● (b) 
O 
Record history of moderate and severe AECOPD within the previous year 
O 
● 
Check subject’s COPD status 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Record demographic data 
● 
Record medical history, including significant comorbidities 
O 
● 
Vaccination history 
O 
● 
Smoking exposure history 
x 
Smoking status 
● 
● 
● 
Physical examination 
● (b) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Measure/ record height and weight 
● 
O 
● 
Pre- and post-bronchodilator spirometry 
x 
x 
x 
Chest X-ray (c) 
● 
Urine pregnancy test (d) 
● (b) 
● 
● 
Blood sampling: 
For safety assessment (~5.5 mL) 
● (b) 
● 
● 
● 
● 
● 
● 
● 
● 
For humoral immunogenicity (~25.5 mL) 
● 
● 
● 
● 
● 
● 
For CMI (~40 mL) (e) 
● 
● 
● 
● 
For biomarkers (~12.8 mL) 
● 
● 
Sputum sampling (f) 
● 
● 
● 
● 
● 
● 
Check contraindications to vaccination 
O 
O (g) 
Record pre-vaccination body temperature 
● 
● 
Treatment number allocation (h) 
● 
● 
Vaccination 
● 
● 
Distribute paper Diary Card for recording of vaccine reactogenicity 
O 
O 
O 
O 
Return paper Diary Card for recording of vaccine reactogenicity 
O 
O 
O 
O 


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Epoch 
Epoch 001 
Type of contact 
Screening (a b) 
Visit 1 Visit 2 Visit 3 
Visit 4 
Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 
Timepoint 
pre-D0 
D0 
D7 
D30 
D60 
D67 
D90 
D180 
D270 D360 
D450 
Sampling timepoint 
Screening 
Pre-Vacc Post-Vac 1 
Pre-Vacc 2 
Post-Vacc 2 
Transcription of paper Diary Card for recording of vaccine reactogenicity 
● 
● 
● 
● 
Record AEs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Report SAEs 
● (b) 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Report pregnancies 
● 
● 
● 
● 
● 
● 
● 
Distribute paper Diary Card for recording of medication 
O 
Record concomitant medications/products and vaccinations 
O 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Return paper Diary Card for recording of medication 
O 
Record intercurrent medical conditions requiring medical attention 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Train subject on the use of electronic Diary Card and assign electronic 
Diary Card to subject 
O 
Return electronic Diary Card 
O (i) 
O (i) 
O 
6-minute walk test (6MWT) 
● 
● 
HRQOL questionnaires: 
CAT 
x 
x 
x 
SGRQ-C 
x 
x 
x 
mMRC 
x 
x 
x 
Record healthcare use for past AECOPD (medical record review) 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Screening conclusion 
● 
Study conclusion 
● 
Note: the double-line borders indicate the statistical analyses which will be performed. The visits highlighted in grey are vaccination visits. D = Day; Vacc = vaccination. 
● is used to indicate a study procedure that requires documentation in the individual eCRF; O is used to indicate a study procedure that does not require documentation in the 
individual eCRF; x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be directly transferred from the provider to GSK. 
a If needed, the Screening Visit can be done in more than one day (up to 7 days). 
b For Screening failures due to reasons that are expected to be temporary (e.g. fever), a re-Screening visit may be scheduled during which the procedures indicated by this footnote 
need to be repeated. Data obtained during re-screening should be entered in the Screening Visit in the eCRF. 
c Only if no chest X-ray/ CT scan available within the last 3 months. 
d Only for women of childbearing potential. 
e Only for subjects in the sub-cohort for CMI. 
f Only if, in the opinion of the investigator, it is safe for the subject. 
g Refer to Section 7.5 for more details on study procedures for subjects meeting contraindications to subsequent vaccination before administration of vaccine Dose 2. 
h Treatment number allocation with randomisation at Visit 1 (Day 0); treatment number allocation without randomisation at Visit 4 (Day 60). 
i Only for Screening failures. 


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6.5.2. 
List of study procedures during AECOPD-driven study visits and 
phone contacts 
 
In addition to the scheduled study visits, ad-hoc AECOPD-driven study contacts will take 
place for each AECOPD occurring from first vaccination up to study conclusion. The 
procedures to be performed during these contacts are listed in Table 8. 
 
In case of AECOPD occurring before Visit 1, subjects should be treated outside the study 
according to standard practice. These subjects can only continue in the study if the entire 
Screening Visit is repeated after they are stable for at least 30 days. 
 
Table 8 
List of study procedures during AECOPD-driven study visits and 
phone contacts 
 
Type of contact 
AECOPD visit 
End of AECOPD contact(s) 
(phone call[s and/ or visit[s) 
Timepoint 
within 96 hours of 
onset symptoms 
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolved (a) 
Sampling timepoint 
AECOPD 
Record date of visit 
● 
Physical examination 
O 
O (b) 
Chest X-ray (c) 
● 
Confirm AECOPD and record its start date 
● 
Blood sampling: 
For biomarkers (~12.8 mL) 
● 
For haematology assessment (~2 mL) 
● 
Sputum sampling (d) 
● 
HRQOL questionnaires: 
CAT 
x 
mMRC 
x 
Record healthcare use for AECOPD (medical record review) 
O 
● 
Record AEs 
● 
● 
Report SAEs 
● 
● 
Report pregnancies (e) 
● 
● 
Record concomitant medications/products and vaccinations 
● 
● (b) 
Record intercurrent medical conditions requiring medical 
attention 
● 
● 
Record AECOPD severity 
O 
● 
Record AECOPD end date 
● 
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
O is used to indicate a study procedure that does not require documentation in the individual eCRF. 
x is used to indicate a study procedure that does not require documentation in the individual eCRF as the data will be 
directly transferred from the provider to GSK. 
a End of AECOPD phone calls/ visits should be scheduled at least every 2 weeks, until the AECOPD has resolved. 
Only the contact during which the end date of the AECOPD can be determined will be recorded in the eCRF as the end 
of the AECOPD contact. All intermediate contacts should be recorded on source documentation. 
b Only applicable if the contact is a visit (not for phone calls). 
c Only if clinically indicated to exclude another cause of worsening of symptoms (e.g. pneumonia). 
d Only if, in the opinion of the investigator, it is safe for the subject. 
e Only for AECOPD visits from first vaccination up to 6 months post-Dose 2 (Day 240). 


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6.5.3. 
Concurrence of AECOPD-driven study visits and scheduled 
study visits 
 
If an AECOPD occurs at the time of a scheduled study visit, it should be handled and 
recorded as an AECOPD visit, with all relevant study procedures performed and, if 
possible, the scheduled visit should be re-scheduled to a later date within the time 
window specified in the protocol. In consultation with GSK, only Visit 8 (Day 270) and 
Visit 10 (Day 450) may exceptionally be conducted outside of the allowed interval if 
necessary. 
 
If an end of AECOPD contact occurs around the same time of a scheduled study visit, 
they can be combined into a single visit with the study procedures relevant to both visit 
types performed. In this case, both visit types will need to be recorded in the eCRF 
separately. 
 
6.5.4. 
Intervals between study visits 
 
Table 9 
Intervals between study visits 
 
Interval 
Optimal length of interval 
Allowed interval 
Scheduled study visits 
Screening Visit completed  Visit 1 
14 - 28 days 1 
14 - 28 days 1 
Visit 1  Visit 2 
7 days 
7 - 9 days 
Visit 1  Visit 3 
30 days 
30 - 45 days 
Visit 1  Visit 4 
60 days 
60 - 75 days 2 
Visit 4  Visit 5 
7 days 
7 - 9 days 
Visit 4  Visit 6 
30 days 
30 - 45 days 2 
Visit 6  Visit 7 
90 days 
90 - 120 days 
Visit 6  Visit 8 
180 days 
180 - 210 days 3 
Visit 6  Visit 9 
270 days 
270 - 300 days 
Visit 6  Visit 10 
360 days 
360 - 390 days 3 
AECOPD-driven study visit(s) and/ or phone contacts 
Onset of AECOPD symptoms as recorded in the electronic 
Diary Card or confirmed by the subject  AECOPD Visit 
- 
max 96 hours 4 
Interval between AECOPD Visit and scheduled study visit 
AECOPD visit  scheduled study visit 
- 
min 7 days 5 
1 Visit 1 should take place 14 - 28 days after Screening completed. If for an eligible subject, a delay occurs so that the 
interval between Screening completed and Visit 1 exceeds 28 days, the entire Screening Visit needs to be repeated. 
2 Subjects will not be eligible for inclusion in the according-to-protocol (ATP) cohort for analysis of immunogenicity if 
they make the study visit outside this interval. 
3 Subjects will not be eligible for inclusion in the ATP cohort for analysis of persistence of immunogenicity if they make 
the study visit outside this interval. 
4 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). 
5 Scheduled study visits should not take place within 7 days of an AECOPD visit. If an AECOPD occurs at the time of a 
scheduled study visit so that this is not adhered to, the scheduled visit should be re-scheduled to a later date within the 
time window specified. In consultation with GSK, only Visit 10 (Day 450) may exceptionally be conducted outside of the 
allowed interval if necessary. 


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6.6. 
Detailed description of study procedures 
6.6.1. 
Informed consent 
 
The signed informed consent of the subject must be obtained before study participation. 
Refer to Section 6.1 for the requirements on how to obtain informed consent. 
6.6.2. 
Check inclusion/ exclusion criteria 
 
Check all inclusion and exclusion criteria as described in Sections 5.2 and 5.3. 
 
6.6.3. 
Record history of moderate and severe AECOPD within the 
previous year 
 
Obtain the subject’s history of moderate and severe AECOPD within the previous year. 
 
At Screening, subjects need documentation for at least 1 moderate or severe AECOPD 
within the previous year to be eligible for study participation. 
 
At Visit 1, both documented (by medical record review) and self-reported, 
non-documented moderate and severe AECOPD within the year before Visit 1 should be 
recorded in the eCRF. The total number of moderate and severe AECOPD (including 
self-reported, non-documented AECOPD) will be entered in SBIR for randomisation. 
 
6.6.4. 
Check subject’s COPD status 
 
Record the subject’s COPD status (stable/ recovered or not recovered) in the eCRF. 
 
6.6.5. 
Record demographic data 
 
Record demographic data such as year of birth, gender and geographic ancestry in the 
eCRF. 
 
6.6.6. 
Medical history, including significant comorbidities 
 
Obtain the subject’s medical history by interview and/ or review of the subject’s medical 
records and record any pre-existing conditions, signs and/ or symptoms present in a 
subject and significant COPD comorbidities prior to the first study vaccination in the 
eCRF. 
 
Significant comorbidities include weight loss, cardiovascular disease, hypertension, 
gastro-oesophageal reflux disease, osteoporosis/ osteopenia, skeletal muscle wasting and 
dysfunction, anxiety/ depression and diabetes. 
 
6.6.7. 
Vaccination history 
 
Record in the eCRF whether the subject received any influenza vaccination within the 
previous 12 months or has ever received any pneumococcal vaccination (including date 
of vaccination [as detailed as possible). 


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6.6.8. 
Smoking exposure history 
 
The subject should self-complete the smoking history questionnaire (which is a shortened 
version of the ATS-DLD-78A questionnaire), which will be provided electronically via a 
SITEpro tablet. The subject will have to provide information about his/ her smoking 
history, including duration (number of years) and number of cigarettes smoked. 
 
From the information obtained via the questionnaire, calculation of the pack-years will be 
done. 
 
The data will be directly transferred from the provider to GSK Biologicals. 
 
Refer to the SPM for details and guidance on the smoking exposure history questionnaire. 
 
6.6.9. 
Smoking status 
 
Record the subject’s smoking status (current or former smoker) in the eCRF. Refer to the 
glossary of terms for the definitions of current and former smoker. 
 
6.6.10. 
Physical examination 
 
At Screening, perform a complete physical examination of the subject, including vital 
signs after at least 10 minutes of rest (systolic/ diastolic blood pressure, heart rate, 
respiratory rate). Record collected information in the eCRF. 
 
Physical examination at each study visit subsequent to the Screening Visit will be 
performed only if deemed necessary by the investigator or delegate. 
 
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. 
 
6.6.11. 
Measure/ record height and weight 
 
Measure height and weight of the subject and record the data in the ‘Physical 
examination’ section of the eCRF. 
 
6.6.12. 
Pre- and post-bronchodilator spirometry 
 
Pre- and post-bronchodilator spirometry should be performed during specified study 
visits as detailed in Table 7. 
 
Only certified study staff can perform spirometry assessment. 
 
Spirometry will be performed using techniques that meet published standards [NICE, 
2010 and following all safety requirements. 
The data will be directly transferred from the provider to GSK Biologicals. 


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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. 
 
6.6.13. 
Chest X-ray 
 
Screening 
A posterior to anterior (PA) chest X-ray must be performed at Screening if no chest 
X-ray/ CT scan is available within the last 3 months. 
 
Subjects with evidence of clinically significant abnormalities not believed to be due to 
the presence of COPD will not be eligible for study participation. 
 
AECOPD visit 
A chest X-ray should be performed at the AECOPD visit if it is clinically indicated to 
exclude another cause of worsening of symptoms (e.g. pneumonia). 
 
All cases of pneumonia (including all signs and symptoms assessed to confirm 
pneumonia) should be documented in the eCRF. 
 
6.6.14. 
Urine pregnancy test 
 
Female subjects of childbearing potential are to have a urine pregnancy test at Screening 
and prior to any study vaccine administration. The study vaccine may only be 
administered if the pregnancy test is negative. Note: The urine pregnancy test must be 
performed even if the subject is menstruating at the time of the study visit. 
 
6.6.15. 
Sampling 
 
Refer to the Module on Biospecimen Management in the SPM and to the central 
laboratory manual for detailed instructions for the collection, handling and processing of 
the samples. 
 
6.6.15.1. 
Blood samples 
 
Blood samples will be taken during specified study visits (scheduled visits and 
exacerbation visits) as detailed in Table 7 and Table 8. 
 
Blood samples for safety assessment 
For scheduled visits: a volume of approximately 5.5 mL of whole blood should be drawn 
from all subjects at each pre-defined timepoint (Table 10) and will be split and processed 
as follows: 
• 
Approximately 2 mL of whole blood will be collected for haematology assessment. 
These samples will not be processed. They should be kept at room temperature and 
shipped on the day of collection. 


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• 
Approximately 3.5 mL of whole blood will be collected for biochemistry assessment 
and will be processed to serum. After processing, serum samples should be kept at 
room temperature and shipped on the day of collection. 
 
(An) additional blood sample(s) for safety assessment may need to be drawn before 
administration of vaccine Dose 2, or during other study visits if deemed necessary by the 
investigator (see Table 10). 
 
Blood samples for humoral immunogenicity 
A volume of approximately 25.5 mL of whole blood should be drawn from all subjects at 
each pre-defined timepoint. After processing, serum samples should be kept at -20°C 
until shipment. 
 
Blood samples for CMI 
A volume of approximately 40 mL of whole blood should be drawn from the subjects 
included in the sub-cohort for CMI at each pre-defined timepoint. The samples should be 
kept at room temperature and will be shipped as soon as possible (maximum 8 hours after 
whole blood collection), so that samples can be processed at the CMI laboratory within 
24 hours of collection. 
 
Blood samples for biomarkers 
At Visit 1, Visit 10 and at each AECOPD visit: a volume of approximately 12.8 mL of 
whole blood should be drawn from all subjects and will be split and processed as follows: 
• 
Approximately 5 mL of whole blood will be processed to serum. After processing: 
 
An aliquot of serum should be kept at room temperature and shipped on the day 
of collection. 
 
The remaining serum should be kept at -70/80°C until shipment. 
• 
Approximately 6 mL of whole blood will be processed to plasma. After processing, 
plasma samples should be kept at -70/80°C until shipment. 
• 
Approximately 1.8 mL of whole blood will be processed to plasma. After processing, 
plasma samples should be kept at -70/80°C until shipment. 
 
At each AECOPD visit: a volume of approximately 2 mL of whole blood will be 
collected for haematology parameters from all subjects (Table 10). They should be kept 
at room temperature and shipped on the day of collection. 
 
6.6.15.2. 
Sputum samples 
 
Sputum samples will be collected during specified study visits (scheduled visits and 
exacerbation visits) as detailed in Table 7 and Table 8 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. 


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Refer to the SPM and to the central laboratory manual for more details and guidance on 
handling of sputum samples. 
 
6.6.16. 
Check contraindications to vaccination 
 
Contraindications to vaccination must be checked before each vaccination. Refer to 
Section 7.5 for more details on contraindication and on study procedures for subjects 
meeting contraindications to subsequent vaccination before administration of vaccine 
Dose 2. 
 
6.6.17. 
Record pre-vaccination body temperature 
 
The axillary or oral body temperature of all subjects needs to be measured prior to any 
study vaccine administration. The preferred route for recording temperature in this study 
will be oral. If the subject has fever (Fever is defined as oral or axillary temperature 
 37.5°C) on the day of vaccination, the vaccination visit will be rescheduled within the 
allowed interval for this visit (see Table 9). 
 
6.6.18. 
Treatment number allocation 
 
Treatment number allocation will be performed as described in Section 6.2.2.2. The 
number of each administered treatment must be recorded in the eCRF. 
 
6.6.19. 
Vaccination 
 
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly in the deltoid of the non-dominant arm 
(refer to Section 7.3 for a detailed description of the vaccines’ administration procedure). 
 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be rescheduled 
within the allowed interval for this visit (see Table 9). 
 
The subjects will be observed closely for at least 60 minutes following the administration 
of the vaccine, with appropriate medical treatment readily available in case of 
anaphylaxis. 
 
6.6.20. 
Recording of adverse events, serious adverse events and 
pregnancies 
 
Refer to Section 9.3 for procedures for the investigator to record AEs, SAEs and 
pregnancies. Refer to Section 9.4 for guidelines on how to submit pIMD, SAE and 
pregnancy 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. 


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Paper Diary Cards for recording of vaccine reactogenicity 
• 
After each vaccination, 2 paper Diary Cards for recording of vaccine reactogenicity 
will be distributed to the subject: 
 
A 1st Diary Card will be distributed on the day of vaccination for daily 
recording of body temperature and of any solicited and unsolicited AEs from 
day 0 to 6 after each vaccination. The subject will be instructed to return the 
completed Diary Card to the study site at the next study visit (7 days post- 
vaccination). 
 
A 2nd Diary Card will be distributed at the 7 day post-vaccination visit for 
recording of any unsolicited AEs from day 7 to 29 after each vaccination. The 
subject will be instructed to return the completed Diary Card to the study site at 
the next study visit (30 days post-vaccination). 
• 
Collect and verify completed Diary Cards during discussion with the subject during 
each 7-days post-vaccination visit and during each 30-day post-vaccination visit. 
• 
Any unreturned Diary Cards will be sought from the subject through telephone 
call(s) or any other convenient procedure. 
• 
The investigator will transcribe the collected information into the eCRF. 
Refer to the SPM for more details and guidance on Diary Card completion 
guidelines. 
 
6.6.21. 
Record concomitant medications/ products and vaccinations 
 
Paper Diary Card for recording of medication 
At the Screening Visit, a paper medications Diary Card will be distributed to the subject: 
• 
All vaccinations and medications (except for vitamins and dietary supplements) 
administered throughout the study period (including dose, unit, frequency and reason 
for use) should be recorded on this medication Diary Card. 
• 
Subjects will be advised to bring all medications they are currently using during each 
of the study visits (including AECOPD-driven visits). At Screening, the medication 
Diary Card will be completed at the study site, with the help of the study staff. After 
that, the subject should update the Diary Card each time additional medication was 
taken, or a change to his/ her standard treatment was made. 
• 
The medications Diary Cards will be reviewed with the subject at each study visit 
and a copy will be retained at the site. 
• 
The investigator will transcribe the collected information into the eCRF. 
Refer to the SPM for more details and guidance on Diary Card completion 
guidelines. 


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6.6.22. 
Record intercurrent medical conditions requiring medical 
attention 
 
Intercurrent medical conditions requiring medical attention must be checked and recorded 
in the eCRF as described in Section 7.7. 
 
6.6.23. 
Train subjects on the use of electronic Diary Card and assign 
electronic Diary Card to subject 
 
During the Screening Visit, subjects will be trained on how to use their electronic Diary 
Card. 
 
At Visit 1, the investigator should evaluate whether or not the subject will be able to 
comply with the daily completion of the electronic Diary Card throughout the study 
(based on electronic Diary Card completion between Screening and Visit 1). 
 
Compliance with electronic Diary Card completion implies that subject learns how to 
translate his/ her respiratory symptoms in answers to the questions as well as acquiring 
the technical expertise to use the device. Refer to the SPM for recommendations on what 
is considered adequate compliance by Visit 1. 
 
Subjects for whom the investigator thinks they will not comply will be considered 
Screening failures. 
 
During the learning period in-between Screening and Visit 1, the site staff will follow 
electronic Diary Card completion closely and should provide timely input/guidance to 
ensure that the subject reaches the targeted learning curve. 
 
In addition, site staff will pro-actively monitor electronic Diary Card compliance 
throughout the study and provide the necessary input to maintain compliance. 
 
6.6.24. 
6-minute walk test 
 
The subject should perform the supervised, standardised 6MWT at specified study visits 
as detailed in Table 7. 
 
The result of the test should be recorded in the eCRF. 
 
Refer to the SPM for more details and guidance on the 6MWT. 
 
6.6.25. 
HRQOL questionnaires 
 
The subject should self-complete the questionnaires on HRQOL (CAT, SGRQ-C and 
mMRC), which will be provided electronically via a SITEpro tablet, during specified 
study visits as detailed in Table 7 and Table 8. 
 
All data from the HRQOL questionnaires will be transferred directly from the SITEpro 
provider to GSK Biologicals. 
 
Refer to the SPM for more details and guidance on the HRQOL questionnaires. 


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6.6.26. 
Record healthcare use for AECOPD 
 
Healthcare use for each AECOPD will be obtained through review of the subject’s 
medical record (aided by subject self-reporting). 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. 
 
6.6.27. 
Confirm AECOPD and record its start date 
 
Indicate the start date of each confirmed AECOPD in the eCRF. 
 
6.6.28. 
Document AECOPD severity and end date 
 
Indicate the severity and end date of each confirmed AECOPD in the eCRF. Refer to 
Table 2 for severity grading of AECOPD and to Section 4.1.1 for determination of end 
date. 
 
6.6.29. 
Screening conclusion 
 
The investigator will: 
• 
Review data collected to ensure accuracy and completeness. 
• 
Complete the Screening conclusion screen in the eCRF. 
For Screening failures, only informed consent, demographic data, inclusion/ exclusion 
criteria, SAEs related to study participation that occurred after signing the informed 
consent and the Screening conclusion pages need to be completed in the eCRF. For other 
activities, ‘not done’ can be indicated. 
 
For subjects who are Screening failures only for reasons that are expected to be 
temporary (e.g. fever), a re-Screening may be organised during which a limited number 
of Screening procedures need to be repeated (see also Table 7). 
 
6.6.30. 
Study conclusion 
 
The investigator will: 
• 
Review data collected to ensure accuracy and completeness. 
• 
Complete the Study Conclusion screen in the eCRF. 
6.7. 
Biological sample handling and analysis 
Refer to the SPM and to the central laboratory manual for details on biospecimen 
management (handling, storage and shipment). 
 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 


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Under the following circumstances, additional testing on the samples may be performed 
by GSK Biologicals outside the scope of this protocol: 
• 
Collected samples may be used in other assays, for test improvement or development 
of analytical methods related to the study vaccine and its constituents or the disease 
under study. 
• 
Collected samples may be used for purposes related to the quality assurance of data 
generated linked to the study vaccine or the disease under study, such as for 
maintenance of assays described in this protocol and comparison between analytical 
methods and/ or laboratories. 
 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals. 
 
Any sample testing will be done in line with the consent of the individual subject. 
 
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s). 
 
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
 
6.7.1. 
Use of specified study materials 
 
When materials are provided by GSK Biologicals or by the central laboratory, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner. The use of other 
materials could result in the exclusion of the subject from the according-to-protocol 
(ATP) analysis (See Section 11.5 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 does not provide material for collecting and storing clinical samples, 
appropriate materials from the investigator’s site must be used. Refer to the Module on 
Clinical Trial Supplies in the SPM. (Amended 15 April 2016) 


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6.7.2. 
Biological samples 
 
Table 10 
Biological samples 
 
Sample type 
Quantity 
Unit 
Timepoints 
Sub-cohort 
Blood for safety 
assessment * 
(haematology and 
biochemistry) 
5.5 
mL 
• 
Screening Visit (pre-Day 0) 
• 
Visit 1 (Day 0) 
• 
Visit 2 (Day 7) 
• 
Visit 3 (Day 30) 
• 
Visit 4 (Day 60) 
• 
Visit 5 (Day 67) 
• 
Visit 6 (Day 90) 
• 
Visit 8 (Day 270) 
• 
Visit 10 (Day 450) 
All screened subjects 
All enrolled subjects 
Blood for humoral 
immunogenicity 
25.5 
mL 
• 
Visit 1 (Day 0) 
• 
Visit 3 (Day 30) 
• 
Visit 4 (Day 60) 
• 
Visit 6 (Day 90) 
• 
Visit 8 (Day 270) 
• 
Visit 10 (Day 450) 
All enrolled subjects 
Blood for CMI 
40 
mL 
• 
Visit 1 (Day 0) 
• 
Visit 6 (Day 90) 
• 
Visit 8 (Day 270) 
• 
Visit 10 (Day 450) 
Sub-cohort for CMI 
Blood for 
biomarkers 
12.8 
mL 
• 
Visit 1 (Day 0) 
• 
Visit 10 (Day 450) 
• 
During each AECOPD from first vaccination 
to study conclusion 
All enrolled subjects 
Blood for 
haematology 
parameters 
~2.0 
mL 
• 
During each AECOPD 
All enrolled subjects 
Sputum 
1 
sample 
• 
Screening Visit (pre-Day 0) 
• 
Visit 6 (Day 90) 
• 
Visit 7 (Day 180) 
• 
Visit 8 (Day 270) 
• 
Visit 9 (Day 360) 
• 
Visit 10 (Day 450) 
• 
During each AECOPD from first vaccination 
to study conclusion 
All screened subjects 
All enrolled subjects 
* Additional blood sample(s) for safety assessment may be taken at the discretion of the investigator if deemed 
necessary. 


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6.7.3. 
Laboratory assays 
 
Refer to APPENDIX A for a detailed description of the assays performed in the study. 
Refer to APPENDIX B for the address of the clinical laboratories used for sample 
analysis. 
 
Haematology/ biochemistry 
Haematology/ biochemistry assays for safety assessment will be performed in a central 
laboratory. Haematology assays on whole blood taken at AECOPD visits will be 
performed in the same central laboratory. 
 
Table 11 
Haematology and biochemistry 
 
System 
Discipline 
Component 
Method 
Scale 
Laboratory* 
Whole 
blood 
Haematology 
Haemoglobin 
commercial 
Quantitative Central 
laboratory 
Platelets 
commercial 
Quantitative 
White Blood Cells (WBC) ** 
commercial 
Quantitative 
Serum 
Biochemistry 
Alanine Aminotransferase (ALT) 
commercial 
Quantitative Central 
laboratory 
Aspartate Aminotransferase (AST) 
commercial 
Quantitative 
Creatinine 
commercial 
Quantitative 
*Refer to APPENDIX B for the laboratory address. 
** Including WBC differential count. 
 
Humoral antibody responses (Amended 15 April 2016) 
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory. 
Standardised procedures will be used for all assays. 
 
Table 12 
Humoral Immunity (Antibody determination) (Amended 15 April 
2016) 
 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-off 
Laboratory* 
Serum 
Anti-PD 
ELISA 
In house 
EL.U/mL 
153 
GSK Biologicals** 
Serum 
Anti-PE 
ELISA 
In house 
EL.U/mL 
8 
GSK Biologicals** 
Serum 
Anti-PilA 
ELISA 
In house 
EL.U/mL 
7 
GSK Biologicals** 
EL.U/mL = ELISA unit per millilitre 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium. 
 
Serum and plasma samples might also be used for development and/ or evaluation of 
other assays to measure the immune response to the investigational NTHi vaccine 
components and/or to other NTHi antigens such as, but not limited to, bactericidal 
activity assay, assays measuring functional antibodies, immunochemistry assays for other 
immunoglobulin classes and/or for anti-IgG subclasses. 
 
Additional testing on serum and plasma samples may be done during the study or after 
study completion, should these data be required for accurate interpretation of the data 
and/ or for further research related to the investigational vaccine and/ or the disease, 
should such test(s) become available at GSK Biologicals’ laboratory or a laboratory 
designated by GSK Biologicals. 


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Cell-mediated immune responses 
CMI assays will be performed at GSK Biologicals’ laboratory using standardised and 
qualified procedures. 
 
Table 13 
Cell-Mediated Immunity 
 
System 
Component 
Scale 
Method 
Unit 
Laboratory* 
PBMCs 
Specific CD4+/CD8+ T-cells Quantitative 
Flow cytometry 
ICS 
Number of specific 
CD4+/CD8+ T-cells /106 
GSK 
Biologicals** 
PBMC = Peripheral Blood Mononuclear Cell; ICS = Intracellular Cytokine Staining 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium. (Amended 15 April 2016) 
 
Additional testing on Peripheral Blood Mononuclear Cells (PBMCs), such as, but not 
limited to, evaluation of NTHi-specific memory B-cells, ICS testing using other bacterial 
antigens, may be done during the study or after study completion, should these data be 
required for accurate interpretation of the data and/ or for further research related to the 
investigational vaccine and/ or the disease, should such test(s) become available at GSK 
Biologicals’ laboratory or a laboratory designated by GSK Biologicals. 
 
Plasma obtained during the processing of whole blood to obtain PBMCs will be stored 
for potential future analyses and/ or assay development purposes. 
 
Microbiological assessments 
Standard bacteriological culture will be performed on fresh sputum samples at the 
investigator’s institution and/ or at a laboratory designated by GSK Biologicals. Quadrant 
assessment will be recorded from the primary culture plates and identification of 
potential bacterial pathogens will be performed according to local routine identification 
methods (potential pathogens including, but not necessarily limited to identification of 
H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus and P. aeruginosa). All results 
should be entered in the eCRF. 
 
Further   characterisation  of  bacterial  serotypes  and/  or  genotypes  on  stored   
H. influenzae sweeps will be done at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using either standard agglutination techniques or 
molecular tools, as microarray serotyping; considering that a “stored H. influenzae 
sweeps” is defined as the “harvest” of all microorganisms that have grown on the 
primary sputum culture plate (e.g. chocolate agar plate for H. influenzae growth) if at 
least one H. influenzae colony was observed on this plate. (Amended 15 April 2016) 
 
Bacterial pathogen identification (including, but not necessarily limited to, 
H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, P. aeruginosa and Streptococcus 
pyogenes [S. pyogenes) and quantification (for H. influenzae, S. pneumoniae, 
M. catarrhalis) on stored sputum samples will be performed at GSK Biologicals’ 
laboratory or a laboratory designated by GSK Biologicals using molecular methods such 
as multiplex RT PCR and/ or quantitative PCR (qPCR). (Amended 15 April 2016) 


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Viral pathogen identification (including, but not necessarily limited to, respiratory 
syncytial virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus) on stored sputum samples will be 
performed using multiplex PCR at GSK Biologicals' laboratory or at a laboratory 
designated by GSK Biologicals using qualified procedures. 
In addition, viral pathogens (such as rhinovirus) in stored sputum samples will be 
quantified on a subset of samples using qPCR at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals using qualified procedures. 
(Amended 15 April 2016) 
 
Table 14 
Microbiology (Amended 15 April 2016) 
 
System 
Component 
Method 
Scale 
Laboratory* 
Bacterial pathogen identification 
Fresh sputum † 
Respiratory bacterial 
pathogens 
(including, but not limited to, 
H. influenzae, 
S. pneumoniae, 
M. catarrhalis, S. aureus and 
P. aeruginosa) 
standard 
bacteriological 
culture and standard 
identification 
methods including 
semi-quantitative 
culture 
qualitative 
semi- 
quantitative 
Investigator’s 
institution and/ or 
laboratory designated 
by GSK Biologicals 
Stored H. influenzae 
positive sputum and/ or 
stored sweep of positive 
H. influenzae culture 
plate 
Characterisation of bacterial 
serotypes and/ or genotypes 
Agglutination and/ or 
molecular tools 
(microarray 
serotyping) 
qualitative 
qualitative 
quantitative 
GSK Biologicals** or 
designated laboratory 
Stored sputum 
Respiratory bacterial 
pathogens 
(including, but not limited to, 
H. influenzae, 
S. pneumoniae, 
M. catarrhalis, S. aureus, 
P. aeruginosa and 
S. pyogenes) 
Molecular methods 
such as multiplex 
PCR 
and/ or qPCR 
GSK Biologicals** or 
designated laboratory 
Viral pathogen identification 
Stored sputum 
Respiratory viral pathogens 
(including respiratory 
syncytial virus, parainfluenza 
virus, enterovirus/ rhinovirus, 
metapneumovirus, influenza 
virus, adenovirus, bocavirus 
and coronavirus) 
Multiplex PCR 
qualitative 
GSK Biologicals** or 
designated laboratory 
Respiratory viral pathogens 
(such as rhinovirus) 
qPCR 
quantitative GSK Biologicals** or 
designated laboratory 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, 
Belgium. 
† Bacterial culture of sputum stored in STGG (alternative storage) might be performed in a subset of samples at 
specific sites and/ or at GSK Biologicals’ designated laboratory. More details will be provided in the SPM and 
associated documents. 
 
Sputum samples might also be used for assay development, such as assays for diagnostic 
purpose or for microbiome analysis. 


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Additional testing on stored sputum samples (such as, but not limited to, qPCR for other 
bacterial and/or viral pathogens, quantitative serotype-specific PCR, microarray typing, 
16sRNA analysis) may be done during the study or after study completion, should these 
data be required for accurate interpretation of the study data and/ or for further research 
related to the investigational vaccine and/ or to COPD, should such test(s) become 
available at GSK Biologicals’ laboratory or a laboratory designated by GSK Biologicals. 
 
Biomarkers 
Table 15 
Biomarkers 
 
System 
Component 
Method 
Scale 
Laboratory* 
Plasma 
Fibrinogen 
Commercial 
Quantitative 
Central laboratory 
Serum 
C-reactive protein (CRP) 
Commercial 
Quantitative 
*Refer to APPENDIX B for the laboratory address. 
 
The presence of other selected biomarkers might be evaluated. 
 
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. 
 
6.7.4. 
Immunological correlates of protection 
 
No generally accepted immunological correlate of protection has been established so far 
for the investigational NTHi vaccine. 
 
7. 
STUDY VACCINES AND ADMINISTRATION 
7.1. 
Description of study vaccines 
The candidate vaccine to be used has been developed and manufactured by GSK 
Biologicals. 
 
The Quality Control Standards and Requirements for the candidate are described in 
separate Quality Assurance documents (e.g. release protocols, certificate of analysis) and 
the required approvals have been obtained. 
 
The study vaccines are labelled and packed according to applicable regulatory 
requirements. 


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Table 16 
Study vaccines 
 
Treatment 
name 
Vaccine/ 
product 
name 
Formulation 
Presentation 
Volume to be 
administered* 
Number 
of doses 
10µgAg/ 
AS01E 
NTHi-10 
AS01E 
PD=10µg; PE-PilA=10µg 
MPL=25µg; QS21=25µg; 
Liposomes 
Freeze-dried antigens in 
monodose vial 
Liquid in monodose vial 
0.5 mL 
2 
Placebo 
NaCl 
NaCl=150mM 
Liquid in monodose vial 
0.5 mL 
2 
*Refer to the SPM for the volume after reconstitution. 
 
7.2. 
Storage and handling of study vaccines 
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorised 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines. 
 
Temperature excursions must be reported in degree Celsius. 
 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 
in the appropriate electronic Temperature Excursion Decision Form (eTDF). The 
impacted IMPs must not be used and must be stored in quarantine at label temperature 
conditions until usage approval has been obtained from the sponsor. 
 
In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in eTDF, but adequate actions must be taken to restore the +2 to +8°C 
label storage temperature conditions. The impacted IMPs may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take. 
 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 


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7.3. 
Dosage and administration of study vaccines 
Table 17 
Dosage and administration 
 
Type of contact 
(timepoint) 
Volume to be 
administered 
Study Group 
Treatment name 
Route 
Site 
Side 
Visit 1 (Day 0) 
0.5 mL 
10-AS01E 
Control 
10µgAg/ AS01E 
Placebo 
IM 
Deltoid 
Non-dominant 
Visit 4 (Day 60) 
0.5 mL 
10-AS01E 
Control 
10µgAg/ AS01E 
Placebo 
IM 
Deltoid 
Non-dominant 
IM = intramuscular. 
 
Refer to the SPM for detailed instructions on study vaccines administration. 
 
7.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 20% additional vaccine doses will be 
supplied to replace those that are unusable. 
 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomisation. 
 
7.5. 
Contraindications to subsequent vaccination 
The following events constitute contraindications to administration of the investigational 
NTHi vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol, or the subject may be withdrawn at the discretion of the 
investigator (see Section 9.5). 
• 
Moderate or severe AECOPD that is on-going or that has not been resolved for at 
least 7 days at the time of vaccination. 
• 
Acute disease and/ or fever at the time of vaccination. 
 
Fever is defined as oral or axillary temperature  37.5°C. The preferred route for 
recording temperature in this study will be oral. 
 
Subjects with a minor illness without fever can be administered all vaccines at 
the discretion of the investigator. 
 
The following events constitute absolute contraindications to further administration of the 
investigational NTHi vaccine. If any of these events occur during the study, the subject 
must not receive vaccine Dose 2. 
• 
Anaphylaxis following the administration of vaccine. 
• 
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• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
• 
Current immune-mediated disease other than COPD. 
• 
Malignancy (excluding non-melanotic skin cancer and carcinoma in situ of the 
cervix, if considered cured) or lymphoproliferative disorder. 
• 
Any other event which the investigator judges may put the safety of the subject at 
risk through vaccination. 
 
For subjects meeting one of the above specified contraindications to subsequent 
vaccination before administration of vaccine Dose 2, the study visit at Day 67 (Visit 5) 
will be cancelled. These subjects will be invited to all other study visits as planned 
(including AECOPD-driven study visit[s and/ or phone contact[s) and will continue all 
study procedures as planned, with the exception of blood sampling for immunogenicity 
(humoral and CMI) and biomarkers and sputum sampling. 
 
7.6. 
Concomitant medications/products and concomitant 
vaccination 
Subjects will be advised to bring all medications they are currently using and their 
medications Diary Card to each study visit. During each visit, the medications Diary Card 
will be reviewed with the subject and a copy will be retained at the study site. 
 
7.6.1. 
Recording of concomitant medications/products and 
concomitant vaccination 
 
All vaccinations and medications (except for vitamins and dietary supplements) 
administered throughout the study period (including dose, unit, frequency and reason for 
use) must be recorded in the eCRF. 
 
7.6.2. 
Concomitant medications/products and vaccines that may lead 
to the elimination of a subject from ATP analysis for 
immunogenicity 
 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
ATP analysis for immunogenicity. 
 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used at any time during the entire study period. 
• 
A vaccine not foreseen by the study protocol administered during the period starting 
30 days before and ending 30 days after each dose of vaccine*, with the exception of 
any influenza or pneumococcal vaccines which may be administered  15 days 
preceding or following any dose of study vaccine. 
* In case an emergency mass vaccination for an unforeseen public health threat (e.g. 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 


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for that vaccine provided it is licensed and used according to its summary of product 
characteristics (SmPC) or prescribing information (PI) and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained. 
• 
Immunoglobulins or any blood products administered at any time during the study 
period. 
 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) at any time during the study period (e.g. methotrexate). Use 
of corticosteroids is allowed as per local treatment recommendations. 
7.6.3. 
Concomitant medications/ products that may lead to the 
elimination of a subject from the ATP analysis for efficacy 
 
In addition to the concomitant medications/ products/ vaccines described in the Section 
7.6.2, the use of the following medications/ products will not require withdrawal of the 
subject from the study but may determine a subject’s evaluability in the ATP analysis for 
efficacy. 
 
• 
Underwent lung transplantation/ lung resection surgery at any time during the entire 
study period. 
• 
Chronic use of antibiotics at any time during the entire study period. 
7.7. 
Intercurrent medical conditions that may lead to elimination 
of a subject from ATP analyses for immunogenicity 
At each study visit subsequent to the first vaccination visit, it must be verified if the 
subject has experienced or is experiencing any intercurrent medical condition(s) requiring 
medical attention. If it is the case, the condition(s) must be recorded in the eCRF. 
 
Subjects may be eliminated from the ATP cohort for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response or if they 
become diagnosed with an immunological disorder. 
 
8. 
HEALTH ECONOMICS 
Not applicable. 
 
9. 
SAFETY 
The investigator or site staff is/ are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an AE or SAE as provided in 
this protocol. 
 
Each subject will be instructed to contact the investigator immediately should he/ she 
manifest any signs or symptoms he/ she perceives as serious. 


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9.1. 
Safety definitions 
9.1.1. 
Definition of an adverse event 
 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
Examples of an AE include: 
• 
Significant or unexpected worsening of the condition under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition, apart from the 
condition under study, including either an increase in frequency and/or intensity of 
the condition. 
• 
New conditions detected or diagnosed after investigational vaccine administration 
even though they may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms temporally associated with vaccine administration. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 
 
AEs to be recorded as endpoints (solicited AEs) are described in Section 9.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
 
Examples of an AE DO NOT include: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/ SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
The disease being studied, or expected progression, signs, or symptoms of the 
disease being studied, unless more severe than expected for the subject’s condition. 
• 
Pre-existing conditions or signs and/ or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 


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9.1.2. 
Definition of a serious adverse event 
 
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. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation, 
Note: In general, hospitalisation signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/ or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/ incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/ birth defect in the offspring of a study subject. 
 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
 
9.1.3. 
Solicited adverse events 
 
Solicited local and general AEs occurring during a 7-day follow-up period after each 
vaccination (i.e. the day of vaccination and the 6 subsequent days), as well as unsolicited 
AEs occurring during a 30-day follow-up period after each vaccination (i.e. the day of 
vaccination an the 29 subsequent days), will be reported via paper Diary Cards for 
vaccine reactogenicity and recorded via the appropriate section of the eCRF. 


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9.1.3.1. 
Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 18 
 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
 
9.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: 
 
Table 19 
Solicited general adverse events 
 
Fatigue 
Fever 
Gastrointestinal symptoms † 
Headache 
† Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
 
Note: temperature will be recorded in the evening. Should additional temperature 
measurements be performed at other times of day, the highest temperature will be 
recorded in the eCRF. 
 
9.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
 
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as AE or SAE if they meet the 
definition of an AE or SAE (refer to Sections 9.1.1 and 9.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs. However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the subject’s condition, or that are present 
or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs. 
 
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
 
9.1.5. 
Adverse events of specific interest (potential immune-mediated 
diseases) 
 
pIMDs are a subset of AEs that include autoimmune diseases and other inflammatory 
and/or neurologic disorders of interest which may or may not have an autoimmune 


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aetiology. AEs that need to be recorded and reported as pIMDs include those listed in 
Table 20. 
 
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD. 


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Table 20 
List of potential immune-mediated diseases 
 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy) 
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
• 
Acute disseminated encephalomyelitis, 
including site specific variants: e.g. 
non-infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis 
• 
Myasthenia gravis, including Lambert- 
Eaton myasthenic syndrome 
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus 
• 
Scleroderma, including diffuse 
systemic form and CREST 
syndrome 
• 
Systemic sclerosis 
• 
Dermatomyositis 
• 
Polymyositis 
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, 
• 
Juvenile chronic arthritis, 
(including Still’s disease) 
• 
Polymyalgia rheumatic 
• 
Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous 
skin diseases 
(including pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis) 
• 
Cutaneous lupus 
erythematosus 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Morphoea 
Liver disorders 
Gastrointestinal disorders 
Metabolic diseases 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune cholangitis 
• 
Crohn’s disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
• 
Celiac disease 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave's or Basedow’s disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
Vasculitides 
Others 
• 
Large vessels vasculitis including: giant 
cell arteritis such as Takayasu's arteritis 
and temporal arteritis. 
• 
Medium sized and/or small vessels 
vasculitis including: polyarteritis nodosa, 
Kawasaki's disease, microscopic 
polyangiitis, Wegener's granulomatosis, 
Churg–Strauss syndrome (allergic 
granulomatous angiitis), Buerger’s 
disease (thromboangiitis obliterans), 
necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch- 
Schonlein purpura, Behcet's syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune thrombocytopenia 
• 
Antiphospholipid syndrome 
• 
Pernicious anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous 
glomerulonephritis, membranoproliferative 
glomerulonephritis, and mesangioproliferative 
glomerulonephritis) 
• 
Uveitis 
• 
Autoimmune myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 


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final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
 
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. 
 
9.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events 
9.2.1. 
AECOPD 
 
AECOPD are common in subjects with COPD. Because they are typically associated 
with the disease under study, only AECOPD meeting the definition of an SAE and 
occurring in the time period defined in Section 9.3.1 will be reported to GSK Biologicals 
as described in Sections 9.4.1 and 9.4.3. 
 
9.2.2. 
Pregnancy 
 
Female subjects who are pregnant or lactating at the time of vaccination must not receive 
additional doses of study vaccine but may continue other study procedures at the 
discretion of the investigator. 
 
While pregnancy itself is not considered an AE or SAE, any adverse pregnancy outcome 
or complication or elective termination of a pregnancy for medical reasons will be 
recorded and reported as an AE or a SAE. 
Note: the pregnancy itself should always be recorded on an electronic pregnancy report. 
 
The following should always be considered as SAE and will be reported as described in 
Sections 9.4.1 and 9.4.3: 
• 
Spontaneous pregnancy loss, including: 
 
Spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation). 
 
Ectopic and molar pregnancy. 
 
Stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognised that national 
regulations might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect (as per [EMA, 2006] guidelines) identified in 
the offspring of a study subject (either during pregnancy, at birth or later) regardless 
of whether the foetus is delivered dead or alive. This includes anomalies identified 
by prenatal ultrasound, amniocentesis or examination of the products of conception 
after elective or spontaneous abortion. 


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Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the investigational vaccine/ product will be 
reported to GSK Biologicals as described in Section 9.4.3. While the investigator is not 
obligated to actively seek this information from former study participants, he/ she may 
learn of a pregnancy through spontaneous reporting. 
 
9.3. 
Detecting and recording adverse events, serious adverse 
events and pregnancies 
9.3.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
 
All AEs starting within 29 days following administration of each dose of study vaccine 
must be recorded into appropriate section of the eCRF, irrespective of intensity or 
whether or not they are considered vaccination-related. 
 
All AEs/ SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine until study conclusion. 
 
The time period for collecting and recording pIMDs will begin at the first receipt of study 
vaccine and will end at study conclusion. See section 9.4 for instructions on reporting of 
pIMDs. 
 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end at study conclusion. See Section 9.4 for instructions on reporting of 
SAEs. 
 
In addition to the above-mentioned reporting requirements for SAEs and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/ he is discharged from the 
study. See Section 9.4 for instructions on reporting of SAEs. 
 
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine and will end 6 months following administration of the last dose of study 
vaccine. See section 9.4 for instructions on reporting of pregnancies. 
 
The time period for collecting and recording intercurrent medical conditions that require 
medical attention will begin at the first receipt of study vaccine and will end at study 
conclusion. 
 
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 21. 


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Table 21 
Reporting periods for adverse events, serious adverse events and 
pregnancies 
 
V = Visit; D = Day. 
* I.e. consent obtained. 
The double-bordered lines indicate timings of vaccination. 
 
9.3.2. 
Post-Study adverse events and serious adverse events 
 
A post-study AE/ SAE is defined as any event that occurs outside of the AE/ SAE 
reporting period defined in Table 21. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/ she considers the 
event reasonably related to the investigational vaccine/ product, the investigator will 
promptly notify the Study Contact for Reporting SAEs. 
V1 
Dose 
1 
D0 
6 days 29 days 
post- 
Dose 1 
D6 
post- 
Dose 1 
D29 
V4 
Dose 
2  
D60 
6 days 29 days 
post- 
post- 
Dose 2 Dose 2 
D66 
D89 
6 months 
post- 
Dose 2 
D240 
Study 
Conclusion 
D450 
Intercurrent 
medical 
conditions 
requiring medical 
Pregnancies 
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
SAEs 
pIMDs 
AEs/ SAEs leading 
to study withdrawal 
Unsolicited AEs 
Solicited local and 
general AEs 
Timepoint 
Scree- 
ning 
Visit* 
Visit 


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9.3.3. 
Evaluation of adverse events and serious adverse events 
 
9.3.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
 
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as: 
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’ 
 
When an AE/ SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an AE/ 
SAE in the eCRF. The investigator is not allowed to send photocopies of the subject’s 
medical records to GSK Biologicals instead of appropriately completing the eCRF. 
However, there may be instances when copies of medical records for certain cases are 
requested by GSK Biologicals. In this instance, all subject identifiers will be blinded on 
the copies of the medical records prior to submission to GSK Biologicals. 
 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/ or other clinical information. In such cases, the diagnosis should 
be documented as the AE/ SAE and not the individual signs/ symptoms. 


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9.3.3.2. 
Assessment of adverse events 
 
9.3.3.2.1.       Assessment of intensity 
 
The intensity of the following solicited AEs will be assessed as described: 
 
Table 22 
Intensity scales for solicited symptoms 
 
Adverse Event 
Intensity grade 
Parameter 
Pain at injection site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing 
normal every day activities. 
2 
Moderate: Painful when limb is moved and interferes with 
every day activities. 
3 
Severe: Significant pain at rest. Prevents normal every 
day activities. 
Redness at injection site 
Record greatest surface diameter in mm 
Swelling at injection site 
Record greatest surface diameter in mm 
Fever* 
Record temperature in °C 
Headache 
0 
Normal 
1 
Mild: Headache that is easily tolerated 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal symptoms 
(nausea, vomiting, diarrhoea and/or 
abdominal pain) 
0 
Gastrointestinal symptoms normal 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with 
normal activity 
3 
Severe: Gastrointestinal symptoms that prevent normal 
activity 
* Fever is defined as oral or axillary temperature  37.5°C. The preferred route for recording temperature in this study 
will be oral. 
 
The maximum intensity of local injection site redness/ swelling will be scored at GSK 
Biologicals as follows: 
 
0 
: 
≤ 20 mm 
1 
: 
> 20 mm to ≤ 50 mm 
2 
: 
> 50 mm to ≤ 100 mm 
3 
: 
> 100 mm 
 
The maximum intensity of fever will be scored at GSK Biologicals as follows: 
 
0 
: 
< 37.5 °C 
1 
: 
≥ 37.5 °C to ≤ 38.5 °C 
2 
: 
> 38.5 °C to ≤ 39.5°C 
3 
: 
> 39.5°C 


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The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
 
The intensity should be assigned to one of the following categories: 
1 (mild) 
: 
An AE which is easily tolerated by the subject, causing 
minimal discomfort and not interfering with everyday 
activities. 
2 (moderate) 
: 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
: 
An AE which prevents normal, everyday activities. Such 
an AE would, for example, prevent attendance at 
work/school and would necessitate the administration of 
corrective therapy. 
 
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 3 
is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-defined 
outcomes as described in Section 9.1.2 
 
9.3.3.2.2.       Assessment of causality 
 
The investigator is obligated to assess the relationship between investigational vaccine/ 
product and the occurrence of each AE/ SAE. The investigator will use clinical 
judgement to determine the relationship. Alternative plausible causes, such as natural 
history of the underlying diseases, concomitant therapy, other risk factors, and the 
temporal relationship of the event to the investigational vaccine/ product will be 
considered and investigated. The investigator will also consult the Investigator Brochure 
and its supplement to determine his/her assessment. 
 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the 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. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
 
In case of concomitant administration of multiple vaccines, it may not be possible to 
determine the causal relationship of general AEs to the individual vaccines administered. 
The investigator should, therefore, assess whether the AE could be causally related to 
vaccination rather than to the individual vaccines. 


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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
Is there a reasonable possibility that the AE may have been caused by the investigational 
vaccine? 
 
YES 
: 
There is a reasonable possibility that the vaccine contributed to 
the AE. 
NO 
: 
There is no reasonable possibility that the AE is causally 
related to the administration of the study vaccine. There are 
other, more likely causes and administration of the study 
vaccine is not suspected to have contributed to the AE. 
 
If an event meets the criteria to be determined as ‘serious’ (see Section 9.1.2), additional 
examinations/ tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
 
Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
 
9.3.3.3. 
Assessment of outcomes 
 
The investigator will assess the outcome of all unsolicited AEs (including SAEs) 
recorded during the study as: 
• 
Recovered/ resolved. 
• 
Recovering/ resolving. 
• 
Not recovered/ not resolved. 
• 
Recovered with sequelae/ resolved with sequelae. 
• 
Fatal (SAEs only). 
 
9.3.3.4. 
Medically attended visits 
 
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/ she received medical attention, defined as hospitalisation or an otherwise 


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unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF. 
 
9.4. 
Reporting of serious adverse events, pregnancies, and 
other events 
9.4.1. 
Prompt reporting of potential immune-mediated diseases, 
serious adverse events and pregnancies to GSK Biologicals 
 
pIMDs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 23, once the investigator becomes aware 
of the pIMD. 
 
SAEs that occur in the time period defined in Section 9.3 will be reported promptly to 
GSK within the timeframes described in Table 23, once the investigator determines that 
the event meets the protocol definition of a SAE. 
 
Pregnancies that occur in the time period defined in Section 9.3 will be reported promptly 
to GSK within the timeframes described in Table 23, once the investigator becomes 
aware of the pregnancy. 
 
Table 23 
Timeframes for submitting potential immune-meditated disease, 
serious adverse event and pregnancy reports to GSK Biologicals 
 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
pIMDs 
24 hours** 
electronic SAE report 
24 hours* 
electronic SAE report 
SAEs 
24 hours* 
electronic SAE report 
24 hours* 
electronic SAE report 
Pregnancies 
2 weeks* 
electronic pregnancy report 
2 weeks* 
electronic pregnancy report 
* Timeframe allowed after receipt or awareness of the information. 
**Timeframe allowed after the diagnosis is established and known to the investigator. 
9.4.2. 
Reporting of pIMDs to GSK Biologicals 
 
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious 
or non-serious) in a study subject, the investigator (or designate) must complete the 
information in the electronic SAE report WITHIN 24 HOURS after he/she becomes 
aware of the diagnosis. A field on the SAE report allows specifying that the event is a 
pIMD and whether it is serious or non-serious. The SAE report will always be completed 
as thoroughly as possible with all available details of the event, in accordance with the 
pIMD standard questionnaire provided. Even if the investigator does not have all 
information regarding a pIMD, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS. 
 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
 
Refer to Section 9.4.3.1 for back-up system in case the electronic SAE reporting system 
does not work. 


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9.4.3. 
Completion and transmission of SAE reports to GSK Biologicals 
 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic SAE report 
WITHIN 24 HOURS. The SAE report will always be completed as thoroughly as 
possible with all available details of the event. Even if the investigator does not have all 
information regarding a SAE, the report should still be completed within 24 hours. Once 
additional relevant information is received, the report should be updated WITHIN 24 
HOURS. 
 
The investigator will always provide an assessment of causality at the time of the initial 
report. 
 
Refer to Section 9.4.3.1 for back-up system in case the electronic SAE reporting system 
does not work. 
 
9.4.3.1. 
Back-up system in case the electronic SAE reporting system does not 
work 
 
If the electronic SAE reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper SAE 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 SAE reporting system is not 
working and NOT if the system is slow. As soon as the electronic SAE reporting system 
is working again, the investigator (or designate) must complete the electronic SAE report 
within 24 hours. The final valid information for regulatory reporting will be the 
information reported through the electronic SAE reporting system. 
 
 
 
9.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals 
 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS. 
 
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
Back-up Study Contact for Reporting SAEs 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Fax: + 
or + 


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9.4.5. 
Updating of pIMD, SAE and pregnancy information after freezing 
of the subject’s eCRF 
 
When additional pIMD, SAE or pregnancy information is received after freezing of the 
subject’s eCRF, new or updated information should be recorded on a paper 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 Back- 
up Study Contact for Reporting SAEs (see Section 9.4.3.1) within the designated 
reporting time frames specified in Table 23. 
 
9.4.6. 
Regulatory reporting requirements for serious adverse events 
 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the investigational vaccine/ product and unexpected. 
The purpose of the report is to fulfil specific regulatory and GCP requirements, regarding 
the product under investigation. 
 
9.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
9.5.1. 
Follow-up of adverse events and serious adverse events 
 
9.5.1.1. 
Follow-up during the study 
 
After the initial AE/ SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 23). 
 
All AEs documented at a previous visit/ contact and designated as not recovered/ not 
resolved or recovering/ resolving will be reviewed at subsequent visits/ contacts until 30 
days after the last vaccination. 
 
All pIMDs (serious or non-serious) and SAEs documented at a previous visit/ contact and 
designated as not recovered/not resolved or recovering/ resolving will be reviewed at 
subsequent visits/contacts. 
 
9.5.1.2. 
Follow-up after the subject is discharged from the study 
 
The investigator will follow subjects with pIMDs (serious or non-serious), SAEs or 
subjects withdrawn from the study as a result of an AE until the event has resolved, 


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subsided, stabilised, disappeared, or until the event is otherwise explained, or the subject 
is lost to follow-up. 
 
If the investigator receives additional relevant information on a previously reported SAE, 
he/ she will provide this information to GSK Biologicals using a paper SAE and/ or 
pregnancy report as applicable. 
 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/ tests and/ or evaluations to elucidate as fully as possible 
the nature and/ or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
 
9.5.2. 
Follow-up of pregnancies 
 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the SAE report, if applicable. Generally, the follow-up period does not need to be longer 
than six to eight weeks after the estimated date of delivery. 
 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE. 
 
9.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of an AE should 
be recorded in the subject’s eCRF (refer to Section 7.6). 
 
9.7. 
Unblinding 
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and USA Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the investigational vaccine/ 
product, prior to regulatory reporting. The GSK Biologicals’ Central Safety Physician is 
responsible for unblinding the treatment assignment in accordance with the specified 
timeframes for expedited reporting of SAEs (refer to Section 9.4.1). 
 
9.8. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the study treatment is essential for the clinical management or welfare of the subject, as 
judged by the investigator. 


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The emergency unblinding process consists of the automated internet-based system SBIR 
that allows the investigator to have unrestricted, immediate and direct access to the 
subject’s individual study treatment. 
 
The investigator has the option of contacting a GSK Biologicals’ On-Call Central Safety 
Physician (or back-up) if he/ she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/ she cannot access the automated internet-based system 
SBIR). 
 
Any emergency unblinding must be fully documented using the Emergency Unblinding 
Documentation Form, which must be appropriately completed by the investigator and 
sent to GSK Biologicals within 24 hours. 
 
 
9.9. 
Subject card 
Study subjects must be provided with the address and telephone number of the main 
contact for information about the clinical study. 
 
The investigator (or designate) must therefore provide a “subject card” to each subject. In 
an emergency situation this card serves to inform the responsible attending physician that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. 
 
Subjects must be instructed to keep subject cards in their possession at all times. 
 
9.10. 
Safety monitoring 
9.10.1. 
Safety Review Team 
 
The project’s SRT includes as core members the GSK Biologicals’ Central Safety 
Physician, the Clinical Research & Development Lead (CRDL), Epidemiologist, Clinical 
Regulatory Affairs representative and the Biostatistician of the project. The SRT is 
responsible for on-going safety monitoring of the entire project and meets on a regular 
basis. The SRT will inform the iSRC about any potential safety concern relevant to the 
study. 
or +PPD
Fax: 
GSK Biologicals’ Central Safety Physician on-call: 
+PPD 
GSK Biologicals’ Central Safety Physician Back-up: 
+PPD 
Emergency Unblinding Documentation Form transmission 
GSK Biologicals’ Contact Information for Emergency Unblinding 
24/24 hour and 7/7 day availability 


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Before each iSRC safety evaluation in this study (see below), the SRT will review the 
same safety data, but in a blinded manner in order to keep all people involved in the 
conduct, cleaning and final analysis of the study blinded. 
 
9.10.2. 
Internal Safety Review Committee 
 
As the investigational vaccine will be administered for the first time to moderate and 
severe COPD patients, an iSRC will be appointed next to the existing project’s SRT and 
safety holding rules have been defined (see Table 24). 
 
The iSRC will be authorised by GSK Biologicals’ VSMB and its core members will 
include a GSK Biologicals’ Safety Physician, a CRDL and a Biostatistician who are not 
otherwise involved in the conduct of the project. If none of the core members listed above 
is a respiratory expert, such an expert will be included. 
 
The iSRC will conduct unblinded reviews of all available safety data from the present 
study, including data on AECOPD (frequency, intensity and duration), while taking into 
account any other findings that could have an impact on the safety of the subjects, and 
will determine whether there is a safety signal that needs to be escalated to GSK 
Biologicals’ VSMB. In the event that a safety signal is observed, GSK Biologicals’ 
VSMB might decide to suspend, modify or continue the conduct of the study. 
 
Administration of vaccine Dose 1 will follow a staggered design, starting with 
vaccination of GOLD 2 subjects only. Administration of vaccine Dose 1 to GOLD 3 
subjects will depend on the favourable outcome of an iSRC evaluation of safety data up 
to at least day 6 after vaccination from about 20 GOLD 2 subjects (i.e. approximately 10 
subjects/ group). 
 
In addition, starting administration of vaccine Dose 2 will for each GOLD grade depend 
on the favourable outcome of an iSRC evaluation of all available safety data. 
 
In addition to the planned iSRC evaluations, ad hoc safety evaluations can take place if a 
safety concern is identified by an investigator (e.g. meeting of holding rules 1a-c) or by 
the SRT. 


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Figure 2 
Overview of iSRC evaluation 
 
 
9.10.3. 
Study holding rules 
 
As the investigational NTHi vaccine will be administered for the first time to moderate 
and severe COPD patients, study holding rules have been defined (see Table 24). 
 
• 
Holding rules 1a, 1b and 1c will be monitored by the investigators on a continuous 
basis for as long as vaccination is on-going in the study. Meeting any of these 
holding rules will trigger a hold of vaccination irrespective of the number of subjects 
vaccinated. 
• 
Holding rules 2a, 2b and 2c will be assessed by the iSRC during the safety 
evaluations. 


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Table 24 
List of holding rules 
 
Holding 
Rule 
Event 
Number/ 
percentage 
of subjects 
1a 
Death or any life-threatening SAE 
≥ 1 
1b 
Any withdrawal from the study (by investigator or subject request) following a Grade 3 
AE that cannot reasonably be attributed to a cause other than vaccination 
≥ 1 
1c 
Any local or general solicited AE leading to hospitalisation, or body temperature 
> 40°C that cannot reasonably be attributed to a cause other than vaccination, or 
necrosis at the injection site, within the 7-day (days 0-6) post-vaccination period 
≥ 1 
2a 
Any Grade 3 solicited local AE lasting 48 hours or more in the investigational group, 
within the 7-day (day 0-6) post-vaccination period 
≥ 25% AND 
≥ 2 subjects/ 
group 
2b 
Any Grade 3 general solicited AE lasting 48 hours or more in the investigational group, 
that cannot reasonably be attributed to a cause other than vaccination, within the 7-day 
(day 0-6) post-vaccination period. 
≥ 25% AND 
≥ 2 subjects/ 
group 
2c 
Any Grade 3 unsolicited AE in the investigational group, that cannot reasonably be 
attributed to a cause other than vaccination, within the 7-day (day 0-6) post-vaccination 
period or 
Any  Grade 3 abnormality* in pre-specified haematology or biochemistry laboratory 
parameter in the investigational group, if it cannot reasonably be attributed to a cause 
other than vaccination, at day 7 post-vaccination. 
≥ 25% AND 
≥ 2 subjects/ 
group 
* Grading of biochemistry parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see APPENDIX C). 
 
Risk assessment curves - probability of meeting holding rules 
Figure 3 illustrates for example that: 
• 
With 10 subjects/ group: 
 
Each holding rule 1 (a-c) has more than 90% chance of not being met for a 
vaccine with a true incidence rate below 1% and has more than 90% chance of 
being met for a vaccine with a true incidence rate above 20%. 
 
Each holding rule 2 (a-c) has almost 100% chance of not being met for a vaccine 
with a true incidence rate below 1% and has more than 30% chance of being met 
for a vaccine with a true incidence rate above 20%. 
• 
With 20 subjects/ group: 
 
Each holding rule 1 (a-c) has more than 80% chance of not being met for a 
vaccine with a true incidence rate below 1% and has more than 98% chance of 
being met for a vaccine with a true incidence rate above 20%. 
 
Each holding rule 2 (a-c) has almost 100% chance of not being met for a vaccine 
with a true incidence rate below 1% and has more than 55% chance of being met 
for a vaccine with a true incidence rate above 20%. 


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Figure 3 
Risk assessment curves for safety holding rules 1 and 2 for 
treatment arms of 10 or 20 subjects (no adjustment for multiplicity) 
 


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10. 
SUBJECT COMPLETION AND WITHDRAWAL 
10.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
 
10.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
 
10.2.1. 
Subject withdrawal from the study 
 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol. 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. 
 
All data collected until the date of withdrawal/ last contact with the subject will be used 
for the analysis. If the subject agrees, the investigator should make an attempt to collect 
safety information until the initially planned date for study conclusion, either by phone, 
or by inviting the subject to a site visit around Day 450. 
 
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/ herself or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
SAE. 
• 
Non-serious AE. 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an AE*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because he/ she has withdrawn consent, 
the investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF. 
 
Subjects who are withdrawn from the study because of (S)AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 


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follow subjects who are withdrawn from the study as result of a (S)AE until resolution of 
the event (see Section 9.5.1.2). 
 
10.2.2. 
Subject withdrawal from investigational vaccine 
 
A ‘withdrawal’ from the investigational vaccine refers to any subject who does not 
receive the complete treatment, i.e. when no further planned dose is administered from 
the date of withdrawal. A subject withdrawn from the investigational vaccine may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (safety or immunogenicity) if planned in the study protocol (see also Section 
7.5). 
 
Information relative to premature discontinuation of the investigational vaccine will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination was made by the 
subject himself/ herself or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
• 
SAE. 
• 
Non-serious AE. 
• 
Other (specify). 
10.3. 
Screening failures 
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria. 
 
The following information will be collected for screening failures: 
• 
Informed consent. 
• 
Demographic data. 
• 
Inclusion/exclusion criteria. 
• 
SAEs related to study participation that occurred after signing informed consent. 
• 
Screening conclusion. 
11. 
STATISTICAL METHODS 
11.1. 
Primary endpoints 
• 
Occurrence of each solicited local adverse event (AE), during the 7-day follow-up 
period (i.e. day 0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of each solicited general AE, during the 7-day follow-up period (i.e. day 
0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of any unsolicited AE, during the 30-day follow-up period (i.e. day 0 - 
29) following each vaccination, in all subjects. 


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• 
Occurrence of each haematological/ biochemical laboratory abnormality at Day 0, 
Day 7, Day 30, Day 60, Day 67, Day 90, Day 270 and Day 450, in all subjects. 
• 
Occurrence of any potential immune-mediated disease (pIMD) from first vaccination 
up to study conclusion, in all subjects. 
• 
Occurrence of any serious adverse event (SAE) from first vaccination up to study 
conclusion, in all subjects. 
 
11.2. 
Secondary endpoints 
• 
Anti-PD, anti-PE and anti-PilA total IgG antibody concentrations as measured by 
ELISA, at Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450, in all subjects. 
• 
NTHi-specific cell-mediated immune responses as measured by flow cytometry 
intracellular cytokine staining (ICS) (frequency of specific CD4+/CD8+ T-cells 
expressing two or more markers, such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and 
CD40L), at Day 0, Day 90, Day 270 and at Day 450, in a sub-cohort of subjects. 
 
11.3. 
Tertiary endpoints (Amended 15 April 2016) 
• 
Number of cases of NTHi-associated moderate and severe AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of NTHi-associated AECOPD (any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of moderate and severe AECOPD (any cause), over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of AECOPD (any cause, any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Time to first AECOPD, in all subjects. 
• 
Assessment of EXACT-PRO score, daily at bedtime throughout the study, in all 
subjects. 
• 
NTHi presence in sputum, at Screening, Day 90, Day 180, Day 270, Day 360 and 
Day 450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
• 
Assessment of CAT score, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Assessment of SGRQ-C score, at Screening, Day 270 and Day 450, in all subjects. 
• 
Assessment of mMRC scale, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Occurrence of rescue medication use, over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Occurrence of healthcare use for AECOPD, over a period starting 1 month post-Dose 
2 and lasting for 1 year, in all subjects. 


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• 
Assessment of FEV1% of predicted normal value at Screening, Day 270 and 
Day 450, in all subjects. 
• 
Assessment of 6MWT score, at Screening and Day 450, in all subjects. 
• 
Occurrence of selected biomarkers in a subset of blood samples, at Day 0 and Day 
450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
 
• 
Presence of respiratory viral pathogens in sputum (including respiratory syncytial 
virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza 
virus, adenovirus, bocavirus and coronavirus) at Screening, Day 90, Day 180, Day 
270, Visit Day 360 and Day 450 and at each AECOPD visit from first vaccination 
to study conclusion, in all subjects. 
 
11.4. 
Determination of sample size 
This study is a Phase II safety study to assess safety and reactogenicity of the 
investigational vaccine in moderate and severe COPD patients. 
 
Considering the sample size of 70 in the group 10-AS01E, Figure 4 illustrates the 
probability of detecting an AE with true occurrence rate 0 - 10%. 
 
Figure 4 
Probability not to observe an AE for 60, 70 or 80 subjects per group 
 
From Figure 4, it can be seen that with a sample size of 70 subjects per group, there is 
more than 50% of chance to detect an AE with a true incidence of 1%, and more than 
97% of chance to detect an AE with a true incidence of 5%. 


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11.5. 
Study cohorts to be analysed 
The following study cohorts will be evaluated. 
 
11.5.1. 
Total vaccinated cohort 
 
The Total vaccinated cohort (TVC) will include all subjects with at least 1 study vaccine 
administration documented: 
• 
A safety analysis based on the TVC will include all vaccinated subjects. 
• 
An immunogenicity/ efficacy analysis based on the TVC will include all vaccinated 
subjects for whom immunogenicity/ efficacy data are available. 
 
The TVC analysis will be performed per treatment actually administered at Dose 1. 
 
11.5.2. 
ATP cohort for analysis of immunogenicity 
 
The ATP cohort for immunogenicity will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule, as specified in Table 9. 
• 
Who received the study vaccines according to protocol procedures. 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity (see Section 7.6.2), up to the 1 month 
post-Dose 2 visit (Day 90). 
• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity (see Section 7.7), up to the 1 month 
post-Dose 2 visit (Day 90). 
• 
Who complied with the blood sample timings as specified in Table 9, at the 1 month 
post-Dose 2 visit (Day 90). 
• 
For whom post-vaccination immunogenicity results are available for at least 1 assay. 
11.5.3. 
ATP cohort for analysis of persistence of immunogenicity 
 
The ATP cohort for persistence of immunogenicity will include all evaluable subjects, 
i.e., those who were included in the ATP cohort for immunogenicity, or were excluded 
from this cohort solely because they had no blood samples taken or because of 
incompliance with blood sample timings up to the 1 month post-Dose 2 visit, and: 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity (see Section 7.6.2). 
• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity (see Section 7.7). 


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• 
Who complied with the blood sample timings after the 1 month post-last vaccination 
visit as specified in Table 9. 
• 
For whom persistence immunogenicity results are available for at least 1 assay. 
11.5.4. 
ATP cohort for analysis of efficacy 
 
The ATP cohort for analysis of efficacy will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule, as specified in Table 9. 
• 
Who received the study vaccine according to protocol procedures. 
• 
Not having received a medication/ product/ vaccine that may lead to elimination 
from the ATP analysis for efficacy (see Section 7.6.3). 
 
11.6. 
Derived and transformed data 
The study groups will be defined by treatment actually administered at Dose 1. 
 
Demography 
• 
For a given subject and a given demographic variable, missing measurement will not 
be replaced. 
 
Safety 
• 
For solicited symptoms, the analysis will exclude subjects with missing or 
un-evaluable measurements (i.e. total analysis of solicited symptoms will include all 
vaccinated subjects with documented solicited symptom sheets). 
• 
For the unsolicited symptoms and concomitant medications/ products/ vaccinations, 
subjects who miss reporting symptoms/concomitant medications/ products/ 
vaccinations will be treated as subjects without unsolicited symptoms or concomitant 
medications/ products/ vaccinations, respectively. 
 
Immunogenicity 
• 
For a given subject and the analysis of a given immunogenicity measurement, 
missing or un-evaluable measurements will not be replaced. 
• 
A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value. 
• 
A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value. 
• 
Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of geometric mean concentration (GMC) 
calculation. 


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• 
Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration transformations. 
 
Impact of the investigational vaccine on AECOPD 
• 
For a given subject and the analysis of a given laboratory assay, missing or 
un-evaluable measurements will not be replaced. 
• 
Subjects who did not have any sputum collected during at least 1 AECOPD (if at 
least 1 AECOPD occurred) will not be taken into account for the NTHI-associated 
AECOPD analyses. 
• 
For summaries of the number of AECOPD occurring during the 1 year follow-up 
period starting 1 month post-Dose 2, an exacerbation rate will be calculated for each 
subject. The number of exacerbations during the 1-year follow-up period will be 
imputed for subjects withdrawing from the study to provide an estimate of the 
number of exacerbations over the follow-up period. This calculation will only be 
performed for purposes of reporting summary statistics for the rate of exacerbations 
during the 1 year follow-up period since the modelling of exacerbations takes into 
account the number of exacerbations and the time of follow-up for each subject. The 
calculation of exacerbation rate will be based on follow-up period intervals to avoid 
obtaining high imputed rates if a subject withdrew very early in the follow-up period 
after experiencing an exacerbation. Since treatment courses for moderate/severe 
exacerbations are  2 - 4 weeks when appropriate, calculated numbers of 
exacerbations for subjects withdrawing from the study will be based on 4-week 
intervals of the follow-up period. For subjects followed for less than 1 year, the 
number of exacerbations during the 1-year follow-up period will be calculated by 
multiplying the number of exacerbations experienced by the subject by 13 and 
dividing by the number of 4-week periods the subject was followed up [Stockley, 
2006]: 
Number of exacerbations per year = Number of exacerbations * 13 /Number of 
4-week treatment period intervals 
 
HRQOL 
• 
The CAT index will be derived as the sum of the ratings recorded for each of the 
eight individual items. Each of these items has 6 possible scores (0, 1, 2, 3, 4 or 5), 
leading to a range of 0 to 40 for CAT score. 
 
11.7. 
Analysis of demographics 
Demographic characteristics (age at the first dose in years, gender and geographical 
ancestry) and cohort description will be summarized by group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as geographical 
ancestry; 
• 
Mean, median and standard error will be provided for continuous data such as age. 
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per group. 


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Withdrawal status will be summarised by group using descriptive statistics: 
• 
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
• 
The number of subjects enrolled into the study as well as the number of subjects 
excluded from ATP analyses will be tabulated. 
 
11.8. 
Analysis of safety 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day (day 0 
– day 6) or the 30-day (day 0 – day 29) follow-up period will be tabulated after each 
vaccination and overall with exact 95% confidence interval (CI). The same computations 
will be done for Grade 3 AEs, for related AEs and for Grade 3 related AEs. 
 
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, related, Grade 3 related) AE during the 7-day 
(day 0 to day 6) follow-up period will be tabulated for each group as follows: 
• 
Overall, the percentage of subjects with the symptom and its exact 95% CI. 
• 
Overall, the percentage of doses with the symptom and its exact 95% CI. 
• 
Per study vaccine dose, the percentage of subjects with the symptom and its exact 
95% CI. 
 
The exact 95% CIs will be calculated assuming independence between doses. For fever, 
additional analyses will be performed by 0.5°C increments. 
 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
preferred term (PT). The percentage of subjects with unsolicited symptoms during the 
30-day follow-up period after any study vaccine dose with its exact 95% CI will be 
tabulated by group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms, for unsolicited symptoms that 
resulted in a medically attended visit, for Grade 3 and causally related unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination. 
 
For each group and for each haematology/ biochemistry parameter: 
• 
The percentage of subjects having results below or above the local laboratory normal 
ranges will be tabulated by time point. 
• 
The maximum grading from Screening up to study conclusion will be tabulated. 
Grades will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 


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Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials” (see APPENDIX C). 
The number of subjects who experienced any pIMD or any SAE from first vaccination 
up to 6 months post-Dose 2 will be reported. 
 
The number of subjects who experienced any AE leading to study withdrawal, from 
first vaccination up to study conclusion, or any SAE related to study participation of 
concurrent GSK medication/ vaccination, during the entire study period, will be 
reported. 
 
Pregnancy exposures from first vaccination up to 6 months after last vaccination and 
pregnancy outcomes will be described in detail. 
 
The percentage of subjects/ dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 7-day follow-up period (day 0 – day 6) and during the 30-day 
follow-up period (day 0 – day 29) will be summarised per group for each dose and 
overall per dose. 
 
11.8.1. 
iSRC safety evaluations 
 
Unblinded review of safety data will be done during iSRC evaluations (refer to Section 
9.10 for more information). No individual clinical study report will be written as a result 
of these safety evaluations. 
 
11.9. 
Analysis of immunogenicity 
The analysis will be performed on the ATP cohort for immunogenicity. If the percentage 
of vaccinated subjects with serological results excluded from the ATP cohort for analysis 
of immunogenicity is more than 10%, a second analysis will be performed on the TVC. 
 
Humoral immune response 
Within group evaluation 
For each group, at each time point during which blood samples are collected for humoral 
immune response and for each assay: 
• 
Seropositivity rate and their exact 95% CI will be tabulated. 
• 
GMCs and their 95% CI will be calculated. 
For each group, at each time point during which blood samples are collected for humoral 
immune response: 
• 
Antibody concentrations distribution will be investigated using Reverse Cumulative 
Curves. 


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Between groups evaluation 
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 2 groups in humoral immune response. 
 
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 by computing 
the 95% CIs of the GMC ratio between groups by using an ANCOVA model that 
considers heterogeneity of variances (via Proc Mixed) on the logarithm10 
transformation of the concentrations. This model will include country, the group, age 
category (40 - 59 years or 60 - 80 years), number of moderate and severe AECOPD in the 
year before vaccine Dose 1 (< 2 or  2), GOLD grade (GOLD 2 or GOLD 3) and pre- 
Dose 1 concentration (as covariate) as fixed effects. (Amended 15 April 2016) 
 
However, these differences should be interpreted with caution considering that there will 
be no adjustment for multiplicity of endpoints. 
 
Cell-mediated immune response 
The frequency of specific CD4+/ CD8+ T-cells will be summarised by group, at each time 
point during which blood samples are collected for CMI (descriptive statistics). 
 
11.10. 
Analysis of impact of the investigational vaccine on 
AECOPD 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is more than 10%, a 
second analysis based on the TVC will be performed to complement the first analysis. 
 
The following incidence rates will be computed over a period starting 1 month 
post-Dose 2 and lasting for 1 year, with 95%CI: 
• 
NTHi-associated moderate and severe AECOPD. 
• 
NTHi-associated all-severity AECOPD. 
• 
All-cause moderate and severe AECOPD. 
• 
All-cause, all-severity AECOPD. 
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. If the model does not converge, the 
Poisson distribution will be used instead of the Negative Binomial one. 


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Vaccine efficacy (VE) for AECOPD events will be defined as: 
VE (AECOPD) = 1 - Rvaccine / Rcontrol 
 
with: 
• 
Rvaccine = average yearly incidence rate of AECOPD events per subject in the 
group 10-AS01E. 
• 
Rcontrol = average yearly incidence rate of AECOPD events per subject in the 
Control group. 
In case the 95% CI of the VE cannot be estimated, e.g. when no event is observed in the 
group 10-AS01E (leading to a VE of 100%), then an exact procedure will be used to 
estimate a VE and its 95% CI. This exact procedure will be based on the number of 
subjects with event instead of on the average number of event per subject in each group. 
 
VE in the prevention of NTHi-associated moderate and severe AECOPD and its 95% CI 
will be calculated. 
 
VE in the prevention of NTHi-associated all-severity AECOPD, of all-cause moderate 
and severe AECOPD and of all-cause, all-severity AECOPD and their 95% CI will also 
be calculated. 
 
The time until first AECOPD as of 1 month post-Dose 2 will be computed with exact 
95% CI by group. Subjects who exacerbate before 1 month post-Dose 2 will not be taken 
into account in this analysis. 
 
The proportion of sputum samples with exact 95% CI obtained at each visit (scheduled 
visits and AECOPD-driven visits) and positive for bacterial pathogens (overall and by 
bacterial pathogen) will be computed by group and overall. The exact 95% CI will be 
estimated assuming independence of bacterial results across sputum samples. 
 
11.11. 
Analysis of HRQOL, lung capacity and exercise capacity 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
 
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the EXACT-PRO, CAT, SGRQ-C and mMRC scores, on FEV1% of predicted 
normal value and on the 6MWT scores will be tabulated by specified visit. 
 
Descriptive summaries rescue medication and healthcare use for AECOPD will be 
provided. 
 
11.12. 
Analysis of selected biomarkers 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is at least 10%, a second 
analysis will be performed on the TVC to complement the first analysis. 


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For each type of timepoint during which blood samples are collected for analysis of 
biomarkers, descriptive statistics (median, mean, range, standard deviation, first and third 
quartiles) will be tabulated for each selected biomarker. 
 
11.13. 
Interpretation of analyses 
Comparative analyses with the aim to characterise the difference in reactogenicity/ 
immunogenicity/ efficacy between groups will be descriptive. These descriptive analyses 
should be interpreted with caution. 
 
11.14. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this 
protocol will be described and justified in the final study report. 
 
11.14.1. 
Sequence of analyses (Amended 15 April 2016) 
 
The analyses will be performed stepwise: 
• 
The analysis of data up to Visit 6 (Day 90) will be performed in a first step. This 
analysis will include: 
 
The final analysis of immunogenicity and solicited AEs post-Dose 1 and post- 
Dose 2. 
 
The assessment of unsolicited AEs, SAEs and pIMDs up to 30 days post-Dose 1 
and post-Dose 2 on as cleaned as possible data. 
This analysis will be documented in a statistical report. At this point, the GSK 
statistician of the project (or delegates) will be unblinded (i.e. will have access to the 
individual subject treatment assignments). 
• 
The analyses of the impact of the investigational vaccine on AECOPD will be 
performed in parallel with the first step. This will include: 
 
the analyses of fresh sputum samples (culture) obtained up to the data lock 
point of the interim analysis. 
 
The analyses of AECOPD obtained up to the data lock point of the interim 
analysis. 
• 
The final analysis of data up to study conclusion will be performed in a second step, 
once those data will be available and cleaned. This analysis will include: 
 
The final analysis of immunogenicity at Day 270 and Day 450. 
 
SAEs and pIMDs up to Day 450 on cleaned data. 
 
Impact of the investigational vaccine on AECOPD, HRQOL, lung function, 
exercise capacity and biomarkers. 
In addition, all previous analyses will be re-produced based on cleaned data at this 
point. 


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Individual listings will only be provided at this stage. An integrated study report 
containing data from the entire study will be written at the end of the study and will 
be made available to the investigators. 
 
11.14.2. 
Statistical considerations for interim analyses 
 
All analyses are descriptive, and performed on final or as clean as possible data therefore 
no adjustment needs to be performed. 
 
12. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled. 
 
12.1. 
Case Report Form/Remote Data Entry instructions 
Remote Data Entry (RDE), a validated computer application, will be used as the method 
for data collection. 
 
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data. 
 
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
 
12.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst others, the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 


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Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform an RDE review and a Source Document 
Verification (SDV). By SDV we understand verifying RDE 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. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which RDE will serve as the source must be identified, agreed and documented 
in the source documentation agreement form. 
 
For RDE, the monitor will freeze completed and approved screens at each visit. 
 
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
 
12.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by ICH GCP, any institutional 
requirements, applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years. 
 
The investigator/ institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site. 
 
12.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 


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completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
 
12.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
 
Summaries of the results of GSK interventional studies (Phase I-IV) are posted on 
publicly available results registers within 12 months of the primary completion date for 
studies of authorised vaccines and 18 months for studies of non-authorised vaccines. 
 
GSK also aims to publish the results of these studies in the searchable, peer reviewed 
scientific literature. Manuscripts are submitted for publication within 24 months of the 
last subject’s last visit. 
 
12.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually- 
agreeable location. 
 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
 
13. 
COUNTRY SPECIFIC REQUIREMENTS 
Not applicable. 


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14. 
REFERENCES 
Alamoudi OS. Bacterial infection and risk factors in outpatients with acute exacerbation 
of chronic obstructive pulmonary disease: a 2-year prospective study. Respirology 2007; 
12: 283-7. 
 
Anthonisen NR, Manfreda J, Warren CP et al. Antibiotic therapy in exacerbations of 
chronic obstructive pulmonary disease. Ann Intern Med. 1987; 106: 196-204. 
 
Bandi V, Jakubowycz M, Kinyon C et al. Infectious exacerbations of chronic obstructive 
pulmonary disease associated with respiratory viruses and non-typeable Haemophilus 
influenzae. FEMS Immunol Med Microbiol. 2003; 37: 69-75. 
 
Cazzola M, MacNee W, Martinez FJ et al. Outcomes for COPD pharmacological trials: 
from lung function to biomarkers. Eur Respir J. 2008; 31: 416-69. 
 
EMA Guideline on the exposure to medicinal products during pregnancy: need for post- 
authorization data (Doc. Ref. EMEA/CHMP/313666/2005 ) ‘adopted at Community level 
in May 2006); 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g 
uideline/2009/11/WC500011303.pdf 
 
Erb-Downward JR, Thompson DL, Han MK et al. Analysis of the lung microbiome in 
the "healthy" smoker and in COPD. PLoS One. 2011; 6: e16384. 
 
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 
 
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. 
 
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. 
 
Larsen MV, Janner JH, Nielsen SD et al. Bacteriology in acute exacerbation of chronic 
obstructive pulmonary disease in patients admitted to hospital. Scand J Infect Dis. 2009; 
41: 26-32. 
 
Moris P, van der Most R, Leroux-Roels I et al. H5N1 influenza vaccine formulated with 
AS03 A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin 
Immunol. 2011; 31: 443-54. 
 
Murphy TF, Brauer AL, Grant BJ et al. Moraxella catarrhalis in chronic obstructive 
pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med. 
2005; 172: 195-9. 


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Murray PR, Baron EJ, Pfaller MA et al. Manual for Clinical Microbiology, 7th edn. 
Washington, DC: American Society for Microbiology, 1999. 
 
National Clinical Guideline Centre. (NICE 2010) Chronic obstructive pulmonary disease: 
management of chronic obstructive pulmonary disease in adults in primary and secondary 
care. London: National Clinical Guideline Centre. Available from: 
http://guidance.nice.org.uk/CG101/Guidance/pdf/English 
 
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. 
 
Sethi S, Evans N, Grant BJ et al. New strains of bacteria and exacerbations of chronic 
obstructive pulmonary disease. N Engl J Med. 2002; 347: 465-71. 
 
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive 
pulmonary disease. N Engl J Med. 2008; 359: 2355-65. 
 
Stockley RA, Chopra N and Rice L. Addition of salmeterol to existing treatment in 
patients with COPD: a 12 month study. Thorax. 2006; 61: 122-8. 
 
Wedzicha JA and Seemungal TA. COPD exacerbations: defining their cause and 
prevention. Lancet. 2007; 370: 786-96. 


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APPENDIX A 
LABORATORY ASSAYS 
Humoral antibody responses (Amended 15 April 2016) 
Anti-PD antibodies 
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The current cut-off of the assay is 153 EL.U/mL. 
 
Anti-PE antibodies 
Anti-PE antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PE antibodies will be determined, using in- 
house made reference serum. The cut-off of the assay is 8 EL.U/mL. 
 
Anti-PilA antibodies 
Anti-PilA antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PilA antibodies will be determined, using an 
in-house made reference serum. The cut-off of the assay is 7 EL.U/mL. 
 
Cell-mediated immunity 
The ICS staining assay will be used to assess CMI responses, using an adaptation of 
previously described methods [Moris, 2011]. After PBMC stimulation with the relevant 
antigens, the frequency of CD4+ and/or CD8+ T-cells expressing selected set of cytokines 
(such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and CD40L) or selected combination of 
cytokines will be evaluated by flow cytometry. 
 
Microbiological assessments 
Bacterial pathogen identification and bacterial load 
Evidence and identification of S. pneumoniae, H. influenzae, M. catarrhalis and other 
bacterial pathogens (including S. aureus, P. aeruginosa and S. pyogenes) in sputum 
specimens will be investigated using standard microbiological culture and standard 
bacteriological procedures [Murray, 1999 according to local laboratory procedures. In 
addition, semi-quantitative data using the culture quadrant assessment method will be 
collected for these pathogens. 
 
H. influenzae, S. pneumoniae and M. catarrhalis will be detected and quantified by mean 
of a qualified GSK proprietary triplex real-time PCR assay P. aeruginosa, S. aureus and 
S. pyogenes will be detected by means of a qualified GSK proprietary triplex real-time 
PCR assay. 
 
Viral pathogen identification and viral load 
Respiratory viral pathogens will be diagnosed by mean of a commercial and qualified 
multiplex PCR assay (RVP Fast, Luminex). 
Rhinovirus-specific quantitative PCRs will be performed on a subset of sputum samples 
at GSK Biologicals or at a designated GSK Biological laboratory. (Amended 15 April 
2016) 


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APPENDIX B 
CLINICAL LABORATORIES 
Table 25 
GSK Biologicals’ laboratories (Amended 15 April 2016) 
 
Laboratory 
Address 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
Table 26 
Outsourced laboratories (Amended 15 April 2016) 
 
Laboratory 
Address 
BARC NV 
Industriepark Zwijnaarde 3b 
B-9052 Gent 
Belgium 
BUGS Bioscience Ltd, 
London Bioscience Innovation Centre 
2 Royal College Street, NW1 0NH 
Greater London, United Kingdom 


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APPENDIX C 
FDA Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials 
(September 2007) 
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking 
on this topic. It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public. You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations. If you want to 
discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify 
the appropriate FDA staff, call the appropriate number listed on the title page of this 
guidance. 
 
i. 
INTRODUCTION 
Preventive vaccines are usually developed to prevent disease in a healthy population. The 
Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, 
regulates preventive vaccines under authority of section 351 of the Public Health Service 
Act (42 U.S.C. 262), as well as specific sections of the Federal Food, Drug, and Cosmetic 
Act, and reviews investigational new drug applications (INDs) and biologics license 
applications (BLAs). (See, for example, Title 21 Code of Federal Regulations (CFR) 
Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines conducted to 
support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The 
enrollment of healthy volunteers warrants a very low tolerance for risk in those clinical 
trials. 
 
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in 
healthy adult and adolescent volunteers enrolled in clinical trials. The grading system 
described in the table can also be useful in defining a particular study’s stopping rules 
(e.g., a certain number of AEs, as defined in the table, may call for stopping the study). 
Less extreme observations (e.g., mild) may not require discontinuing the study vaccine 
but can still contribute to evaluating safety by identifying parameters to focus upon in 
subsequent product development. Uniform criteria for categorizing toxicities in healthy 
volunteers can improve comparisons of safety data among groups within the same study 
and also between different studies. We, FDA, recommend using toxicity grading scale 
tables, provided below, as a guideline for selecting the assessment criteria to be used in a 
clinical trial of a preventive vaccine. We recommend incorporation of such appropriate, 
uniform, criteria into the investigational plan, case report forms, and study reports and 
correspondence with FDA, sponsors, monitors, investigators, and IRBs. 
 
This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 
22664, May 2, 2005). 
 
FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements 


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are cited. The use of the word should in FDA’s guidances means that something is 
suggested or recommended, but not required. 
 
ii. BACKGROUND 
Standardized toxicity assessment scales have been widely used to evaluate products 
treating specific diseases. For example, the National Cancer Institute’s Common Toxicity 
Criteria Scale and the Division of AIDS’ Toxicity Grading Scale standardize the 
evaluation of adverse events among patients with cancer and HIV/AIDS, respectively 
(Refs. 1, 2). The defined toxicity parameters in those scales are designed for patients who 
may already experience mild, moderate, or severe adverse clinical or laboratory events 
due to the disease process, and may not be appropriate for healthy volunteers. 
 
In the development of the toxicity grading scales for healthy volunteers, we chose 
parameter limit values based on published information, when such values were available 
(Refs. 1-6). For example, the Brighton Collaboration has developed case definitions and 
guidelines to evaluate some adverse events associated with administering vaccines (Ref. 
3). In some cases, parameter limit values were based on clinical experience and 
experience reviewing vaccine clinical trials that enroll normal healthy subjects. 
 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory 
reference values when the parameter limit values are defined. The characterization of 
laboratory parameters among some populations of healthy adults and adolescents may 
require the exercise of clinical judgment, for example, consideration of the potential for 
ethnic differences in white blood cell (WBC) counts or gender differences in creatine 
phosphokinase (CPK) values. 
 
iii. TOXICITY GRADING SCALE TABLES 
Adverse events in a clinical trial of an investigational vaccine must be recorded and 
monitored and, when appropriate, reported to FDA and others involved in an 
investigation (sponsors, IRBs, and investigators). (See, for example, 21 CFR 312.32, 
312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66). Although the use of 
a toxicity grading scale for adverse events would not replace these regulatory 
requirements, using a scale to categories adverse events observed during a clinical trial 
may assist you in monitoring safety and making required reports. Nonetheless, we believe 
that categorization or grading of data as outlined in this document is supplementary to 
and should not replace full and complete data analysis. 
 
These guidelines for toxicity grading scales are primarily intended for healthy adult and 
adolescent volunteers. The parameters in the tables below are not necessarily applicable 
to every clinical trial of healthy volunteers. The parameters monitored should be 
appropriate for the specific study vaccine. For some preventive vaccines under 
development, it may be appropriate to include additional parameters to be monitored 
during a clinical trial or to alter the choice of values in the toxicity table. For example, 
additional parameters might be added based on one or more of the following: safety 
signals observed in pre-clinical toxicology studies, the biological plausibility of the 
occurrence of certain adverse events, or previous experience with a similar licensed 
product. 


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As discussed above, the tables do not represent a recommendation to monitor all the 
listed parameters in all clinical trials of healthy volunteers, nor do the tables represent all 
possible parameters to be monitored. In addition, these tables do not represent study 
inclusion or exclusion criteria. We recommend that the parameters monitored be 
appropriate for the study vaccine administered to healthy volunteers participating in the 
clinical trial. 
 
a. Tables for Clinical Abnormalities 
Note from the sponsor: The tables in this section of the guidance will not be used in this 
particular study. Instead, the parameters as provided in the NTHI-004 study protocol are 
to be used. 
 
b. Tables for Laboratory Abnormalities 
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate. 


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Table 27 
FDA toxicity grading scales for hematology/ biochemistry 
parameters 
 
Serum * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – Hyponatremia mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – Hypernatremia mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – Hypokalemia mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – Hypoglycemia mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
100 – 110 
110 – 125 
111 – 125 
126 – 200 
>125 
>200 
Insulin requirements or 
hyperosmolar coma 
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia mg/dL 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 
12.0 
> 12.0 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
1.25 – 1.5 x 
ULN*** 
1.6 – 3.0 x ULN 
3.1 –10 x 
ULN 
> 10 x ULN 
Albumin – Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate – 
increase by factor 
1.1 – 2.0 x 
ULN 
2.1 – 3.0 x ULN 
D3.1 – 10 
x ULN 
> 10 x ULN 
Liver Function Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x 
ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x 
ULN 
> 10 x ULN 
Bilirubin – when accompanied 
by any increase in Liver 
Function Test 
increase by factor 
1.1 – 1.25 x 
ULN 
1.26 – 1.5 x 
ULN 
1.51 – 
1.75 x 
ULN 
> 1.75 x ULN 
Bilirubin – when Liver Function 
Test is normal; increase by 
factor 
1.1 – 1.5 x 
ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x 
ULN 
> 3.0 x ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic enzymes – amylase, 
lipase 
1.1 – 1.5 x 
ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x 
ULN 
> 5.0 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125-129 mE/L) should be recorded as a Grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value. 
*** “ULN” is the upper limit of the normal range. 


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Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life Threatening 
(Grade 4) 
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (Female) 
change from baseline value - 
gm/dL 
Any decrease 
– 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (Male) 
change from baseline value – 
gm/dL 
Any decrease 
– 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC Increase - cell/mm
3 
10 800 – 
15 000 
15 001 – 
20 000 
20 001 – 
25 000 
> 25 000 
WBC Decrease - cell/mm
3 
2 500 – 3 500 
1 500 – 2 499 
1 000 – 1 
499 
< 1 000 
Lymphocytes Decrease - 
cell/mm
3 
750 – 1 000 
500 – 749 
250 – 499 
< 250 
Neutrophils Decrease - 
cell/mm
3 
1 500 – 2 000 
1 000 – 1 499 
500 – 999 
< 500 
Eosinophils - cell/mm
3 
650 – 1 500 
1 501 - 5 000 
> 5 000 
Hypereosinophilic 
Platelets Decreased - 
cell/mm
3 
125 000 – 
140 000 
100 000 – 
124 000 
25 000 – 
99 000 
< 25 000 
PT – increase by factor 
(prothrombin time) 
1.0 – 1.10 x 
ULN** 
D1.11 – 1.20 
x ULN 
1.21 – 1.25 
x ULN 
> 1.25 ULN 
PTT – increase by factor 
(partial thromboplastin time) 
1.0 – 1.2 x 
ULN 
1.21 – 1.4 x 
ULN 
1.41 – 1.5 x 
ULN 
> 1.5 x ULN 
Fibrinogen increase - mg/dL 
400 – 500 
501 – 600 
> 600 
-- 
Fibrinogen decrease - mg/dL 
150 – 200 
125 – 149 
100 – 124 
< 100 or associated with 
gross bleeding or 
disseminated intra vascular 
coagulation (DIC) 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** “ULN” is the upper limit of the normal range. 
 
iv. REFERENCES for the Appendix A 
1. 
National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html) 
2. 
Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 
1992. (http://rcc.tech-res-intl.com/tox_tables.htm) 
3. 
The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition  
guidelines.html) 
4. 
HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; 
September 18, 2002. (http://rcc.tech-res-intl.com/tox_tables.htm) 
5. 
Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAID 
SAEGradingTable.pdf) 
6. 
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. 
New England Journal of Medicine. 2004;351:1548-1563. 


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APPENDIX D 
AMENDMENTS AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL 
 
GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Amendment 1 
eTrack study number 
200157 (NTHI-004) 
and Abbreviated Title 
EudraCT number 
2013-003062-13 
Amendment number: 
Amendment 1 
Amendment date: 
27 March 2014 
Co-ordinating author: 
PPD 
(XPE Pharma & Science for GSK 
Biologicals) 
Rationale/background for changes: 
Protocol amendment 1 was prepared: 
• 
Because the volumes of the individual blood samples that will be collected were 
re-distributed after discussion with the central laboratory. The total volume of 
blood collected per subject across scheduled visits and at AECOPD visits remains 
similar. 
• 
Because information on processing and storage temperature until shipment was 
updated for some of the samples after discussion with the central laboratory. 
• 
To clarify that the plasma obtained during PBMC processing will be kept for 
potential future additional testing. 
• 
To clarify that white blood cell differential count will be done on blood samples 
for safety assessment. 
In addition, some other, minor clarifications have been made and the list of 
contributing authors has been updated. 
Added text is presented in bold italics and deleted text in strikethrough in the following 
sections: 
Title page 
Contributing authors 
• 
and 
(Business & Decision for GSK 
Biologicals), GVCL Study Managers 


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List of abbreviations 
PBMC 
Peripherical blood mononuclear cell 
 
Section 6.5.1. 
List of study procedures during scheduled study visits 
Table 7 
List of study procedures during scheduled study visits 
Epoch 
Type of contact 
Timepoint 
Sampling timepoint 
Blood sampling: 
For safety assessment (~5.5 5 mL) 
For humoral immunogenicity (~25.5 27 mL) 
For CMI (~40 mL) (e) 
For biomarkers (~12.8 12 mL) 
Section 6.5.2. 
List of study procedures during AECOPD-driven study 
visits and phone contacts 
Table 8 
List of study procedures during AECOPD-driven study visits 
and phone contacts 
 
Type of contact 
Timepoint 
Sampling timepoint 
Blood sampling: 
For biomarkers (~12.8 12 mL) 
Section 6.6.15. 
Sampling 
Refer to the Module on Biospecimen Management in the SPM and to the central 
laboratory manual for detailed instructions for the collection, handling and processing of 
the samples. 
 
Section 6.6.15.1. 
Blood Samples 
Blood samples for safety assessment 
A volume of approximately 5.5 5 mL of whole blood should be drawn from all subjects 
at each pre-defined timepoint and will be split and processed as follows: 
• 
Approximately 2 mL of whole blood will be collected for haematology assessment. 
These samples will not be processed They should be kept at room temperature and 
shipped on the day of collection. 
• 
Approximately 3.5 mL of whole blood will be collected for biochemistry assessment 
and will be processed to serum. After processing, serum samples should be kept at 
room temperature and shipped on the day of collection. 
 
(An) additional blood sample(s) for safety assessment may need to be drawn before 
administration of vaccine Dose 2, or during other study visits if deemed necessary by the 
investigator (see Table 10). These samples will not be processed. They should be kept at 
room temperature and shipped on the day of collection. 


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Blood samples for humoral immunogenicity 
A volume of approximately 25.5 27 mL of whole blood should be drawn from all 
subjects at each pre-defined timepoint (to provide at least 9 mL and ideally 13 mL of 
serum). After processing, serum samples should be kept at -20°C until shipment. 
 
Blood samples for biomarkers 
A volume of approximately 12.8 12 mL of whole blood should be drawn from all 
subjects at each predefined timepoint and will be split and processed as follows: 
• 
Approximately 5 mL of whole blood will be processed to serum used to provide at 
least 1.5 mL and ideally 2.5 mL of serum. After processing: 
 
An aliquot of serum should be kept at room temperature and shipped on the 
day of collection. 
 
The remaining serum samples should be kept at -70/80 -20°C until shipment. 
• 
Approximately 6 5mL of whole blood will be processed to plasma used to provide at 
least 1.5 mL and ideally 2.5 mL of plasma. After processing, plasma samples should 
be kept at -70/80°C until shipment. 
• 
Approximately 1.8 mL of whole blood will be processed to plasma not be processed. 
After processing, plasma These samples should be kept at -70/80°C until shipment 
kept at room temperature and shipped on the day of collection. 
 
Section 6.6.15.2. 
Sputum samples 
Refer to the SPM and to the central laboratory manual for more details and guidance on 
handling of sputum samples. 
 
Section 6.7.2. 
Biological samples 
Table 10 
Biological samples 
Sample type 
Quantity 
Unit 
Blood for safety assessment 
5.5 5 
mL 
Blood for humoral immunogenicity 25.5 27 
mL 
Blood for CMI 
40 
mL 
Blood for biomarkers 
12.8 12 
mL 
Section 6.7.3 Laboratory assays 
Haematology/ biochemistry 
Table 11 
Haematology and biochemistry 
 
System 
Discipline 
Component 
Method 
Scale 
Laboratory* 
Whole 
blood 
Haematology 
Haemoglobin 
commercial 
Quantitative Central 
laboratory 
Platelets 
commercial 
Quantitative 
White Blood Cells (WBC) ** 
commercial 
Quantitative 
*Refer to APPENDIX B for the laboratory address. 
** Including WBC differential count. 


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Humoral antibody responses 
Table 12 
Humoral Immunity (Antibody determination) 
 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-off 
Laboratory* 
Serum 
Anti-PD 
ELISA 
In house 
EL.U/mL 
100 *** 
GSK Biologicals** 
EL.U/mL = ELISA unit per millilitre 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Global Vaccines Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, 
Belgium; Laval, Canada. 
*** A new cut-off may be defined after re-validation of the anti-PD ELISA. 
 
Serum and plasma samples might also be used for development and/ or evaluation of 
other assays to measure the immune response to the investigational NTHi vaccine 
components and/or to other NTHi antigens such as, but not limited to, serum 
bactericidal activity assay, assays measuring functional antibodies, immunochemistry 
assays for other immunoglobulin classes and/or for anti-IgG subclasses. 
 
Additional testing on serum and plasma samples may be done during the study or after 
study completion, should these data be required for accurate interpretation of the data 
and/ or for further research related to the investigational vaccine and/ or the disease, 
should such test(s) become available at GSK Biologicals’ laboratory or a laboratory 
designated by GSK Biologicals. 
 
Cell-mediated immune responses 
Additional testing on Peripherical Blood Mononuclear Cells (PBMCs), such as, but not 
limited to, evaluation of NTHi-specific memory B-cells, ICS testing using other bacterial 
antigens, may be done during the study or after study completion, should these data be 
required for accurate interpretation of the data and/ or for further research related to the 
investigational vaccine and/ or the disease, should such test(s) become available at GSK 
Biologicals’ laboratory or a laboratory designated by GSK Biologicals. 
 
Plasma obtained during the processing of whole blood to obtain PBMCs will be stored 
for potential future analyses and/ or assay development purposes. 
 
Appendix A Laboratory assays 
Humoral antibody responses 
Anti-PD antibodies 
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The current cut-off of the assay is 100 EL.U/mL. This 
assay will however be re-validated according to the latest validation standards and a 
new cut-off might be defined based on a precise and accurate limit of quantification. 


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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Amendment 2 
eTrack study number 
200157 (NTHI-004) 
and Abbreviated Title 
EudraCT number 
2013-003062-13 
Amendment number: 
Amendment 2 
Amendment date: 
15 December 2014 
Co-ordinating author: 
PPD 
(XPE Pharma & Science for GSK 
Biologicals) 
Rationale/background for changes: 
Protocol amendment 2 was prepared: 
• 
To add clarification in the tertiary objectives: because acute exacerbations of 
COPD are complex events, triggered by multiple (interacting) pathogens, assessing 
the natural immunity to other pathogens might be important for interpretation of 
the data. 
• 
To add an additional blood sample for haematology assessment at each AECOPD 
visit. This blood sample will be collected to describe the systemic inflammation at 
time of exacerbation in terms of white blood cells and differential cell counts. 
• 
To clarify the list of concomitant medication that may lead to elimination of a 
subject from ATP analysis of immunogenicity (Section 7.6.2): because oral 
corticosteroids are commonly used in treatment of exacerbations, the 
administration of oral corticosteroids given for this indication will not fall under 
the definition of “chronic administration of immunosuppressants or other 
immune-modifying drugs at any time during the study period”, used to determine 
elimination from the ATP analysis of immunogenicity. 
• 
To add a benefit: risk assessment section (Section 1.3). 
In addition, a typo in the footnote of the table of intervals between visits (Table 9) has 
been corrected and the list of contributing authors has been updated. 
 
Added text is presented in bold italics and deleted text in strikethrough in the following 
sections: 
Title page 
Contributing authors 
• 
(PPD 
Novellas Healthcare for GSK Biologicals), 
Study Delivery Manager 


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and PPD 
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and 
, 
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Safety Representatives 
 
• 
(Aixial Pharma for GSK Biologicals) and 
, Study Data 
Manager 
 
Section 1.3 Benefit: Risk assessment 
Please refer to the current IB for the summary of potential risks and benefits of the 
NTHi investigational vaccine. 
 
The following section outlines the risk assessment and mitigation strategy for the study 
protocol: 
 
1.3.1 Risk Assessment 
 
Important 
Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
NTHi investigational vaccine 
Theoretical risk of 
No confirmed signals related 
Close monitoring of potential 
acquiring a vaccine- 
to this potential risk have 
immune-mediated diseases 
induced autoimmune 
been identified during the 
in clinical development 
disease after vaccination 
preclinical and clinical 
programs using adjuvants 
programs so far (data from 
systems. The potential risk 
two studies using NTHi 
of events of possible 
vaccines: NTHI-002 (non- 
autoimmune aetiology to 
adjuvanted formulations) and occur is mentioned in the 
NTHI-003 (adjuvanted and 
Informed Consent Form 
non-adjuvanted 
(ICF). 
formulations). 
 
1.3.2 Benefit Assessment 
Benefits considerations include: 
• 
Contribution to the process of developing of a vaccine against AECOPD. 
• 
Medical evaluations/assessments associated with this study (i.e. physical 
examination, blood testing [haematology and biochemistry data], spirometry). 
 
1.3.3 Overall Benefit : Risk Conclusion 
 
Taking into account the measures taken to minimize risks to subjects participating in 
this study, the potential and/or known risks identified in association with the candidate 
NTHi vaccine are justified by the anticipated benefits that may be afforded to patients 
for the prevention of AECOPD. 


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Synopsis: Tertiary objectives + Section 2.3 
Tertiary objectives 
• 
To collect blood and sputum samples for assay development, for disease diagnostic 
purpose, for lung microbiome analysis and/ or for additional evaluation of the 
immune responses to the investigational vaccine and to other potential pathogens 
involved in AECOPD. 
 
Synopsis: Sampling schedule 
 
Blood samples for assessment of haematology parameters will be collected at 
each AECOPD visit. 
 
Section 6.1 Regulatory and ethical considerations, including the informed 
consent process 
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. 
 
Section 6.5.2. 
List of study procedures during AECOPD-driven study 
visits and phone contacts 
Table 8 
List of study procedures during AECOPD-driven study 
visits and phone contacts 
 
Type of contact 
AECOPD visit 
End of AECOPD contact(s) 
(phone call[s and/ or visit[s) 
Timepoint 
within 96 hours of 
onset symptoms 
at least every 2 weeks as of 
AECOPD visit until AECOPD 
has resolved (a) 
Sampling timepoint 
AECOPD 
Blood sampling: 
For biomarkers (~12.8 mL) 
● 
For haematology assessment (~2.0 mL) 
● 
Section 6.5.4. Interval between study visits 
Table 9 
Interval between study visits 
Footnote: 
5 Scheduled study visits should not take place within 7 days of an AECOPD visit. If an AECOPD occurs at the time of a 
scheduled study visit so that this is not adhered to, the scheduled visit should be re-scheduled to a later date within the 
time window specified. In consultation with GSK, only Visit 8 (Day 270) and Visit 10 (Day 450) may exceptionally be 
conducted outside of the allowed interval if necessary. 
 
Section 6.6.15 Blood samples 
Blood samples for safety assessment 
For scheduled visits: a A volume of approximately 5.5 mL of whole blood should be 
drawn from all subjects at each pre-defined timepoint (Table 10) and will be split and 
processed as follows: 


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Blood samples for biomarkers 
At Visit 1, Visit 10 and at each AECOPD visit: A a volume of approximately 12.8 mL of 
whole blood should be drawn from all subjects at each pre-defined timepoint and will be 
split and processed as follows: 
• 
Approximately 5 mL of whole blood will be processed to serum. After processing: 
 
An aliquot of serum should be kept at room temperature and shipped on the day 
of collection. 
 
The remaining serum should be kept at -70/80°C until shipment. 
• 
Approximately 6 mL of whole blood will be processed to plasma. After processing, 
plasma samples should be kept at -70/80°C until shipment. 
• 
Approximately 1.8 mL of whole blood will be processed to plasma. After processing, 
plasma samples should be kept at -70/80°C until shipment. 
 
At each AECOPD visit: a volume of approximately 2 mL of whole blood will be 
collected for haematology parameters from all subjects (Table 10). These samples will 
not be processed. They should be kept at room temperature and shipped on the day of 
collection. 
 
Section 6.7.2. 
Biological samples 
Table 10 
Biological samples 
Blood for safety 
assessment * 
(haematology 
and 
biochemistry) 
5.5 
mL 
• 
Screening Visit (pre-Day 0) 
All screened 
subjects 
• 
Visit 1 (Day 0) 
• 
Visit 2 (Day 7) 
• 
Visit 3 (Day 30) 
• 
Visit 4 (Day 60) 
• 
Visit 5 (Day 67) 
• 
Visit 6 (Day 90) 
• 
Visit 8 (Day 270) 
• 
Visit 10 (Day 450) 
All enrolled subjects 
Blood for 
haematology 
parameters 
~2.0 
mL 
• 
During each AECOPD 
All enrolled subjects 
Section 6.7.3. 
Laboratory assays 
Haematology/ biochemistry 
Haematology/ biochemistry assays for safety assessment will be performed in a central 
laboratory. Haematology assays on whole blood taken at AECOPD visits will be 
performed in the same central laboratory. 


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Section 7.6.2. 
Concomitant medications/products and vaccines that may 
lead to the elimination of a subject from ATP analysis for immunogenicity 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days) at any time during the study period (e.g. methotrexate). For 
corticosteroids, this will mean prednisone  10 mg/day, or equivalent. Topical 
steroids are allowed. Use of corticosteroids is allowed as per local treatment 
recommendations. 


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GlaxoSmithKline Biologicals 
Clinical Research & Development 
Protocol Amendment 3 
eTrack study number 
200157 (NTHI-004) 
and Abbreviated Title 
EudraCT number 
2013-003062-13 
Amendment number: 
Amendment 3 
Amendment date: 
15 April 2016 
Co-ordinating author: 
PPD 
(XPE Pharma & Science for GSK 
Biologicals) 
Rationale/background for changes: 
• 
In compliance with ICH requirements, the protocol mentions that all results will be 
presented in an integrated report at the end of the study. 
• 
Following re-development and re-validation of the anti-PD ELISA, a new cut-off 
was defined. 
• 
Reference to the GSK Biologicals’ Laval laboratory was removed, as this 
laboratory will not be used in the study. In addition, this laboratory is no longer 
part of GSK Biologicals’ laboratories. 
• 
Internal assay qualification procedures were revised and it was decided that the 
level of characterisation of the ELISA assays can be minimal (set-up level) for this 
study as immunogenicity data are descriptive. In consequence, the assays will be 
standardized but not qualified as stated in the original version.This change will not 
impact the validity of the results. 
• 
A tertiary endpoint was added as the presence of viral pathogens in sputum will be 
examined as part of microbiome analysis. 
• 
In order to see early effects of the vaccine on the microbiome, analysis on fresh 
sputum samples (culture results) will be done on all available data up to the data 
lock point of the interim analysis. 
• 
In order to have a first look whether or not the investigational vaccine has an 
impact on AECOPD, AECOPD analyses will be done up to the data lock point of 
the interim analysis. 
• 
Wording was added to clarify process for collection of sputum H. influenzae 
sweeps. 
• 
Wording was updated in order to be aligned with the Statistical Ananlysis Plan. 
• 
In addition, minor edits in other sections were made for clarification purposes. 


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PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
PPD 
, PPD 
, PPD
and PPD 
, PPD 
PPD 
PPD 
PPD 
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Added text is presented in bold italics and deleted text in strikethrough in the following 
sections: 
Title page 
Co-ordinating and contributing authors 
Co-ordinating author 
, PPD 
Science for GSK Biologicals) 
 
Contributing authors 
• 
, PPD 
(XPE Pharma & 
 
 
, Clinical 
Research & Development Lead 
• 
, PPD 
Biostatistician 
 
, Lead 
• 
, Project Biostatistician 
• 
, Study Delivery Lead 
• 
(Novellas Healthcare 
for GSK Biologicals), 
, Study 
Delivery Manager 
• 
, GVCL Project ManagerCLS 
Clinical Read-Out Team Leader 
• 
and PPD 
(Business 
& Decision for GSK Biologicals), CLSGVCL 
Laboratory Study Managers 
•

Safety Representatives 
• 
(Aixial Pharma for GSK 
Biologicals) and 
, Study Data 
Manager 
• 
, Project Data Manager 
•
Regulatory Lead 
, Global 
, 


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Protocol Amendment 3 Sponsor Signatory Approval page 
Sponsor signatory 
Jeanne-Marie                                  Devaster, 
Director Clinical Research and Translational Science 
Ashwani Kumar Arora, Clinical and Epidemiology 
Project Lead 
 
Synopsis and Section 11.3 Tertiary endpoints 
Presence of respiratory viral pathogens in sputum (including respiratory syncytial 
virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza virus, 
adenovirus, bocavirus and coronavirus) at Screening, Day 90, Day 180, Day 270, Visit 
Day 360 and Day 450 and at each AECOPD visit from first vaccination to study 
conclusion, in all subjects. 
List of abbreviations 
CLS 
Clinical Laboratory Sciences 
 
Section 6.7.1 Use of specific study materials 
When materials are provided by GSK Biologicals or by the central laboratory, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner. 
 
Section 6.7.3 Laboratory assays 
Humoral antibody responses 
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory. 
Standardised and qualified procedures will be used for all assays. 
 
Table 12 
Humoral Immunity (Antibody determination) 
 
System 
Component 
Method 
Kit / 
Manufacturer 
Unit 
Cut-off 
Laboratory* 
Serum 
Anti-PD 
ELISA 
In house 
EL.U/mL 
153 100 *** 
GSK Biologicals** 
Serum 
Anti-PE 
ELISA 
In house 
EL.U/mL 
8 
GSK Biologicals** 
Serum 
Anti-PilA 
ELISA 
In house 
EL.U/mL 
7 
GSK Biologicals** 
EL.U/mL = ELISA unit per millilitre 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories Global Vaccines 
Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada. 
*** A new cut-off may be defined after re-validation of the anti-PD ELISA. 
 
Table 13 
Cell-Mediated Immunity 
 
System 
Component 
Scale 
Method 
Unit 
Laboratory* 
PBMCs 
Specific CD4+/CD8+ T-cells Quantitative 
Flow cytometry 
ICS 
Number of specific 
CD4+/CD8+ T-cells /106 
GSK 
Biologicals** 
PBMC = Peripheral Blood Mononuclear Cell; ICS = Intracellular Cytokine Staining 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Global Vaccines Clinical Laboratories 
(GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada. 


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Further   characterisation  of  bacterial  serotypes  and/  or  genotypes  on  stored    
H. influenzae positive sputum and/  or  on  stored  H.  influenzae  sweeps  of  positive 
H. influenzae culture plates may will be done at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals using either standard agglutination techniques 
or molecular tools, as microarray serotyping; considering that a “stored H. influenzae 
sweeps” is defined as the “harvest” of all microorganisms that have grown on the 
primary sputum culture plate (e.g. chocolate agar plate for H. influenzae growth) if at 
least one H. influenzae colony was observed on this plate. 
 
Bacterial pathogen identification (including, but not necessarily limited to, 
H. influenzae, S. pneumoniae, M. catarrhalis, S. aureus, P. aeruginosa and Streptococcus 
pyogenes [S. pyogenes) and quantification (for H. influenzae, S. pneumoniae, 
M. catarrhalis) on stored sputum samples will be performed at GSK Biologicals’ 
laboratory or a laboratory designated by GSK Biologicals using molecular methods such 
as multiplex RT PCR and/ or quantitative PCR (qPCR). 
 
In addition, viral pathogens (such as rhinovirus) in stored sputum samples might will be 
quantified on a subset of samples using qPCR at GSK Biologicals' laboratory or at a 
laboratory designated by GSK Biologicals using qualified procedures. 
 
Table 14 
Microbiology 
 
System 
Component 
Method 
Scale 
Laboratory* 
Bacterial pathogen identification 
semi- 
quantitative 
Stored H. influenzae 
Characterisation of bacterial 
Agglutination and/ or qualitative 
GSK Biologicals** or 
positive sputum and/ or 
serotypes and/ or genotypes molecular tools 
designated laboratory 
stored sweep of positive 
(microarray 
H. influenzae culture 
serotyping) 
plate 
*Refer to APPENDIX B for the laboratory addresses. 
** GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) Laboratories Global Vaccines 
Clinical Laboratories (GVCL) in Rixensart, Belgium; Wavre, Belgium; Laval, Canada. 
† Bacterial culture of sputum stored in STGG (alternative storage) might be performed in a subset of samples at 
specific sites and/ or at GSK Biologicals’ designated laboratory. More details will be provided in the SPM and 
associated documents. 
Section 11.9 Analysis of immunogenicity 
Between groups evaluation 
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 by computing 
the 95% CIs of the GMC ratio between groups by using an one-way ANCOVA model 
that considers heterogeneity of variances (via Proc Mixed) on the logarithm10 
transformation of the concentrations on the logarithm10 transformation of the 
concentrations. This model e ANCOVA model will include country, the group, age 
category (40 - 59 years or 60 - 80 years), number of moderate and severe AECOPD in the 
year before vaccine Dose 1 (< 2 or  2), and GOLD grade (GOLD 2 or GOLD 3) and 
pre-Dose 1 concentration (as covariate) as fixed effects and the pre-Dose 1 
concentration as regressor. The groups will be considered significantly different if the 
95% CI for the GMC ratio between the 2 groups does not contain the value 1. 


15-APR-2016 
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CONFIDENTIAL 
200157 (NTHI-004) 
Protocol Amendment 3 Final 
CONFIDENTIAL 
200157 (NTHI-004)
Protocol Amendment 3 Final
 
 
 
 
 
Section 11.14.1 
Sequence of analysis 
• 
The analyses of the impact of the investigational vaccine on AECOPD will be 
performed in parallel with the first step. This will include: 
 
the analyses of fresh sputum samples (culture) obtained up to the data lock 
point of the interim analysis. 
 
The analyses of AECOPD obtained up to the data lock point of the interim 
analysis. 
Individual listings will only be provided at this stage. An integrated final study 
report containing data from the entire study will be written at the end of the study 
and will be made available to the investigators. 
 
Appendix A Laboratory assays 
Humoral antibody responses 
Anti-PD antibodies 
Anti-PD antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The current cut-off of the assay is 153 100 EL.U/mL. 
This assay will however be re-validated according to the latest validation standards and a 
new cut-off might be defined based on a precise and accurate limit of quantification. 
 
Viral pathogen identification and viral load 
Respiratory viral pathogens will be diagnosed by mean of a commercial and qualified 
multiplex PCR assay (RVP Fast, Luminex). 
Rhinovirus- and respiratory syncytial virus-specific real-time quantitative PCRs will be 
developed and qualified performed on a subset of sputum samples at GSK Biologicals 
or at a designated GSK Biological laboratory. 
 
Appendix C Clinical laboratories 
Table 25 
GSK Biologicals’ laboratories 
 
Laboratory 
Address 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart - Belgium 
GSK Biologicals Global Vaccine Clinical 
Laboratory, North America- Laval 
Biospecimen      Reception      -      Clinical       Serology 
525 Cartier blvd West - Laval - Quebec - Canada - H7V 3S8 
GSK Biologicals Global Vaccine Clinical 
Laboratory, Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
 
Table 26 
Outsourced laboratories 
 
Laboratory 
Address 
BARC NV 
Industriepark Zwijnaarde 3b 
B-9052 Gent 
Belgium 
BUGS Bioscience Ltd, 
London Bioscience Innovation Centre 
2 Royal College Street, NW1 0NH 
Greater London, United Kingdom 


 
 
 
 
 
 
CONFIDENTIAL  
200157 (NTHl-004) 
Protocol Amendment 3 Final 
Protocol Amendment 3 Sponsor ignatory Approval 
 
eTrack study number and 
Abbreviated Title 
 
EudraCT number 
 
Date of protocol 
amendment 
Detailed Title 
200157 (NTHI-004) 
 
 
2013-003062-13 
 
Amendment 3 Final: 5 April 2016 
 
A Phase II, randomis d, observer-blind, placebo- 
controlled, multi-cen e study to evaluate the safety, 
reactogenicity and· 
 unogenicity of GSK 
Biologicals' investig tional vaccine GSK2838504A, 
when administered i 
amuscularly according to a 0, 2 
month schedule to C PD patients aged 40 to 80 years 
 
Signature 
Date 
For internal use only 
---..checksum---!Ver.!CreatedOn- - 
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15-APR-2016 
a9f5ee6b637f1 aa8db5303a6f2085a397484e806 
3 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Study alias & e-track number(s): NTHi-004 (200157) 
 
FORM-9000026972-01 Statistical Analysis Plan Template  
Effective date: 01 June 2014 
GSK SOP Reference: SOP-9000026972  
Form Owner: VVHS Biometrics, 
 
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Detailed Title: 
A Phase II, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A, 
when administered intramuscularly according to a 0, 2 
month schedule to COPD patients aged 40 to 80 years 
SAP version 
Final 
SAP date 
09-FEB-2016 
Scope: 
All data pertaining to the above study.  
Co-ordinating author: 
 
Other author(s): 
 
Adhoc reviewers: 
, Global Regulatory Lead (RA) 
, 
, Safety 
Representatives 
CTRS team 
Approved by: 
, Clinical Research & 
Development Lead 
, Lead Statistician 
, Scientific Writer 
, Statistician 
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Statistical Analysis Plan 
 
Study alias & e-track number(s): NTHi-004 (200157) 
 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 4 
1. 
DOCUMENT HISTORY ............................................................................................ 7 
2. 
STUDY DESIGN ...................................................................................................... 7 
3. 
OBJECTIVES ........................................................................................................... 8 
3.1. 
Primary objective .......................................................................................... 8 
3.2. 
Secondary objective ..................................................................................... 8 
3.3. 
Tertiary objectives ......................................................................................... 8 
4. 
ENDPOINTS ............................................................................................................ 9 
4.1. 
Primary endpoints ......................................................................................... 9 
4.2. 
Secondary endpoints .................................................................................... 9 
4.3. 
Tertiary endpoints ......................................................................................... 9 
5. 
STUDY POPULATION ........................................................................................... 10 
5.1. 
Total vaccinated cohort ............................................................................... 10 
5.2. 
ATP cohort for analysis of immunogenicity ................................................. 11 
5.3. 
ATP cohort for analysis of persistence of immunogenicity .......................... 11 
5.4. 
ATP cohort for analysis of efficacy .............................................................. 11 
6. 
STATISTICAL METHODS ...................................................................................... 12 
6.1. 
Analysis up to Visit 6 (Day 90) .................................................................... 12 
6.1.1. 
Analysis of demographics ............................................................ 12 
6.1.2. 
Analysis of safety ......................................................................... 13 
6.1.3. 
Analysis of immunogenicity .......................................................... 14 
6.1.4. 
Analysis of HRQOL, lung capacity and exercise capacity ............ 15 
6.1.5. 
Analysis of selected biomarkers ................................................... 16 
6.2. 
Final analysis (up to day 450) ..................................................................... 16 
6.2.1. 
Analysis of demographics ............................................................ 16 
6.2.2. 
Analysis of safety ......................................................................... 16 
6.2.3. 
Analysis of immunogenicity .......................................................... 18 
6.2.4. 
Analysis of impact of the investigational vaccine on 
AECOPD incidence ..................................................................... 19 
6.2.5. 
AECOPD visits and daily questionnaires...................................... 20 
6.2.6. 
Analysis of HRQOL, lung capacity and exercise capacity ............ 21 
6.2.7. 
Analysis of selected biomarkers ................................................... 21 
6.2.8. 
Analysis of sputum ....................................................................... 21 
6.2.8.1. 
Sputum sample collection and quality ......................... 21 
6.2.8.2. 
Sputum bacterial/viral results from culture or 
from PCR ................................................................... 22 
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6.2.8.3. 
Impact of previous antibiotic administration on 
sputum bacterial results .............................................. 22 
6.2.8.4. 
Impact of induction of sample on sputum 
bacterial results .......................................................... 22 
6.2.8.5. 
Impact of previous occurrence of Hi bacterial 
pathogen in sputum on AECOPDs ............................. 22 
7. 
STATISTICAL CALCULATIONS ............................................................................ 23 
7.1. 
Derived and transformed data ..................................................................... 23 
7.1.1. 
Demography ................................................................................ 23 
7.1.2. 
Safety .......................................................................................... 23 
7.1.3. 
Immunogenicity ............................................................................ 24 
7.1.4. 
NTHi associated AECOPD........................................................... 25 
7.1.5. 
HRQOL ........................................................................................ 25 
7.1.6. 
EXACT-PRO derived AECOPD definitions and calculation 
rules ............................................................................................. 25 
7.1.7. 
“e-diary derived AECOPD” definitions and calculation 
rules ............................................................................................. 26 
7.1.8. 
End/Duration of an e-diary signal of an exacerbation: .................. 27 
7.1.9. 
Time between 2 e-diary signals for 
exacerbations/evaluation of baseline symptom score: ................. 27 
7.1.10. 
Missing data ................................................................................ 28 
7.1.11. 
AECOPDs definitions and calculation rules .................................. 28 
7.1.11.1. AECOPD definition (from clinical evaluation) .............. 28 
7.1.11.2. Characterization of inconsistencies between 
morning e-diary signals and exacerbation site 
visits ........................................................................... 29 
7.1.12. 
Grading of severity of an exacerbation ......................................... 30 
7.2. 
Data presentation description ..................................................................... 30 
8. 
CONDUCT OF ANALYSES .................................................................................... 31 
8.1. 
Sequence of analyses ................................................................................. 31 
8.2. 
Statistical considerations for interim analyses ............................................. 31 
9. 
CHANGES FROM PLANNED ANALYSES ............................................................. 32 
10. REFERENCES ....................................................................................................... 32 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AECOPD 
Acute exacerbation of COPD 
ALT 
Alanine aminotransferase 
ATP 
According-To-Protocol 
ANCOVA 
Analysis of covariance 
CAT 
COPD assessment test 
CI 
Confidence Interval 
CMI 
Cell-mediated immunity 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CTRS 
Clinical Trial Registry 
EF 
Internal GSK database code for Efficacy analysis (elimination 
codes) link to FORM-BIO-CLIN-9004-05 Criteria for eliminating 
subjects from the analyses 
EL.U/ml 
ELISA unit per milliliter 
ELISA 
Enzyme-linked immunosorbent assay 
Eli Type 
Internal GSK database code for type of elimination code 
EXACT-PRO 
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
FU 
Internal GSK database code for Follow-up analysis (elimination 
codes) link to FORM-BIO-CLIN-9004-05 Criteria for eliminating 
subjects from the analyses 
GMC 
Geometric mean antibody concentration 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
H. influenzae 
Haemophilus influenzae 
HRQOL 
Health-Related Quality of Life 
ICF 
Informed consent form 
ICS 
Intracellular cytokine staining 
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IU/ml 
International units per milliliter 
LL 
Lower Limit of the confidence interval 
MA 
Internal GSK database code for Main analysis (elimination codes) 
link to FORM-BIO-CLIN-9004-05 Criteria for eliminating subjects 
from the analyses 
MATEX 
MATerial EXcellence 
M. catarrhalis 
Moraxella catarrhalis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMRC scale 
mMRC scale 
N.A. 
Not Applicable 
NTHi 
Non-Typeable Haemophilus influenzae 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Protein D 
PE 
Protein E 
PI 
Prescribing information 
PilA 
Type IV pili subunit of non-typeable Haemophilus influenzae 
pIMD 
Potential immune-mediated disease 
PT 
Preferred term 
SAE 
Serious adverse event 
S. aureus 
Staphylococcus aureus 
SAP 
Statistical Analysis Plan 
SBIR 
GSK Biological’s Internet Randomization System 
SD 
Standard Deviation 
SR 
Study Report 
STGG 
Skim milk, tryptone, glucose, and glycerin transport medium 
SYN 
Synopsis 
TFL 
Tables Figures and Listing template annexed to SAP 
TVC 
Total vaccinated cohort 
UL 
Upper Limit of the confidence interval 
VE 
Vaccine efficacy 
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6MWT 
6-Minute Walk Test 
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The complete statistical analysis plan and results presentation is divided into 2 parts: the 
first part detailing the analyses to be performed (known as SAP, current document) and a 
second part, annex (-es) (called TFL) describing the flow and format of tables, figures 
and listings to be annexed to the SR. 
1. 
DOCUMENT HISTORY 
Date 
Description 
Protocol Version 
29-JAN-2016 
Version 1 
Amendment 2 - 15-DEC-
2014 
 
2. 
STUDY DESIGN 
Figure 1 
Study design overview 
 
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Experimental design: Phase II randomised, observer-blind, placebo-controlled, multi-
centre study with 2 parallel groups. 
Duration of the study: for each subject enrolled, the study will last approximately 
16 months from Visit 1 up to study end 
The following group names will be used for the statistical analyses: 
Group order 
in tables 
Group label in tables 
Group definition for footnote 
1 
10-AS01E 
2 doses of AS01e adjuvanted vaccine containing 
10 mcg of each antigen 
2 
Control 
2 doses of saline solution 
 
3. 
OBJECTIVES 
3.1. 
Primary objective 
• 
To describe the safety and reactogenicity of the investigational vaccine.  
3.2. 
Secondary objective 
• 
To describe the humoral and cellular immunogenicity of the investigational vaccine.  
3.3. 
Tertiary objectives 
• 
To explore the impact of the investigational vaccine on AECOPD.  
• 
To explore the impact of the investigational vaccine on NTHi presence in sputum. 
• 
To explore the impact of the investigational vaccine on health-related quality of life 
(HRQOL).  
• 
To explore the impact of the investigational vaccine on lung function.  
• 
To explore the impact of the investigational NTHi vaccine on exercise capacity. 
• 
To describe selected biomarkers in stable COPD and during AECOPD.  
• 
To collect blood and sputum samples for assay development, for disease diagnostic 
purpose, for lung microbiome analysis and/ or for additional evaluation of the 
immune responses to the investigational vaccine and to other potential pathogens 
involved in AECOPD.  
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4. 
ENDPOINTS 
4.1. 
Primary endpoints 
• 
Occurrence of each solicited local adverse event (AE), during the 7-day follow-up 
period (i.e. day 0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of each solicited general AE, during the 7-day follow-up period (i.e. day 
0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of any unsolicited AE, during the 30-day follow-up period (i.e. day 0 - 
29) following each vaccination, in all subjects. 
• 
Occurrence of each haematological/ biochemical laboratory abnormality at Day 0, 
Day 7, Day 30, Day 60, Day 67, Day 90, Day 270 and Day 450, in all subjects. 
• 
Occurrence of any potential immune-mediated disease (pIMD) from first vaccination 
up to study conclusion, in all subjects. 
• 
Occurrence of any serious adverse event (SAE) from first vaccination up to study 
conclusion, in all subjects. 
4.2. 
Secondary endpoints 
• 
Anti-PD, anti-PE and anti-PilA total IgG antibody concentrations as measured by 
ELISA, at Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450, in all subjects. 
• 
NTHi-specific cell-mediated immune responses as measured by flow cytometry 
intracellular cytokine staining (ICS) (frequency of specific CD4+/CD8+ T-cells 
expressing two or more markers, such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and 
CD40L), at Day 0, Day 90, Day 270 and at Day 450, in a sub-cohort of subjects. 
4.3. 
Tertiary endpoints 
• 
Number of cases of NTHi-associated moderate and severe AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of NTHi-associated AECOPD (any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of moderate and severe AECOPD (any cause), over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of AECOPD (any cause, any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Time to first AECOPD, in all subjects. 
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• 
Assessment of EXACT-PRO score, daily at bedtime throughout the study, in all 
subjects. 
• 
NTHi presence in sputum, at Screening, Day 90, Day 180, Day 270, Day 360 and 
Day 450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
• 
Assessment of CAT score, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Assessment of SGRQ-C score, at Screening, Day 270 and Day 450, in all subjects. 
• 
Assessment of mMRC scale, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Occurrence of rescue medication use, over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Occurrence of healthcare use for AECOPD, over a period starting 1 month post-Dose 
2 and lasting for 1 year, in all subjects. 
• 
Assessment of FEV1% of predicted normal value at Screening, Day 270 and 
Day 450, in all subjects. 
• 
Assessment of 6MWT score, at Screening and Day 450, in all subjects. 
• 
Occurrence of selected biomarkers in a subset of blood samples, at Day 0 and Day 
450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
5. 
 STUDY POPULATION 
The following study cohorts will be evaluated. 
5.1. 
Total vaccinated cohort 
The Total vaccinated cohort (TVC) will include all subjects with at least 1 study vaccine 
administration documented: 
• 
A safety analysis based on the TVC will include all vaccinated subjects. 
• 
An immunogenicity/ efficacy analysis based on the TVC will include all vaccinated 
subjects for whom immunogenicity/ efficacy data are available. 
The TVC analysis will be performed per treatment actually administered at Dose 1. 
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5.2. 
ATP cohort for analysis of immunogenicity 
The ATP cohort for immunogenicity will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule. 
• 
Who received the study vaccines according to protocol procedures. 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity up to the 1 month post-Dose 2 visit (Day 90). 
• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity up to the 1 month post-Dose 2 visit (Day 
90). 
• 
Who complied with the blood sample timings, at the 1 month post-Dose 2 visit (Day 
90). 
• 
For whom post-vaccination immunogenicity results are available for at least 1 assay. 
5.3. 
ATP cohort for analysis of persistence of immunogenicity 
The ATP cohort for persistence of immunogenicity (starting at Day 180) will include all 
evaluable subjects, i.e., those who were included in the ATP cohort for immunogenicity, 
or were excluded from this cohort solely because they had no blood samples taken or 
because of incompliance with blood sample timings up to the 1 month post-Dose 2 visit, 
and: 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity. 
• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity. 
• 
Who complied with the blood sample timings after the 1 month post-last vaccination 
visit. 
• 
For whom persistence immunogenicity results are available for at least 1 assay. 
5.4. 
ATP cohort for analysis of efficacy 
The ATP cohort for analysis of efficacy will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
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• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule 
• 
Who received the study vaccine according to protocol procedures. 
• 
Not having received a medication/ product/ vaccine that may lead to elimination 
from the ATP analysis for efficacy. 
The list of applicable elimination codes for each cohort can be found in the study specific 
form FORM-BIO-CLIN-9004-05 Criteria for eliminating subjects from the analyses. 
Cohort 
Elimination codes 
Eli Type 
ATP cohort for analysis of immunogenicity 
1010-2500 
MA 
ATP cohort for analysis of efficacy 
1010-2500 
EF 
ATP cohort for analysis of persistence of 
immunogenicity 
1010-2500 
FU 
 
6. 
STATISTICAL METHODS 
6.1. 
Analysis up to Visit 6 (Day 90) 
6.1.1. 
Analysis of demographics 
Demographic characteristics (age at the first dose in years, gender and geographical 
ancestry), cohort description and other characteristics such as smoking/exposure history 
status, pulmonary function test baseline results and COPD history, history of 
exacerbation present/past medical history/intercurrent morbidity, and previous 
vaccination with a pneumococcal vaccine or an influenza vaccine will be summarized by 
group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as geographical 
ancestry; 
• 
Mean, median and standard error will be provided for continuous data such as age. 
Other characteristics such as height, weight, BMI selected results and several risk factors 
from the six-minutes-walk test, and distribution of several severity stages using CAT or 
mMRC or SGRQ-C at enrolment visit will also be summarized. 
The number of subjects enrolled into the study as well as the number of subjects excluded 
from ATP analyses will be tabulated. 
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per group. 
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The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
6.1.2. 
Analysis of safety 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day (day 0 
– day 6) or the 30-day (day 0 – day 29) follow-up period will be tabulated after each 
vaccination and overall with exact 95% confidence interval (CI). The same computations 
will be done for Grade 3 AEs, for related AEs and for Grade 3 related AEs.  
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, related, Grade 3 related) AE during the 7-day 
(day 0 to day 6) follow-up period will be tabulated for each group as follows: 
• 
Overall, the percentage of subjects with the symptom and its exact 95% CI. 
• 
Overall, the percentage of doses with the symptom and its exact 95% CI. 
• 
Per study vaccine dose, the percentage of subjects with the symptom and its exact 
95% CI. 
The exact 95% CIs will be calculated assuming independence between doses. For fever, 
additional analyses will be performed by 0.5°C increments.  
As during the study, 22 subjects have completed wrong diary cards (paediatric ones 
instead of adults), a sensitivity analysis will be done on subjects that have completed the 
correct diary cards only, to be sure that they were no impact on results. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
preferred term (PT). The percentage of subjects with unsolicited symptoms during the 
30-day follow-up period after any study vaccine dose with its exact 95% CI will be 
tabulated by group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms, for unsolicited symptoms that 
resulted in a medically attended visit, for Grade 3 and causally related unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination. 
PPD


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For each group and for each haematology/ biochemistry parameter: 
• 
The percentage of subjects having results below or above the local laboratory normal 
ranges will be tabulated by time point. 
• 
The maximum grading from Screening up to 30 days post-Dose 2 will be tabulated. 
Grades will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials” (See Protocol). 
The number of subjects who experienced any pIMD or any SAE from first vaccination 
up to 30 days post-Dose 2 will be reported. 
The number of subjects who experienced any AE leading to study withdrawal, from 
first vaccination up to study conclusion, or any SAE related to study participation of 
concurrent GSK medication/ vaccination, during the entire study period, will be 
reported. 
Pregnancy reports from first vaccination up to 30 days post-Dose 2 and pregnancy 
outcomes will be described in detail. 
The percentage of subjects/ dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 7-day follow-up period (day 0 – day 6) and during the 30-day 
follow-up period (day 0 – day 29) will be summarised per group for each dose and 
overall per dose. 
6.1.3. 
Analysis of immunogenicity 
The analysis will be performed on the ATP cohort for immunogenicity. If the percentage 
of vaccinated subjects with serological results excluded from the ATP cohort for analysis 
of immunogenicity is more than 10%, a second analysis will be performed on the TVC. 
Humoral immune response 
Within group evaluation 
For each group, at each time point during which blood samples are collected for humoral 
immune response and for each assay: 
• 
Seropositivity rate and their exact 95% CI will be tabulated. 
• 
GMCs and their 95% CI will be calculated. 
PPD


Statistical Analysis Plan 
 
Study alias & e-track number(s): NTHi-004 (200157) 
 
FORM-9000026972-01 Statistical Analysis Plan Template  
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For each group, at each time point during which blood samples are collected for 
humoral immune response: 
• 
Antibody concentrations distribution will be investigated using Reverse Cumulative 
Curves. 
Between groups evaluation 
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 2 groups in humoral immune response. 
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 by computing 
the 95% CIs of the GMC ratio between groups by using an ANCOVA model  that 
consider heterogeneity of variances (via Proc Mixed) on the logarithm10 transformation 
of the concentrations. This model will include the country, the group, age category (40 - 
59 years or 60 - 80 years), number of moderate and severe AECOPD in the year before 
vaccine Dose 1 (< 2 or ≥ 2), GOLD grade (GOLD 2 or GOLD 3) and pre-Dose 1 
concentration (as covariate) as fixed effects. 
However, these differences should be interpreted with caution considering that there will 
be no adjustment for multiplicity of endpoints. 
Cell-mediated immune response 
The frequency of specific CD4+/ CD8+ T-cells will be summarised (mean, SD, minimum, 
Q1, median, Q3, and maximum) by group, at each time point during which blood samples 
are collected for CMI (descriptive statistics).  
Each data will be obtained by subtracting the summary of the background value to 
each summary value. Values less than or equal to zero will be set to 1 for the purpose 
of geometric mean calculation and graphical representation. 
 
 
6.1.4. 
Analysis of HRQOL, lung capacity and exercise capacity 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the EXACT-PRO, CAT, SGRQ-C and mMRC scores, on FEV1% of predicted 
normal value and on the 6MWT scores will be tabulated by specified visit. 
Descriptive summaries rescue medication and healthcare use for AECOPD will be 
provided. 
PPD


Statistical Analysis Plan 
 
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FORM-9000026972-01 Statistical Analysis Plan Template  
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6.1.5. 
Analysis of selected biomarkers 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is at least 10%, a second 
analysis will be performed on the TVC to complement the first analysis. 
For each type of timepoint (Pre, Exacerbation visit) during which blood samples are 
collected for analysis of biomarkers, descriptive statistics (median, mean, range, standard 
deviation, first and third quartiles) will be tabulated for each selected biomarker. 
 
6.2. 
Final analysis (up to day 450) 
6.2.1. 
Analysis of demographics 
Withdrawal status will be summarised by group using descriptive statistics: 
The number of subjects enrolled into the study as well as the number of subjects excluded 
from ATP analyses will be tabulated.  
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
6.2.2. 
Analysis of safety 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day (day 0 
– day 6) or the 30-day (day 0 – day 29) follow-up period will be tabulated after each 
vaccination and overall with exact 95% confidence interval (CI). The same computations 
will be done for Grade 3 AEs, for related AEs and for Grade 3 related AEs.  
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, related, Grade 3 related) AE during the 7-day 
(day 0 to day 6) follow-up period will be tabulated for each group as follows: 
• 
Overall, the percentage of subjects with the symptom and its exact 95% CI. 
• 
Overall, the percentage of doses with the symptom and its exact 95% CI. 
• 
Per study vaccine dose, the percentage of subjects with the symptom and its exact 
95% CI. 
PPD


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The exact 95% CIs will be calculated assuming independence between doses. For fever, 
additional analyses will be performed by 0.5°C increments.  
As during the study, some subjects have completed wrong diary cards (paediatric ones 
instead of adults), a sensitivity analysis will be done on subjects that have completed the 
correct diary cards to be sure that they were no impact on results. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
preferred term (PT). The percentage of subjects with unsolicited symptoms during the 
30-day follow-up period after any study vaccine dose with its exact 95% CI will be 
tabulated by group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms, for unsolicited symptoms that 
resulted in a medically attended visit, for Grade 3 and causally related unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination. 
For each group and for each haematology/ biochemistry parameter: 
• 
The percentage of subjects having results below or above the local laboratory normal 
ranges will be tabulated by time point. 
• 
The maximum grading from Screening up to study conclusion will be tabulated. 
Grades will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials” (see Appendix C of the protocol). 
The number of subjects who experienced any pIMD or any SAE from from first 
vaccination up to 6 months post-Dose 2 will be reported will be reported. 
The number of subjects who experienced any AE leading to study withdrawal, from 
first vaccination up to study conclusion, or any SAE related to study participation of 
concurrent GSK medication/ vaccination, during the entire study period, will be 
reported. 
Pregnancy reports from first vaccination up to 6 months after last vaccination and 
pregnancy outcomes will be described in detail. 
The percentage of subjects/ dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 7-day follow-up period (day 0 – day 6) and during the 30-day 
follow-up period (day 0 – day 29) will be summarised per group for each dose and 
overall per dose. 
PPD


Statistical Analysis Plan 
 
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FORM-9000026972-01 Statistical Analysis Plan Template  
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6.2.3. 
Analysis of immunogenicity 
The analysis will be performed on the ATP cohort for immunogenicity. If the percentage 
of vaccinated subjects with serological results excluded from the ATP cohort for analysis 
of immunogenicity is more than 10%, a second analysis will be performed on the TVC. 
Humoral immune response 
Within group evaluation 
For each group, at each time point during which blood samples are collected for humoral 
immune response and for each assay: 
• 
Seropositivity rate and their exact 95% CI will be tabulated. 
• 
GMCs and their 95% CI will be calculated. 
For each group, at each time point during which blood samples are collected for humoral 
immune response: 
• 
Antibody concentrations distribution will be investigated using Reverse Cumulative 
Curves. 
Between groups evaluation 
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 2 groups in humoral immune response. 
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 and at Day 
450 by computing the 95% CIs of the GMC ratio between groups by using an ANCOVA 
model  that consider heterogeneity of variances (via Proc Mixed) on the logarithm10 
transformation of the concentrations. This model will include the country, the group, age 
category (40 - 59 years or 60 - 80 years), number of moderate and severe AECOPD in the 
year before vaccine Dose 1 (< 2 or ≥ 2), GOLD grade (GOLD 2 or GOLD 3) and pre-
Dose 1 concentration (as covariate) as fixed effects. 
However, these differences should be interpreted with caution considering that there will 
be no adjustment for multiplicity of endpoints. 
Cell-mediated immune response 
The frequency of specific CD4+/ CD8+ T-cells will be summarised (mean, SD, minimum, 
Q1, median, Q3, and maximum) by group, at each time point during which blood samples 
are collected for CMI (descriptive statistics).  
Each data will be obtained by subtracting the summary of the background value to 
each summary value. Values less than or equal to zero will be set to 1 for the purpose 
of geometric mean calculation and graphical representation. 
PPD


Statistical Analysis Plan 
 
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FORM-9000026972-01 Statistical Analysis Plan Template  
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6.2.4. 
Analysis of impact of the investigational vaccine on AECOPD 
incidence 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is more than 10%, a 
second analysis based on the TVC will be performed to complement the first analysis. 
The following incidence rates will be computed over a period starting 1 month 
post-Dose 2 and lasting for 1 year, with 95%CI: 
• 
NTHi-associated moderate and severe AECOPD. (See definition in section 7.1.4) 
• 
NTHi-associated all-severity AECOPD. 
• 
All-cause moderate and severe AECOPD. 
• 
All-cause, all-severity AECOPD. 
Vaccine efficacy (VE) for AECOPD events will be defined as: 
VE (AECOPD) = 1 - Rvaccine / Rcontrol 
with: 
• 
Rvaccine = average yearly incidence rate of AECOPD events per subject in the group 
10-AS01E. 
• 
Rcontrol = average yearly incidence rate of AECOPD events per subject in the Control 
group. 
In case the 95% CI of the VE cannot be estimated, e.g. when no event is observed in the 
group 10-AS01E (leading to a VE of 100%), then an exact procedure will be used to 
estimate a VE and its 95% CI. This exact procedure will be based on the number of 
subjects with event instead of on the average number of event per subject in each group. 
VE in the prevention of NTHi-associated moderate and severe AECOPD and its 95% CI 
will be calculated.  
VE in the prevention of NTHi-associated all-severity AECOPD, of all-cause moderate 
and severe AECOPD and of all-cause, all-severity AECOPD and their 95% CI will also 
be calculated. 
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. In addition, the following covariates 
(as per randomization) will be taken into account: 
 
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- 
country, 
- 
number of moderate/severe exacerbations reported in the 12 months prior to 
enrolment,  
- 
COPD status at enrolment (derived by GSK from the Visit 1 spirometry results) 
- 
Age (below or equal to median/above median) 
 
If the model does not converge, the Poisson distribution will be used instead of the 
Negative Binomial one. 
The frequency of all these AECOPDs will be presented. The estimated incidence rate with 
95%CI of AECOPDs in which Hi (resp. Mcat, Sp) is present in culture and was not present 
in the previous visit estimated by a Generalised linear model assuming the Negative 
Binomial distribution will be estimated.  
 
Time to first AECOPD event by baseline status - Cox regression model 
The Cox’s regression model including the risk factors:   
- 
country,  
- 
number of moderate/severe exacerbations reported in the 12 months prior to 
enrolment,  
- 
COPD status at enrolment (derived by GSK from the Visit 1 spirometry results) 
- 
Age (below or equal to median/above median) 
as covariates (as per randomization) will be performed to model the time until the first 
occurrence of AECOPD episodes. Additional stratification/risk factor may be defined 
during the analyses like sex factor as exploratory analysis. 
 
6.2.5. 
AECOPD visits and daily questionnaires 
The time until first AECOPD as of 1 month post-Dose 2 will be computed with exact 
95% CI by group. Subjects who exacerbate before 1 month post-Dose 2 will not be taken 
into account in this analysis.  
The number of morning e-dairy (PHT) alerts (resp. evening e-diary alerts (EXACT-PRO)) 
with and without corresponding site visits will be tabulated. The reason for inconsistency 
between morning e-diaries and site visits will also be presented. 
The number of exacerbation site visits with confirmed AECOPD with and without morning 
e-diary alerts (resp. evening e-diary alerts (EXACT-PRO) will be tabulated along with the 
reason for no e-diary alert. 
Concordance/discordance of exacerbations periods as defined clinically or via the morning 
diary cards or the evening diary cards will tabulated and presented graphically. 
PPD


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The percentage of spontaneous exacerbation visits will be tabulated as well as the 
percentage of monthly visits with recovered/stable status. 
6.2.6. 
Analysis of HRQOL, lung capacity and exercise capacity 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the EXACT-PRO, CAT, SGRQ-C and mMRC scores, on FEV1% of predicted 
normal value and on the 6MWT scores will be tabulated by specified visit. 
Descriptive summaries rescue medication and healthcare use for AECOPD will be 
provided. 
6.2.7. 
Analysis of selected biomarkers 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is at least 10%, a second 
analysis will be performed on the TVC to complement the first analysis. 
For each type of timepoint (Pre, Exacerbation visit, Day 450) during which blood 
samples are collected for analysis of biomarkers, descriptive statistics (median, mean, 
range, standard deviation, first and third quartiles) will be tabulated for each selected 
biomarker. 
6.2.8. 
Analysis of sputum 
6.2.8.1. 
Sputum sample collection and quality 
The proportion of subjects (at each stable and exacerbation visit) who provided a sputum 
sample will be computed; overall and by the sample method (spontaneous or induced). 
 
The proportion of subjects with induced sputum will be tabulated by COPD status at 
enrolment and by severity of the AECOPD. 
 
The distribution of the time (in days) between the start of exacerbation and the day of the 
sputum sample collection will be presented. 
 
 
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6.2.8.2. 
Sputum bacterial/viral results from culture or from PCR 
The distribution of the proportion of sputum samples positive given the number of days 
between start of exacerbation and sample collection will be presented. 
 
The proportion of sputum samples obtained at each - stable and exacerbation - visit and 
positive for specific bacterial/viral pathogens (overall and by bacterial culture, bacterial 
PCR, or viral species) will be computed. The average infection rate by type of visit will 
also be calculated. 
 
The bacterial presence in culture versus the bacterial presence in PCR detected in sputum 
will be tabulated. 
The viral infections versus the bacterial presence in PCR detected in sputum will be 
tabulated. 
 
The incidence of exacerbations and of exacerbations containing Hi, Mcat, Sp, and all 
bacterial and/or virus that are planned to be tested by the laboratory will be presented. 
 
For specific bacterial pathogens, the quantitative assessment of PCR results will be 
provided overall, for sputum samples positive in culture, or negative in culture of the 
specific pathogen. 
 
6.2.8.3. 
Impact of previous antibiotic administration on sputum bacterial 
results 
The impact of antibiotic administration before sputum collection on the bactericidal 
culture or PCR results will be evaluated, for stable (scheduled) visits, exacerbation visits, 
or any visit. 
 
6.2.8.4. 
Impact of induction of sample on sputum bacterial results 
The impact of sputum induction on the bactericidal culture or PCR results will be 
evaluated, for stable (scheduled) visits, exacerbation visits, or any visit. 
 
6.2.8.5. 
Impact of previous occurrence of Hi bacterial pathogen in sputum on 
AECOPDs 
The impact of the occurrence or presence of respiratory pathogenic bacteria detected in 
sputum at the exacerbation visit given the presence of the bacteria at previous visits on the 
number of exacerbations will also be studied. In order to do this, 2 types of AECOPDs will 
be distinguished: 
- 
AECOPDs in which Hi is present and was not present any previous visit 
- 
AECOPDs in which Hi is present and was not present in the previous stable visit; 
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7. 
STATISTICAL CALCULATIONS 
7.1. 
Derived and transformed data 
The study groups will be defined by treatment actually administered at Dose 1. 
7.1.1. 
Demography 
• 
For a given subject and a given demographic variable, missing measurement will not 
be replaced. 
• Age: Age at the reference activity, computed as the number of units between the date 
of birth and the reference activity In case of partial dates of any of these 2 dates: 
- 
15th of month, If only the day is missing 
- 
30th of June, if day and months are missing 
7.1.2. 
Safety 
• 
For solicited symptoms, the analysis will exclude subjects with missing or 
un-evaluable measurements (i.e. total analysis of solicited symptoms will include all 
vaccinated subjects with documented solicited symptom sheets).  
• 
For the unsolicited symptoms and concomitant medications/ products/ vaccinations, 
subjects who miss reporting symptoms/concomitant medications/ products/ 
vaccinations will be treated as subjects without unsolicited symptoms or concomitant 
medications/ products/ vaccinations, respectively. 
• 
Note that for all tables described in this section, the way the percentage of subjects 
will be derived will depend on the event analysed (see table below for details). As a 
result, the N value will differ from one table to another. 
Event 
N used for deriving % per subject  
Concomitant vaccination 
All subjects with study vaccine administered 
Solicited general symptom 
All subjects with at least one solicited general symptom documented as 
either present or absent (i.e. symptom screen completed) 
Solicited local symptom 
All subjects with at least one solicited local symptom documented as either 
present or absent (i.e. symptom screen completed) 
Unsolicited symptom 
All subjects with study vaccine administered  
Concomitant medication 
All subjects with study vaccine administered  
 
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7.1.3. 
Immunogenicity 
• 
For a given subject and the analysis of a given immunogenicity measurement, 
missing or un-evaluable measurements will not be replaced. 
• 
A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value. 
• 
A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value.  
• 
Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of geometric mean concentration (GMC) 
calculation. 
• 
Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration transformations. 
• The assay cut-off is the value under which there is no quantifiable result available. 
For an assay with a specific ‘cut_off’ , numerical immuno result is derived from a 
character field (rawres): 
- 
If rawres is ‘NEG’ or ‘-’ or ‘(-)’, numeric result= cutt_off/2, 
- 
if rawres is ‘POS’ or ‘+’ or ‘(+)’, numeric result = cut_off, 
- 
if rawres is ‘< value’ and value<=cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘< value’ and value>cut_off, numeric result =value, 
- 
if rawres is ‘> value’ and value<cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘> value’ and value>=cut_off, numeric result =value, 
- 
if rawres is ‘<= value’ or ‘>= value’ and value<cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘<= value’ or ‘>= value’ and value>=cut_off, numeric result =value, 
- 
if rawres is a value < cut_off, numeric result = cut_off/2, 
- 
if rawres is a value >= cut_off, numeric result = rawres, 
- 
else numeric result is left blank. 
 
• All CI computed will be two-sided 95% CI. 
Impact of the investigational vaccine on AECOPD  
• 
For a given subject and the analysis of a given laboratory assay, missing or 
un-evaluable measurements will not be replaced. 
• 
Subjects who did not have any sputum collected during at least 1 AECOPD (if at 
least 1 AECOPD occurred) will not be taken into account for the NTHI-associated 
AECOPD analyses. 
• 
For summaries of the number of AECOPD occurring during the 1 year follow-up 
period starting 1 month post-Dose 2, an exacerbation rate will be calculated for each 
subject. The number of exacerbations during the 1-year follow-up period will be 
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imputed for subjects withdrawing from the study to provide an estimate of the 
number of exacerbations over the follow-up period. This calculation will only be 
performed for purposes of reporting summary statistics for the rate of exacerbations 
during the 1 year follow-up period since the modelling of exacerbations takes into 
account the number of exacerbations and the time of follow-up for each subject. The 
calculation of exacerbation rate will be based on follow-up period intervals to avoid 
obtaining high imputed rates if a subject withdrew very early in the follow-up period 
after experiencing an exacerbation. Since treatment courses for moderate/severe 
exacerbations are ≤ 2 - 4 weeks when appropriate, calculated numbers of 
exacerbations for subjects withdrawing from the study will be based on 4-week 
intervals of the follow-up period. For subjects followed for less than 1 year, the 
number of exacerbations during the 1-year follow-up period will be calculated by 
multiplying the number of exacerbations experienced by the subject by 13 and 
dividing by the number of 4-week periods the subject was followed up:  
Number of exacerbations per year = Number of exacerbations * 13 /Number of 
4-week treatment period intervals 
7.1.4. 
NTHi associated AECOPD 
An NTHI associated to AECOPD is not yet well defined at the time of the SAP is written. 
Here is the first approach:  
- 
An AECOPD for which NTHi was observed: Hi confirmed first by culture and 
then by PCR. 
7.1.5. 
HRQOL 
The CAT index will be derived as the sum of the ratings recorded for each of the eight 
individual items. Each of these items has 6 possible scores (0, 1, 2, 3, 4 or 5), leading to a 
range of 0 to 40 for CAT score. 
 
7.1.6. 
EXACT-PRO derived AECOPD definitions and calculation rules 
Start of an EXACT-PRO signal for exacerbation (as in EXACT-PRO user Manual and 
in Makay, et al., 2014): 
1. An EXACT-PRO exacerbation is defined as a 12 point increase above baseline for 
2 consecutive days, or a nine point increase for 3 consecutive days. 
2. The baseline score corresponds to the average EXACT score during a baseline 
period defined as days 14 to 8 preceding exacerbation onset 
3. Exacerbation onset will be taken as the first day in which at least two symptoms 
(at least 1 major) are present and have not been discounted (see above). 
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4. Only symptom data collected during the study period will be used to define the 
start of an exacerbation. 
End/recovering of an EXACT-PRO signal of an exacerbation: 
1. The end/recovering of an EXACT-PRO signal of an exacerbation corresponds to 
the day at the EXACT-PRO score return to its baseline value.  
2. The length of a signal of an exacerbation will be at least of 2 days. So rule 1 will 
only apply from the third day onwards.  
Missing data: 
Days with missing data will not be ignored when defining start of a signal: e.g., if a 
patient has two qualifying symptoms followed by a missing day, if the next day with data 
has two qualifying symptoms this will not be defined as an exacerbation. 
 
7.1.7. 
“e-diary derived AECOPD” definitions and calculation rules 
The definition of an AECOPD case definition from section 5.3.1.2 of the Protocol is what 
we will call here an “e-diary derived (AECOPD) signal”. In this paragraph, only the 
derivation of occurrence and length of e-diary signals is described. Derivation of 
occurrence and length of AECOPDs is described in Section 7.1.11. 
Start of an e-diary signal for exacerbation: 
1. An exacerbation is defined as a worsening of at least 2 symptoms for ≥ 2 
consecutive days where at least one of the symptoms is major.  
2. 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. 
3. Any symptom that has occurred consecutively for 5 days or more prior to a 
potential exacerbation should be discounted from the symptoms that define an 
exacerbation. 
4. Exacerbation onset will be taken as the first day in which at least two symptoms 
(at least 1 major) are present and have not been discounted (see above). 
5. Only symptom data collected during the study period will be used to define the 
start of an exacerbation. 
 
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7.1.8. 
End/Duration of an e-diary signal of an exacerbation: 
1. The end/recovering of an e-diary signal of an exacerbation corresponds to 
the day at which the 3-day moving average of the daily symptom count score 
(average between the day the day before and the day after) to return to 
baseline symptom count score (the mean daily symptom count score over 
days 14 to 8 preceding exacerbation onset). For a specific day, the daily 
symptom count score is defined as the sum of the symptom scores 
experienced in this day (a major symptom accounts for 2 points, a minor 
symptom accounts for 1 point, as in Trappenburg et al., 2011, but contrary to 
Seemungal et al. 2000 and Mackay et al. 2014, in which all symptoms 
accounted to 1). Note that the symptoms that have occurred consecutively for 5 
days or more prior to a potential exacerbation and that are discarded for these 
exacerbations are not discarded from the symptoms counts. 
2. The length of an e-diary signal of an exacerbation will be at least of 2 days. So 
rule 1 will only apply from the third day onwards.  
3. The baseline symptom count score is calculated as the average count score of 
the observed days in the period used to calculate the baseline symptom count 
score. For example, if an exacerbation occurs from day 10 onwards, the 
baseline period will be the average between day1 and day2 (day10 - 8 days= 
day2, day10 – 9 days = day1, Day1 being the first study day). For 
exacerbations before day 9 but after day 2, the baseline symptom score will 
be considered to be day1 
4. If the first e-diary signal of an exacerbation is occurring before day 3:  
duration will be counted until the day in which there is at most 2 majors or 1 
major and one minor symptom. 
5. Recovery time is calculated as the number of days from exacerbation e-diary 
signal onset (included) to exacerbation e-diary signal end (not included). 
 
7.1.9. 
Time between 2 e-diary signals for exacerbations/evaluation of 
baseline symptom score: 
The minimum duration between 2 e-diary signals with distinct baseline value is 15 days, 
which is the minimal period for which a new full exacerbation-free baseline can be 
calculated for the next e-diary episode. 
If a new worsening of symptoms occurs between 6 and 14 days of a previous 
exacerbation, the baseline period used will be the same baseline as the one of the original 
exacerbation. Therefore, it will last until the daily symptom count score has gone 
below the baseline symptom score of the previous event. 
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7.1.10. 
Missing data 
1. Days with missing data will not be ignored when defining start of an e-diary  signal: 
e.g., if a patient has two qualifying symptoms followed by a missing day, if the next 
day with data has two qualifying symptoms this will not be defined as an 
exacerbation. Hence, the start of an e-diary signal of an exacerbation will require 2 
consecutive non-missing days of worsening. If there is partially recorded symptom 
data at a visit, however, only the observed values will be considered but the day will 
not be discarded. 
2. Days with missing data will be ignored when defining end of an e-diary signal of an 
exacerbation: e.g., if a patient has two days missing in the baseline period and one 
day missing in the 3- day moving average, both baseline and 3-day moving average 
values will be calculated using observed data only. Similar rules will apply when 
there is partially recorded symptom data at a visit (and daily average values will be 
calculated among the observed values). 
3. All available data will be used for each patient. 
4. As a general rule, the baseline symptom count score, and 3 day moving averages 
are calculated as the average count score of the observed days in the baseline 
period. For example, if an e-diary signal occurs from day 10 onwards, the 
baseline period will be the average between day1 and day2 (day1 being the first 
study day). If day 13 is missing, the 3 day moving average at day 14 will only 
take into account day 14 and day 15. 
5. If there are greater than 2 consecutive days of missing data after an e-diary signal not 
resolved, the e-diary signal will not be considered resolved until the next day with 
observed data if the corresponding moving average is below the baseline value. In 
order words, if the 3-day average daily score is missing, the day will be counted in 
the duration of the episode. 
 
7.1.11. 
AECOPDs definitions and calculation rules 
7.1.11.1. 
AECOPD definition (from clinical evaluation) 
Due to the sensitivity and specificity of the e-diary device, false alerts may occur, and 
exacerbations resulting in site visits may also occur without e-diary alert. Therefore, 
only unscheduled AECOPD visits with clinical confirmation of AECOPD (with or 
without associated signals) will be considered as AECOPD events in the primary 
analysis.  
 
In addition, missed AECOPD visits may have occurred and can be: 
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- 
a signal from the e-diary (PHT) without a site visit but that cannot be 
discounted as a possible exacerbation signal after reconciliation, 
and/or 
- 
an exacerbation  reported  retrospectively in the Safety database or medical 
records for which there has not been in the same period of retrospective 
reporting a corresponding exacerbation visit declared. 
 
7.1.11.2. 
Characterization of inconsistencies between morning e-diary signals 
and exacerbation site visits 
The reconciliation between morning e-diary (PHT) signals and site visits for exacerbation 
will aim at characterizing the following 2 cases: 
Case A : an e-diary alert with absent/delayed exacerbation visit (i.e. no exacerbation visit 
within the calculated length of the e-diary episode) 
Case B : a exacerbation visit with absent/delayed e-diary exacerbation alert (i.e. RDE 
exacerbation not within e-diary exacerbation period) 
 
The different reasons of inconsistencies of Case A will be categorized by the site after 
review according to the following explanation: 
1) Not an exacerbation after further evaluation : eg. when a patient does not feel well but 
this is due to increased exercise, or patient does not feel well but this is not clinically 
significant. 
2) Ongoing exacerbation : e.g., previous exacerbation is not terminated according to the 
clinician. 
3) RDE or other technical issues: e.g., due to technical issues e-diary alerts were not sent 
and when the site was aware of it was too late to determine whether this was an 
exacerbation or not. 
4) Other reasons: specify : e.g. subject was on holidays / subject unable to visit the site / 
delayed RDE visit/early RDE entry. 
 
The different reasons of inconsistencies of Case B will be categorized by the site after 
review according to the following explanation: 
5) Spontaneous visit clinically deemed exacerbating i.e. exacerbation visit took place 
before the e-diary alert (spontaneous visit, visit triggered by GP / Patient call asked to be 
seen/ felt too unwell to complete e-diary abrupt onset) 
6) Planned monthly visit clinically deemed exacerbating 
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7) e-diary diary card recording issue or other technical issues : e.g. late e-diary alerts, 
subject missed or did not correctly record diary card, broken log pad device. 
8) Other reasons: specify 
For a Case A, no laboratory data has been collected, but if the answer about the 
inconsistency is 3) or sometimes 4) (depending on the specification), it will qualify as 
AECOPD. All Cases B will be considered to be an AECOPD if the AECOPD is 
confirmed by the site. 
7.1.12. 
Grading of severity of an exacerbation 
Severity of exacerbations is defined as (Protocol Section 5.3.1.2): 
• Mild: Worsening symptoms of COPD that are self-managed by the patient. 
• Moderate: Worsening symptoms of COPD that require treatment with oral 
corticosteroids and/or antibiotics. 
• Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalisation or home care intervention. 
 
Severity of the exacerbation will not be derived but taken directly from the information 
entered in the CRF. 
7.2. 
Data presentation description 
The following decimal description will be used for the demography and safety/ 
reactogenicity. 
 
Display Table 
Parameters 
Number of decimal 
digits 
All summaries 
% of count, including LL & UL of CI 
1 
All summaries 
% of difference, including LL & UL of CI 
2 
Demographic characteristics 
Mean, median age 
1 
Demographic characteristics 
SD (age) 
2 
Immunogenicity   
GMT ratio 
2 
The following data presentation description will be used for the immunogenicity 
analyses. 
Component 
GMC/T 
Assay 
Assay cut-
off 
Number of decimal 
digits 
Tick marks on 
RCC's 
GMC/T 
GMC/T 
ratio 
method 
Unit 
 
Low 
value 
High 
value 
Anti-PD 
GMC 
ELISA 
EL.U/mL 
100 
1 
2 
1 
10000 
Anti-PE 
GMC 
ELISA 
EL.U/mL 
8 
1 
2 
1 
10000 
Anti-PilA 
GMC 
ELISA 
EL.U/mL 
7 
1 
2 
1 
10000 
 
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8. 
CONDUCT OF ANALYSES 
8.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
• 
The analysis of data up to Visit 6 (Day 90) will be performed in a first step. This 
analysis will include: 
− 
The final analysis of immunogenicity and solicited AEs post-Dose 1 and post-
Dose 2.  
− 
The assessment of unsolicited AEs, SAEs and pIMDs up to 30 days post-Dose 1 
and post-Dose 2 on as cleaned as possible data.  
This analysis will be documented in a statistical report. At this point, the GSK 
statistician of the project (or delegates) will be unblinded (i.e. will have access to the 
individual subject treatment assignments). 
• 
The final analysis of data up to study conclusion will be performed in a second step, 
once those data will be available and cleaned. This analysis will include: 
− 
The final analysis of immunogenicity at Day 270 and Day 450. 
− 
SAEs and pIMDs up to Day 450 on cleaned data. 
− 
Impact of the investigational vaccine on AECOPD, HRQOL, lung function, 
exercise capacity and biomarkers. 
In addition, all previous analyses will be re-produced based on cleaned data at this 
point. 
Individual listings will only be provided at this stage. A final study report containing 
data from the entire study will be written and will be made available to the 
investigators. 
Description 
Analysis ID  
(SDD & CARS sub-folder) 
Analysis up to Visit 6 (Day 90) 
E1_06 
Final analysis (up to day 450) 
E1_01 
 
8.2. 
Statistical considerations for interim analyses 
Not applicable. 
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9. 
CHANGES FROM PLANNED ANALYSES 
As during the study, some subjects have completed wrong diary cards (paediatric ones 
instead of adults), a sensitivity analysis will be done on subjects that have completed the 
correct diary cards to be sure that they were no impact on results. 
10. 
REFERENCES 
The exact 95% CIs for a proportion within a group will be calculated from Proc StatXact 
[Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
binomial. Biometrika. 1934;26:404-413]. 
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Detailed Title: 
A Phase II, randomised, observer-blind, placebo-
controlled, multi-centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals’ investigational vaccine GSK2838504A, 
when administered intramuscularly according to a 0, 2 
month schedule to COPD patients aged 40 to 80 years 
SAP version 
Amendment 1 
SAP date 
27-JUN-2016 
Scope: 
All data pertaining to the above study.  
Co-ordinating author: 
 
Other author(s): 
 
Adhoc reviewers: 
, Global Regulatory Lead (RA) 
, Project Leader 
, CLS Clinical Read-Out Team 
Leader 
, 
, 
Safety Representatives 
CTRS team 
Approved by: 
, Clinical and Epidemiology 
Project Lead 
, Clinical Research & Development 
Lead 
, Lead Statistician 
, Scientific Writer 
, Statistician 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 4 
1. 
DOCUMENT HISTORY ............................................................................................ 7 
2. 
STUDY DESIGN ...................................................................................................... 8 
3. 
OBJECTIVES ........................................................................................................... 9 
3.1. 
Primary objective .......................................................................................... 9 
3.2. 
Secondary objective ..................................................................................... 9 
3.3. 
Tertiary objectives ......................................................................................... 9 
4. 
ENDPOINTS ............................................................................................................ 9 
4.1. 
Primary endpoints ......................................................................................... 9 
4.2. 
Secondary endpoints .................................................................................. 10 
4.3. 
Tertiary endpoints ....................................................................................... 10 
5. 
STUDY POPULATION ........................................................................................... 11 
5.1. 
Total vaccinated cohort ............................................................................... 11 
5.2. 
ATP cohort for analysis of immunogenicity ................................................. 11 
5.3. 
ATP cohort for analysis of persistence of immunogenicity .......................... 12 
5.4. 
ATP cohort for analysis of efficacy .............................................................. 12 
6. 
STATISTICAL METHODS ...................................................................................... 13 
6.1. 
Analysis of demographics ........................................................................... 13 
6.1.1. 
Analysis of safety ......................................................................... 13 
6.1.2. 
Analysis of immunogenicity .......................................................... 15 
6.1.3. 
Analysis of impact of the investigational vaccine on 
AECOPD incidence ..................................................................... 16 
6.1.4. 
AECOPD visits and daily questionnaires...................................... 18 
6.1.5. 
Analysis of HRQOL, lung capacity and exercise capacity ............ 18 
6.1.6. 
Analysis of selected biomarkers ................................................... 18 
6.1.7. 
Analysis of sputum ....................................................................... 19 
6.1.7.1. 
Sputum sample collection and quality ......................... 19 
6.1.7.2. 
Sputum bacterial/viral results from culture or 
from PCR ................................................................... 19 
6.1.7.3. 
Impact of previous antibiotic administration on 
sputum bacterial results .............................................. 20 
6.1.7.4. 
Impact of induction of sample on sputum 
bacterial results .......................................................... 20 
6.1.7.5. 
Impact of previous occurrence of Hi bacterial 
pathogen in sputum on AECOPDs ............................. 20 
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7. 
STATISTICAL CALCULATIONS ............................................................................ 20 
7.1. 
Derived and transformed data ..................................................................... 20 
7.1.1. 
Demography ................................................................................ 20 
7.1.2. 
Safety .......................................................................................... 21 
7.1.3. 
Immunogenicity ............................................................................ 21 
7.1.4. 
NTHi associated AECOPD........................................................... 23 
7.1.5. 
HRQOL ........................................................................................ 23 
7.1.6. 
EXACT-PRO derived AECOPD definitions and calculation 
rules ............................................................................................. 23 
7.1.7. 
“e-diary derived AECOPD” definitions and calculation 
rules ............................................................................................. 24 
7.1.8. 
End/Duration of an e-diary signal of an exacerbation: .................. 24 
7.1.9. 
Time between 2 e-diary signals for 
exacerbations/evaluation of baseline symptom score: ................. 25 
7.1.10. 
Missing data ................................................................................ 25 
7.1.11. 
AECOPDs definitions and calculation rules .................................. 26 
7.1.11.1. AECOPD definition (from clinical evaluation) .............. 26 
7.1.11.2. Characterization of inconsistencies between 
morning e-diary signals and exacerbation site 
visits ........................................................................... 26 
7.1.12. 
Grading of severity of an exacerbation ......................................... 27 
7.1.13. 
Sputum Quality ............................................................................ 28 
7.2. 
Data presentation description ..................................................................... 28 
8. 
CONDUCT OF ANALYSES .................................................................................... 28 
8.1. 
Sequence of analyses ................................................................................. 28 
8.2. 
Statistical considerations for interim analyses ............................................. 29 
9. 
CHANGES FROM PLANNED ANALYSES ............................................................. 30 
10. REFERENCES ....................................................................................................... 30 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AECOPD 
Acute exacerbation of COPD 
ALT 
Alanine aminotransferase 
ATP 
According-To-Protocol 
ANCOVA 
Analysis of covariance 
CAT 
COPD assessment test 
CI 
Confidence Interval 
CMI 
Cell-mediated immunity 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case Report Form 
CTRS 
Clinical Trial Registry 
EF 
Internal GSK database code for Efficacy analysis (elimination 
codes) link to FORM-BIO-CLIN-9004-05 Criteria for eliminating 
subjects from the analyses 
EL.U/ml 
ELISA unit per milliliter 
ELISA 
Enzyme-linked immunosorbent assay 
Eli Type 
Internal GSK database code for type of elimination code 
EXACT-PRO 
EXAcerbations of Chronic Pulmonary Disease Tool - Patient 
Reported Outcome 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
FU 
Internal GSK database code for Follow-up analysis (elimination 
codes) link to FORM-BIO-CLIN-9004-05 Criteria for eliminating 
subjects from the analyses 
GMC 
Geometric mean antibody concentration 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
H. influenzae 
Haemophilus influenzae 
HRQOL 
Health-Related Quality of Life 
ICF 
Informed consent form 
ICS 
Intracellular cytokine staining 
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IU/ml 
International units per milliliter 
LL 
Lower Limit of the confidence interval 
MA 
Internal GSK database code for Main analysis (elimination codes) 
link to FORM-BIO-CLIN-9004-05 Criteria for eliminating subjects 
from the analyses 
MATEX 
MATerial EXcellence 
M. catarrhalis 
Moraxella catarrhalis 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMRC scale 
mMRC scale 
N.A. 
Not Applicable 
NTHi 
Non-Typeable Haemophilus influenzae 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Protein D 
PE 
Protein E 
PI 
Prescribing information 
PilA 
Type IV pili subunit of non-typeable Haemophilus influenzae 
pIMD 
Potential immune-mediated disease 
PT 
Preferred term 
SAE 
Serious adverse event 
S. aureus 
Staphylococcus aureus 
SAP 
Statistical Analysis Plan 
SBIR 
GSK Biological’s Internet Randomization System 
SD 
Standard Deviation 
SR 
Study Report 
STGG 
Skim milk, tryptone, glucose, and glycerin transport medium 
SYN 
Synopsis 
TFL 
Tables Figures and Listing template annexed to SAP 
TVC 
Total vaccinated cohort 
UL 
Upper Limit of the confidence interval 
VE 
Vaccine efficacy 
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6MWT 
6-Minute Walk Test 
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The complete statistical analysis plan and results presentation is divided into 2 parts: the 
first part detailing the analyses to be performed (known as SAP, current document) and a 
second part, annex (-es) (called TFL) describing the flow and format of tables, figures 
and listings to be annexed to the SR. 
1. 
DOCUMENT HISTORY 
Date 
Description 
Protocol Version 
29-JAN-2016 
Version 1 
Amendment 2 - 15-DEC-2014 
21-JUN-2016 
Amendment 1 
In order to see early effects of the vaccine on 
the microbiome, analysis on fresh sputum 
samples (culture results) will be done on all 
available data up to the data lock point of the 
interim analysis.  
In order to have a first look whether or not the 
investigational vaccine has an impact on 
AECOPD, AECOPD analyses will be done up 
to the data lock point of the interim analysis 
Amendment 3 - 15-APR-2016 
 
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2. 
STUDY DESIGN 
Figure 1 
Study design overview 
 
Experimental design: Phase II randomised, observer-blind, placebo-controlled, multi-
centre study with 2 parallel groups. 
Duration of the study: for each subject enrolled, the study will last approximately 
16 months from Visit 1 up to study end 
The following group names will be used for the statistical analyses: 
Group order 
in tables 
Group label in tables 
Group definition for footnote 
1 
10-AS01E 
2 doses of AS01e adjuvanted vaccine containing 
10 mcg of each antigen 
2 
Control 
2 doses of saline solution 
 
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3. 
OBJECTIVES 
3.1. 
Primary objective 
• 
To describe the safety and reactogenicity of the investigational vaccine.  
3.2. 
Secondary objective 
• 
To describe the humoral and cellular immunogenicity of the investigational vaccine.  
3.3. 
Tertiary objectives 
• 
To explore the impact of the investigational vaccine on AECOPD.  
• 
To explore the impact of the investigational vaccine on NTHi presence in sputum. 
• 
To explore the impact of the investigational vaccine on health-related quality of life 
(HRQOL).  
• 
To explore the impact of the investigational vaccine on lung function.  
• 
To explore the impact of the investigational NTHi vaccine on exercise capacity. 
• 
To describe selected biomarkers in stable COPD and during AECOPD.  
• 
To collect blood and sputum samples for assay development, for disease diagnostic 
purpose, for lung microbiome analysis and/ or for additional evaluation of the 
immune responses to the investigational vaccine and to other potential pathogens 
involved in AECOPD.  
4. 
ENDPOINTS 
4.1. 
Primary endpoints 
• 
Occurrence of each solicited local adverse event (AE), during the 7-day follow-up 
period (i.e. day 0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of each solicited general AE, during the 7-day follow-up period (i.e. day 
0 - 6) following each vaccination, in all subjects. 
• 
Occurrence of any unsolicited AE, during the 30-day follow-up period (i.e. day 0 - 
29) following each vaccination, in all subjects. 
• 
Occurrence of each haematological/ biochemical laboratory abnormality at Day 0, 
Day 7, Day 30, Day 60, Day 67, Day 90, Day 270 and Day 450, in all subjects. 
• 
Occurrence of any potential immune-mediated disease (pIMD) from first vaccination 
up to study conclusion, in all subjects. 
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• 
Occurrence of any serious adverse event (SAE) from first vaccination up to study 
conclusion, in all subjects. 
4.2. 
Secondary endpoints 
• 
Anti-PD, anti-PE and anti-PilA total IgG antibody concentrations as measured by 
ELISA, at Day 0, Day 30, Day 60, Day 90, Day 270 and at Day 450, in all subjects. 
• 
NTHi-specific cell-mediated immune responses as measured by flow cytometry 
intracellular cytokine staining (ICS) (frequency of specific CD4+/CD8+ T-cells 
expressing two or more markers, such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and 
CD40L), at Day 0, Day 90, Day 270 and at Day 450, in a sub-cohort of subjects. 
4.3. 
Tertiary endpoints 
• 
Number of cases of NTHi-associated moderate and severe AECOPD, over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of NTHi-associated AECOPD (any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of moderate and severe AECOPD (any cause), over a period 
starting 1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Number of cases of AECOPD (any cause, any severity), over a period starting 
1 month post-Dose 2 and lasting for 1 year, in all subjects. 
• 
Time to first AECOPD, in all subjects. 
• 
Assessment of EXACT-PRO score, daily at bedtime throughout the study, in all 
subjects. 
• 
NTHi presence in sputum, at Screening, Day 90, Day 180, Day 270, Day 360 and 
Day 450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
• 
Assessment of CAT score, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Assessment of SGRQ-C score, at Screening, Day 270 and Day 450, in all subjects. 
• 
Assessment of mMRC scale, at Screening, Day 270 and Day 450, and from first 
vaccination to study conclusion for each AECOPD, in all subjects. 
• 
Occurrence of rescue medication use, over a period starting 1 month post-Dose 2 and 
lasting for 1 year, in all subjects. 
• 
Occurrence of healthcare use for AECOPD, over a period starting 1 month post-Dose 
2 and lasting for 1 year, in all subjects. 
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• 
Assessment of FEV1% of predicted normal value at Screening, Day 270 and 
Day 450, in all subjects. 
• 
Assessment of 6MWT score, at Screening and Day 450, in all subjects. 
• 
Occurrence of selected biomarkers in a subset of blood samples, at Day 0 and Day 
450, and from first vaccination to study conclusion for each AECOPD, in all 
subjects. 
• 
Presence of respiratory viral pathogens in sputum (including respiratory syncytial 
virus, parainfluenza virus, enterovirus/ rhinovirus, metapneumovirus, influenza virus, 
adenovirus, bocavirus and coronavirus) at Screening, Day 90, Day 180, Day 270, 
Visit Day 360 and Day 450 and at each AECOPD visit from first vaccination to 
study conclusion, in all subjects.  
5. 
 STUDY POPULATION 
The following study cohorts will be evaluated. 
5.1. 
Total vaccinated cohort 
The Total vaccinated cohort (TVC) will include all subjects with at least 1 study vaccine 
administration documented: 
• 
A safety analysis based on the TVC will include all vaccinated subjects. 
• 
An immunogenicity/ efficacy analysis based on the TVC will include all vaccinated 
subjects for whom immunogenicity/ efficacy data are available. 
The TVC analysis will be performed per treatment actually administered at Dose 1. 
5.2. 
ATP cohort for analysis of immunogenicity 
The ATP cohort for immunogenicity will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule. 
• 
Who received the study vaccines according to protocol procedures. 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity up to the 1 month post-Dose 2 visit (Day 90). 
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• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity up to the 1 month post-Dose 2 visit (Day 
90). 
• 
Who complied with the blood sample timings, at the 1 month post-Dose 2 visit (Day 
90). 
• 
For whom post-vaccination immunogenicity results are available for at least 1 assay. 
5.3. 
ATP cohort for analysis of persistence of immunogenicity 
The ATP cohort for persistence of immunogenicity (starting at Day 180) will include all 
evaluable subjects, i.e., those who were included in the ATP cohort for immunogenicity, 
or were excluded from this cohort solely because they had no blood samples taken or 
because of incompliance with blood sample timings up to the 1 month post-Dose 2 visit, 
and: 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the ATP analysis for immunogenicity. 
• 
Who did not present with an intercurrent medical condition leading to elimination 
from the ATP analysis for immunogenicity. 
• 
Who complied with the blood sample timings after the 1 month post-last vaccination 
visit. 
• 
For whom persistence immunogenicity results are available for at least 1 assay. 
5.4. 
ATP cohort for analysis of efficacy 
The ATP cohort for analysis of efficacy will include all subjects in the TVC: 
• 
Who met all eligibility criteria. 
• 
For whom the administration route and site of the vaccines was according to 
protocol. 
• 
Who complied with the vaccination schedule 
• 
Who received the study vaccine according to protocol procedures. 
• 
Not having received a medication/ product/ vaccine that may lead to elimination 
from the ATP analysis for efficacy. 
The list of applicable elimination codes for each cohort can be found in the study specific 
form FORM-BIO-CLIN-9004-05 Criteria for eliminating subjects from the analyses. 
Cohort 
Elimination codes 
Eli Type 
ATP cohort for analysis of immunogenicity 
1010-2500 
MA 
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ATP cohort for analysis of efficacy 
1010-2500 
EF 
ATP cohort for analysis of persistence of 
immunogenicity 
1010-2500 
FU 
 
6. 
STATISTICAL METHODS 
6.1. 
Analysis of demographics 
Demographic characteristics (age at the first dose in years, gender and geographical 
ancestry), cohort description and other characteristics such as smoking/exposure history 
status, pulmonary function test baseline results and COPD history, history of 
exacerbation present/past medical history/intercurrent morbidity, and previous 
vaccination with a pneumococcal vaccine or an influenza vaccine will be summarized by 
group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as geographical 
ancestry; 
• 
Mean, median and standard error will be provided for continuous data such as age. 
Other characteristics such as height, weight, BMI selected results and several risk factors 
from the six-minutes-walk test, and distribution of several severity stages using CAT or 
mMRC or SGRQ-C at enrolment visit will also be summarized. 
The number of subjects enrolled into the study as well as the number of subjects excluded 
from ATP analyses will be tabulated. 
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per group. 
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal. 
Withdrawal status will be summarised by group using descriptive statistics: 
6.1.1. 
Analysis of safety 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
The percentage of subjects with at least one local AE (solicited and unsolicited), with at 
least one general AE (solicited and unsolicited) and with any AE during the 7-day (day 0 
– day 6) or the 30-day (day 0 – day 29) follow-up period will be tabulated after each 
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vaccination and overall with exact 95% confidence interval (CI). The same computations 
will be done for Grade 3 AEs, for related AEs and for Grade 3 related AEs.  
The percentage of subjects/doses reporting each individual solicited local (any grade, 
Grade 3) and general (any grade, Grade 3, related, Grade 3 related) AE during the 7-day 
(day 0 to day 6) follow-up period will be tabulated for each group as follows: 
• 
Overall, the percentage of subjects with the symptom and its exact 95% CI. 
• 
Overall, the percentage of doses with the symptom and its exact 95% CI. 
• 
Per study vaccine dose, the percentage of subjects with the symptom and its exact 
95% CI. 
The exact 95% CIs will be calculated assuming independence between doses. For fever, 
additional analyses will be performed by 0.5°C increments.  
As during the study, some subjects have completed wrong diary cards (paediatric ones 
instead of adults), a sensitivity analysis will be done on subjects that have completed the 
correct diary cards to be sure that they were no impact on results. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
preferred term (PT). The percentage of subjects with unsolicited symptoms during the 
30-day follow-up period after any study vaccine dose with its exact 95% CI will be 
tabulated by group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms, for unsolicited symptoms that 
resulted in a medically attended visit, for Grade 3 and causally related unsolicited 
symptoms and for unsolicited symptoms causally related to vaccination. 
For each group and for each haematology/ biochemistry parameter: 
• 
The percentage of subjects having results below or above the local laboratory normal 
ranges will be tabulated by time point. 
• 
The maximum grading from Screening up to study conclusion will be tabulated. 
Grades will be based on the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials” (see Appendix C of the protocol). 
The number of subjects who experienced any pIMD or any SAE from from first 
vaccination up to 6 months post-Dose 2 will be reported will be reported. 
The number of subjects who experienced any AE leading to study withdrawal, from 
first vaccination up to study conclusion, or any SAE related to study participation of 
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concurrent GSK medication/ vaccination, during the entire study period, will be 
reported. 
Pregnancy reports from first vaccination up to 6 months after last vaccination and 
pregnancy outcomes will be described in detail. 
The percentage of subjects/ dose using concomitant medication/ product (any 
medication/ product, any antipyretic and any antipyretic taken prophylactically, 
respectively) during the 7-day follow-up period (day 0 – day 6) and during the 30-day 
follow-up period (day 0 – day 29) will be summarised per group for each dose and 
overall per dose. 
6.1.2. 
Analysis of immunogenicity 
The analysis will be performed on the ATP cohort for immunogenicity. If the percentage 
of vaccinated subjects with serological results excluded from the ATP cohort for analysis 
of immunogenicity is more than 10%, a second analysis will be performed on the TVC. 
Humoral immune response 
Within group evaluation 
For each group, at each time point during which blood samples are collected for humoral 
immune response and for each assay: 
• 
Seropositivity rate and their exact 95% CI will be tabulated. 
• 
GMCs and their 95% CI will be calculated. 
For each group, at each time point during which blood samples are collected for humoral 
immune response: 
• 
Antibody concentrations distribution will be investigated using Reverse Cumulative 
Curves. 
Between groups evaluation 
Comparative analyses will be exploratory with the aim to characterise the difference 
between the 2 groups in humoral immune response. 
The difference in terms of GMCs will be evaluated at 1 month post-Dose 2 and at Day 
450 by computing the 95% CIs of the GMC ratio between groups by using an ANCOVA 
model  that considers heterogeneity of variances (via Proc Mixed) on the logarithm10 
transformation of the concentrations. This model will include the country, the group, age 
category (40 - 59 years or 60 - 80 years), number of moderate and severe AECOPD in the 
year before vaccine Dose 1 (< 2 or ≥ 2), GOLD grade (GOLD 2 or GOLD 3) and pre-
Dose 1 concentration (as covariate) as fixed effects. 
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However, these differences should be interpreted with caution considering that there will 
be no adjustment for multiplicity of endpoints. 
Cell-mediated immune response 
The frequency of specific CD4+/ CD8+ T-cells will be summarised (mean, SD, minimum, 
Q1, median, Q3, and maximum) by group, at each time point during which blood samples 
are collected for CMI (descriptive statistics).  
Each data will be obtained by subtracting the summary of the background value to each 
summary value. Values less than or equal to zero will be set to 1 for the purpose of 
geometric mean calculation and graphical representation. 
6.1.3. 
Analysis of impact of the investigational vaccine on AECOPD 
incidence 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is more than 10%, a 
second analysis based on the TVC will be performed to complement the first analysis. 
The following incidence rates will be computed over a period starting 1 month 
post-Dose 2 and lasting for 1 year, with 95%CI: 
• 
NTHi-associated moderate and severe AECOPD. (See definition in section 7.1.4) 
• 
NTHi-associated all-severity AECOPD. 
• 
All-cause moderate and severe AECOPD. 
• 
All-cause, all-severity AECOPD. 
Vaccine efficacy (VE) for AECOPD events will be defined as: 
VE (AECOPD) = 1 - Rvaccine / Rcontrol 
with: 
• 
Rvaccine = average yearly incidence rate of AECOPD events per subject in the group 
10-AS01E. 
• 
Rcontrol = average yearly incidence rate of AECOPD events per subject in the Control 
group. 
In case the 95% CI of the VE cannot be estimated, e.g. when no event is observed in the 
group 10-AS01E (leading to a VE of 100%), then an exact procedure will be used to 
estimate a VE and its 95% CI. This exact procedure will be based on the number of 
subjects with event instead of on the average number of event per subject in each group. 
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VE in the prevention of NTHi-associated moderate and severe AECOPD and its 95% CI 
will be calculated.  
VE in the prevention of NTHi-associated all-severity AECOPD, of all-cause moderate 
and severe AECOPD and of all-cause, all-severity AECOPD and their 95% CI will also 
be calculated. 
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. In addition, the following covariates 
(as per randomization) will be taken into account: 
 
- 
country, 
- 
number of moderate/severe exacerbations reported in the 12 months prior to 
enrolment,  
- 
COPD status at enrolment (derived by GSK from the Visit 1 spirometry results) 
- 
Age (below or equal to median/above median) 
 
If the model does not converge, the Poisson distribution will be used instead of the 
Negative Binomial one. 
The frequency of all these AECOPDs will be presented. The estimated incidence rate 
with 95%CI of AECOPDs in which Hi (resp. Mcat, Sp) is present in culture and was not 
present in the previous visit estimated by a Generalised linear model assuming the 
Negative Binomial distribution will be estimated.  
 
Time to first AECOPD event by baseline status - Cox regression model 
The Cox’s regression model including the risk factors:   
- 
country,  
- 
number of moderate/severe exacerbations reported in the 12 months prior to 
enrolment,  
- 
COPD status at enrolment (derived by GSK from the Visit 1 spirometry results) 
- 
Age (below or equal to median/above median) 
as covariates (as per randomization) will be performed to model the time until the first 
occurrence of AECOPD episodes. Additional stratification/risk factor may be defined 
during the analyses like sex factor as exploratory analysis. 
 
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6.1.4. 
AECOPD visits and daily questionnaires 
The time until first AECOPD as of 1 month post-Dose 2 will be computed with exact 
95% CI by group. Subjects who exacerbate before 1 month post-Dose 2 will not be taken 
into account in this analysis.  
The number of morning e-dairy (PHT) alerts (resp. evening e-diary alerts (EXACT-
PRO)) with and without corresponding site visits will be tabulated. The reason for 
inconsistency between morning e-diaries and site visits will also be presented. 
The number of exacerbation site visits with confirmed AECOPD with and without 
morning e-diary alerts (resp. evening e-diary alerts (EXACT-PRO) will be tabulated 
along with the reason for no e-diary alert. 
Concordance/discordance of exacerbations periods as defined clinically or via the 
morning diary cards or the evening diary cards will tabulated and presented graphically. 
The percentage of spontaneous exacerbation visits will be tabulated as well as the 
percentage of monthly visits with recovered/stable status. 
6.1.5. 
Analysis of HRQOL, lung capacity and exercise capacity 
The analysis will be performed on the TVC. If the percentage of vaccinated subjects 
excluded from the ATP cohort for efficacy is at least 10%, a second analysis will be 
performed on the ATP cohort for efficacy to complement the first analysis. 
Descriptive statistics (median, mean, range, standard deviation, first and third quartiles) 
on the EXACT-PRO, CAT, SGRQ-C and mMRC scores, on FEV1% of predicted 
normal value and on the 6MWT scores will be tabulated by specified visit. 
Descriptive summaries rescue medication and healthcare use for AECOPD will be 
provided. 
6.1.6. 
Analysis of selected biomarkers 
The analysis will be performed on the ATP cohort for efficacy. If the percentage of 
vaccinated subjects excluded from the ATP cohort for efficacy is at least 10%, a second 
analysis will be performed on the TVC to complement the first analysis. 
For each type of timepoint (Pre, Exacerbation visit, Day 450) during which blood 
samples are collected for analysis of biomarkers, descriptive statistics will be tabulated 
for each selected biomarker. 
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6.1.7. 
Analysis of sputum 
The analysis will be performed: 
- 
By aggregating all laboratory sites where the sputum was tested  
- 
By laboratory site in order to evaluate if differences exist in the way of testing 
sputum 
- 
By country (aggregating all laboratory sites by country). 
6.1.7.1. 
Sputum sample collection and quality 
The proportion of subjects (at each stable and exacerbation visit) who provided a sputum 
sample will be computed; overall and by the sample method (spontaneous or induced). 
 
The proportion of sputum of good quality will be computed. 
 
The proportion of subjects with induced sputum will be tabulated by COPD status at 
enrolment and by severity of the AECOPD. 
 
The distribution of the time (in days) between the start of exacerbation and the day of the 
sputum sample collection will be presented. 
 
 
6.1.7.2. 
Sputum bacterial/viral results from culture or from PCR 
The distribution of the proportion of sputum samples positive given the number of days 
between start of exacerbation and sample collection will be presented. 
 
The proportion of sputum samples obtained at each - stable and exacerbation - visit and 
positive for specific bacterial/viral pathogens (overall and by bacterial culture, by 
bacterial PCR, or by viral species) will be computed. The average infection rate by type 
of visit will also be calculated. 
 
The bacterial presence in culture versus the bacterial presence in PCR detected in sputum 
will be tabulated. 
The viral infections versus the bacterial presence in PCR detected in sputum will be 
tabulated. 
 
The incidence of exacerbations and of exacerbations containing Hi, Mcat, Sp, and all 
bacterial and/or virus that are planned to be tested by the laboratory will be presented. 
 
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For specific bacterial pathogens, the quantitative assessment of PCR results will be 
provided overall, for sputum samples positive in culture, or negative in culture of the 
specific pathogen. 
 
The same analyses should be performed by taking into account only the sputum that has a 
good quality. 
 
6.1.7.3. 
Impact of previous antibiotic administration on sputum bacterial 
results 
The impact of antibiotic administration before sputum collection on the bactericidal 
culture or PCR results will be evaluated, for stable (scheduled) visits, exacerbation visits, 
or any visit. 
 
6.1.7.4. 
Impact of induction of sample on sputum bacterial results 
The impact of sputum induction on the bactericidal culture or PCR results will be 
evaluated, for stable (scheduled) visits, exacerbation visits, or any visit. 
 
6.1.7.5. 
Impact of previous occurrence of Hi bacterial pathogen in sputum on 
AECOPDs 
The impact of the occurrence or presence of respiratory pathogenic bacteria detected in 
sputum at the exacerbation visit given the presence of the bacteria at previous visits on 
the number of exacerbations will also be studied. In order to do this, 2 types of 
AECOPDs will be distinguished: 
- 
AECOPDs in which Hi is present and was not present any previous visit 
- 
AECOPDs in which Hi is present and was not present in the previous stable visit; 
7. 
STATISTICAL CALCULATIONS 
7.1. 
Derived and transformed data 
The study groups will be defined by treatment actually administered at Dose 1. 
7.1.1. 
Demography 
• 
For a given subject and a given demographic variable, missing measurement will not 
be replaced. 
• Age: Age at the reference activity, computed as the number of units between the date 
of birth and the reference activity In case of partial dates of any of these 2 dates: 
- 
15th of month, If only the day is missing 
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- 
30th of June, if day and months are missing 
7.1.2. 
Safety 
• 
For solicited symptoms, the analysis will exclude subjects with missing or 
un-evaluable measurements (i.e. total analysis of solicited symptoms will include all 
vaccinated subjects with documented solicited symptom sheets).  
• 
For the unsolicited symptoms and concomitant medications/ products/ vaccinations, 
subjects who miss reporting symptoms/concomitant medications/ products/ 
vaccinations will be treated as subjects without unsolicited symptoms or concomitant 
medications/ products/ vaccinations, respectively. 
• 
Note that for all tables described in this section, the way the percentage of subjects 
will be derived will depend on the event analysed (see table below for details). As a 
result, the N value will differ from one table to another. 
Event 
N used for deriving % per subject  
Concomitant vaccination 
All subjects with study vaccine administered 
Solicited general symptom 
All subjects with at least one solicited general symptom documented as either 
present or absent (i.e. symptom screen completed) 
Solicited local symptom 
All subjects with at least one solicited local symptom documented as either 
present or absent (i.e. symptom screen completed) 
Unsolicited symptom 
All subjects with study vaccine administered  
Concomitant medication 
All subjects with study vaccine administered  
 
7.1.3. 
Immunogenicity 
• 
For a given subject and the analysis of a given immunogenicity measurement, 
missing or un-evaluable measurements will not be replaced. 
• 
A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value. 
• 
A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value.  
• 
Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of geometric mean concentration (GMC) 
calculation. 
• 
Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration transformations. 
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• The assay cut-off is the value under which there is no quantifiable result for which no 
accuracy and precision can be reported. For an assay with a specific ‘cut_off’ , 
numerical immuno result is derived from a character field (rawres): 
- 
If rawres is ‘NEG’ or ‘-’ or ‘(-)’, numeric result= cutt_off/2, 
- 
if rawres is ‘POS’ or ‘+’ or ‘(+)’, numeric result = cut_off, 
- 
if rawres is ‘< value’ and value<=cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘< value’ and value>cut_off, numeric result =value, 
- 
if rawres is ‘> value’ and value<cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘> value’ and value>=cut_off, numeric result =value, 
- 
if rawres is ‘<= value’ or ‘>= value’ and value<cut_off, numeric result =cut_off/2, 
- 
if rawres is ‘<= value’ or ‘>= value’ and value>=cut_off, numeric result =value, 
- 
if rawres is a value < cut_off, numeric result = cut_off/2, 
- 
if rawres is a value >= cut_off, numeric result = rawres, 
- 
else numeric result is left blank. 
 
• All CI computed will be two-sided 95% CI. 
Impact of the investigational vaccine on AECOPD  
• 
For a given subject and the analysis of a given laboratory assay, missing or 
un-evaluable measurements will not be replaced. 
• 
Subjects who did not have any sputum collected during at least 1 AECOPD (if at 
least 1 AECOPD occurred) will not be taken into account for the NTHI-associated 
AECOPD analyses. 
• 
For summaries of the number of AECOPD occurring during the 1 year follow-up 
period starting 1 month post-Dose 2, an exacerbation rate will be calculated for each 
subject. The number of exacerbations during the 1-year follow-up period will be 
imputed for subjects withdrawing from the study to provide an estimate of the 
number of exacerbations over the follow-up period. This calculation will only be 
performed for purposes of reporting summary statistics for the rate of exacerbations 
during the 1 year follow-up period since the modelling of exacerbations takes into 
account the number of exacerbations and the time of follow-up for each subject. The 
calculation of exacerbation rate will be based on follow-up period intervals to avoid 
obtaining high imputed rates if a subject withdrew very early in the follow-up period 
after experiencing an exacerbation. Since treatment courses for moderate/severe 
exacerbations are ≤ 2 - 4 weeks when appropriate, calculated numbers of 
exacerbations for subjects withdrawing from the study will be based on 4-week 
intervals of the follow-up period. For subjects followed for less than 1 year, the 
number of exacerbations during the 1-year follow-up period will be calculated by 
multiplying the number of exacerbations experienced by the subject by 13 and 
dividing by the number of 4-week periods the subject was followed up:  
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Number of exacerbations per year = Number of exacerbations * 13 /Number of 
4-week treatment period intervals 
7.1.4. 
NTHi associated AECOPD 
An NTHI associated to AECOPD is not yet well defined at the time of the SAP is written. 
Here is the first approach:  
- 
An AECOPD for which NTHi was observed: Hi confirmed first by culture and 
then by PCR. 
7.1.5. 
HRQOL 
The CAT index will be derived as the sum of the ratings recorded for each of the eight 
individual items. Each of these items has 6 possible scores (0, 1, 2, 3, 4 or 5), leading to a 
range of 0 to 40 for CAT score. 
 
7.1.6. 
EXACT-PRO derived AECOPD definitions and calculation rules 
Start of an EXACT-PRO signal for exacerbation (as in EXACT-PRO user Manual and 
in Makay, et al., 2014): 
1. An EXACT-PRO exacerbation is defined as a 12 point increase above baseline for 
2 consecutive days, or a nine point increase for 3 consecutive days. 
2. The baseline score corresponds to the average EXACT score during a baseline 
period defined as days 14 to 8 preceding exacerbation onset 
3. Exacerbation onset will be taken as the first day in which at least two symptoms 
(at least 1 major) are present and have not been discounted (see above). 
4. Only symptom data collected during the study period will be used to define the 
start of an exacerbation. 
End/recovering of an EXACT-PRO signal of an exacerbation: 
1. The end/recovering of an EXACT-PRO signal of an exacerbation corresponds to 
the day at the EXACT-PRO score return to its baseline value.  
2. The length of a signal of an exacerbation will be at least of 2 days. So rule 1 will 
only apply from the third day onwards.  
Missing data: 
Days with missing data will not be ignored when defining start of a signal: e.g., if a 
patient has two qualifying symptoms followed by a missing day, if the next day with data 
has two qualifying symptoms this will not be defined as an exacerbation. 
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7.1.7. 
“e-diary derived AECOPD” definitions and calculation rules 
The definition of an AECOPD case definition from section 5.3.1.2 of the Protocol is what 
we will call here an “e-diary derived (AECOPD) signal”. In this paragraph, only the 
derivation of occurrence and length of e-diary signals is described. Derivation of 
occurrence and length of AECOPDs is described in Section 7.1.11. 
Start of an e-diary signal for exacerbation: 
1. An exacerbation is defined as a worsening of at least 2 symptoms for ≥ 2 
consecutive days where at least one of the symptoms is major.  
2. 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. 
3. Any symptom that has occurred consecutively for 5 days or more prior to a 
potential exacerbation should be discounted from the symptoms that define an 
exacerbation. 
4. Exacerbation onset will be taken as the first day in which at least two symptoms 
(at least 1 major) are present and have not been discounted (see above). 
5. Only symptom data collected during the study period will be used to define the 
start of an exacerbation. 
 
7.1.8. 
End/Duration of an e-diary signal of an exacerbation: 
1. The end/recovering of an e-diary signal of an exacerbation corresponds to 
the day at which the 3-day moving average of the daily symptom count score 
(average between the day the day before and the day after) to return to 
baseline symptom count score (the mean daily symptom count score over 
days 14 to 8 preceding exacerbation onset). For a specific day, the daily 
symptom count score is defined as the sum of the symptom scores 
experienced in this day (a major symptom accounts for 2 points, a minor 
symptom accounts for 1 point, as in Trappenburg et al., 2011, but contrary to 
Seemungal et al. 2000 and Mackay et al. 2014, in which all symptoms 
accounted to 1). Note that the symptoms that have occurred consecutively for 5 
days or more prior to a potential exacerbation and that are discarded for these 
exacerbations are not discarded from the symptoms counts. 
2. The length of an e-diary signal of an exacerbation will be at least of 2 days. So 
rule 1 will only apply from the third day onwards.  
3. The baseline symptom count score is calculated as the average count score of 
the observed days in the period used to calculate the baseline symptom count 
score. For example, if an exacerbation occurs from day 10 onwards, the 
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baseline period will be the average between day1 and day2 (day10 - 8 days= 
day2, day10 – 9 days = day1, Day1 being the first study day). For 
exacerbations before day 9 but after day 2, the baseline symptom score will 
be considered to be day1 
4. If the first e-diary signal of an exacerbation is occurring before day 3:  
duration will be counted until the day in which there is at most 2 majors or 1 
major and one minor symptom. 
5. Recovery time is calculated as the number of days from exacerbation e-diary 
signal onset (included) to exacerbation e-diary signal end (not included). 
 
7.1.9. 
Time between 2 e-diary signals for exacerbations/evaluation of 
baseline symptom score: 
The minimum duration between 2 e-diary signals with distinct baseline value is 15 days, 
which is the minimal period for which a new full exacerbation-free baseline can be 
calculated for the next e-diary episode. 
If a new worsening of symptoms occurs between 6 and 14 days of a previous 
exacerbation, the baseline period used will be the same baseline as the one of the original 
exacerbation. Therefore, it will last until the daily symptom count score has gone 
below the baseline symptom score of the previous event. 
7.1.10. 
Missing data 
1. Days with missing data will not be ignored when defining start of an e-diary signal: 
e.g., if a patient has two qualifying symptoms followed by a missing day, if the next 
day with data has two qualifying symptoms this will not be defined as an 
exacerbation. Hence, the start of an e-diary signal of an exacerbation will require 2 
consecutive non-missing days of worsening. If there is partially recorded symptom 
data at a visit, however, only the observed values will be considered but the day will 
not be discarded. 
2. Days with missing data will be ignored when defining end of an e-diary signal of an 
exacerbation: e.g., if a patient has two days missing in the baseline period and one 
day missing in the 3- day moving average, both baseline and 3-day moving average 
values will be calculated using observed data only. Similar rules will apply when 
there is partially recorded symptom data at a visit (and daily average values will be 
calculated among the observed values). 
3. All available data will be used for each patient. 
4. As a general rule, the baseline symptom count score, and 3 day moving averages 
are calculated as the average count score of the observed days in the baseline 
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period. For example, if an e-diary signal occurs from day 10 onwards, the 
baseline period will be the average between day1 and day2 (day1 being the first 
study day). If day 13 is missing, the 3 day moving average at day 14 will only 
take into account day 14 and day 15. 
5. If there are greater than 2 consecutive days of missing data after an e-diary signal 
not resolved, the e-diary signal will not be considered resolved until the next day 
with observed data if the corresponding moving average is below the baseline value. 
In order words, if the 3-day average daily score is missing, the day will be counted in 
the duration of the episode. 
 
7.1.11. 
AECOPDs definitions and calculation rules 
7.1.11.1. 
AECOPD definition (from clinical evaluation) 
Due to the sensitivity and specificity of the e-diary device, false alerts may occur, and 
exacerbations resulting in site visits may also occur without e-diary alert. Therefore, only 
unscheduled AECOPD visits with clinical confirmation of AECOPD (with or without 
associated signals) will be considered as AECOPD events in the primary analysis.  
 
In addition, missed AECOPD visits may have occurred and can be: 
- 
a signal from the e-diary (PHT) without a site visit but that cannot be discounted 
as a possible exacerbation signal after reconciliation, 
and/or 
- 
an exacerbation  reported  retrospectively in the Safety database or medical 
records for which there has not been in the same period of retrospective reporting 
a corresponding exacerbation visit declared. 
 
7.1.11.2. 
Characterization of inconsistencies between morning e-diary signals 
and exacerbation site visits 
The reconciliation between morning e-diary (PHT) signals and site visits for exacerbation 
will aim at characterizing the following 2 cases: 
Case A : an e-diary alert with absent/delayed exacerbation visit (i.e. no exacerbation visit 
within the calculated length of the e-diary episode) 
Case B : a exacerbation visit with absent/delayed e-diary exacerbation alert (i.e. RDE 
exacerbation not within e-diary exacerbation period) 
 
The different reasons of inconsistencies of Case A will be categorized by the site after 
review according to the following explanation: 
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1) Not an exacerbation after further evaluation : eg. when a patient does not feel well but 
this is due to increased exercise, or patient does not feel well but this is not clinically 
significant. 
2) Ongoing exacerbation : e.g., previous exacerbation is not terminated according to the 
clinician. 
3) RDE or other technical issues: e.g., due to technical issues e-diary alerts were not sent 
and when the site was aware of it was too late to determine whether this was an 
exacerbation or not. 
4) Other reasons: specify : e.g. subject was on holidays / subject unable to visit the site / 
delayed RDE visit/early RDE entry. 
 
The different reasons of inconsistencies of Case B will be categorized by the site after 
review according to the following explanation: 
5) Spontaneous visit clinically deemed exacerbating i.e. exacerbation visit took place 
before the e-diary alert (spontaneous visit, visit triggered by GP / Patient call asked to be 
seen/ felt too unwell to complete e-diary abrupt onset) 
6) Planned monthly visit clinically deemed exacerbating 
7) e-diary diary card recording issue or other technical issues : e.g. late e-diary alerts, 
subject missed or did not correctly record diary card, broken log pad device. 
8) Other reasons: specify 
For a Case A, no laboratory data has been collected, but if the answer about the 
inconsistency is 3) or sometimes 4) (depending on the specification), it will qualify as 
AECOPD. All Cases B will be considered to be an AECOPD if the AECOPD is 
confirmed by the site. 
7.1.12. 
Grading of severity of an exacerbation 
Severity of exacerbations is defined as (Protocol Section 5.3.1.2): 
• Mild: Worsening symptoms of COPD that are self-managed by the patient. 
• Moderate: Worsening symptoms of COPD that require treatment with oral 
corticosteroids and/or antibiotics. 
• Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalisation or home care intervention. 
 
Severity of the exacerbation will not be derived but taken directly from the information 
entered in the CRF. 
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7.1.13. 
Sputum Quality 
The quality of sputum is defined as follow: 
- 
< 10 squamous epithelial cells/field: sample of good quality  
 
- 
10-25 squamous epithelial cells/field with significant numbers of cells derived 
from the lower respiratory tractus (ciliary epithelial cells, bronchial cells, 
round cells): sample of moderate quality 
 
- 
> 25 squamous epithelial cells/field: sample of bad quality  
7.2. 
Data presentation description 
The following decimal description will be used for the demography and safety/ 
reactogenicity. 
 
Display Table 
Parameters 
Number of decimal digits 
All summaries 
% of count, including LL & UL of CI 
1 
All summaries 
% of difference, including LL & UL of CI 
2 
Demographic characteristics 
Mean, median age 
1 
Demographic characteristics 
SD (age) 
2 
Immunogenicity   
GMT ratio 
2 
The following data presentation description will be used for the immunogenicity 
analyses. 
Component 
GMC/T 
Assay 
Assay cut-
off 
Number of decimal 
digits 
Tick marks on RCC's 
GMC/T 
GMC/T ratio 
method 
Unit 
 
Low 
value 
High 
value 
Anti-PD 
GMC 
ELISA 
EL.U/mL 
153 
1 
2 
1 
10000 
Anti-PE 
GMC 
ELISA 
EL.U/mL 
8 
1 
2 
1 
10000 
Anti-PilA 
GMC 
ELISA 
EL.U/mL 
7 
1 
2 
1 
10000 
 
8. 
CONDUCT OF ANALYSES 
8.1. 
Sequence of analyses 
The analyses will be performed stepwise: 
• 
The analysis of data up to Visit 6 (Day 90) will be performed in a first step. This 
analysis will include: 
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− 
The final analysis of immunogenicity and solicited AEs post-Dose 1 and post-
Dose 2.  
− 
The assessment of unsolicited AEs, SAEs and pIMDs up to 30 days post-Dose 1 
and post-Dose 2 on as cleaned as possible data.  
This analysis will be documented in a statistical report. At this point, the GSK 
statistician of the project (or delegates) will be unblinded (i.e. will have access to the 
individual subject treatment assignments). 
• 
The analyses of the impact of the investigational vaccine on AECOPD will be 
performed in parallel with the first step. This will include: 
− 
 the analyses of fresh sputum samples (culture) obtained up to the data lock 
point of the interim analysis.  
− 
The analyses of AECOPD obtained up to the data lock point of the interim 
analysis. 
• 
The final analysis of data up to study conclusion will be performed in a second step, 
once those data will be available and cleaned. This analysis will include: 
− 
The final analysis of immunogenicity at Day 270 and Day 450. 
− 
SAEs and pIMDs up to Day 450 on cleaned data. 
− 
Impact of the investigational vaccine on AECOPD, HRQOL, lung function, 
exercise capacity and biomarkers. 
In addition, all previous analyses will be re-produced based on cleaned data at this 
point. 
Individual listings will only be provided at this stage. A final study report containing 
data from the entire study will be written and will be made available to the 
investigators. 
Description 
Analysis ID  
(SDD & CARS sub-folder) 
Analysis up to Visit 6 (Day 90) 
E1_06 
Final analysis (up to day 450) 
E1_01 
 
8.2. 
Statistical considerations for interim analyses 
Not applicable. 
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9. 
CHANGES FROM PLANNED ANALYSES 
As during the study, some subjects have completed wrong diary cards (paediatric ones 
instead of adults), a sensitivity analysis will be done on subjects that have completed the 
correct diary cards to be sure that they were no impact on results. 
10. 
REFERENCES 
The exact 95% CIs for a proportion within a group will be calculated from Proc StatXact 
[Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
binomial. Biometrika. 1934;26:404-413]. 
PPD