An Observer-blind Study to Evaluate the Safety, Reactogenicity and Immunogenicity of the Investigational GSK Biologicals' COPD Vaccine (GSK3277511A) in Adults
Phase: PHASE2
Conditions: Respiratory Disorders
Sponsor: GlaxoSmithKline

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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’institut 89,1330 Rixensart, Belgium 
Primary Study vaccine and 
number 
GlaxoSmithKline (GSK) Biologicals non-
typeable Haemophilus influenzae (NTHi) and 
Moraxella catarrhalis (Mcat) multi-antigen 
vaccine consisting of three conserved surface 
proteins (PD, PE and PilA) from Haemophilus 
influenzae and one conserved surface protein 
(UspA2) from Mcat (GSK3277511A). 
Other Study vaccine 
Placebo 
eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
Investigational New Drug (IND) 
number 
16531 
EudraCT number 
2017-002941-31 
Date of protocol 
Final Version 1: 28 July 2017 
Date of protocol amendment: 
Amendment 1 Final: 24 July 2018  
Amendment 2 Final: 24 July 2019 
Amendment 3 Final: 26 May 2020 
Title 
An observer-blind study to evaluate the safety, 
reactogenicity and immunogenicity of the 
investigational GSK Biologicals’ COPD vaccine 
(GSK3277511A) in adults. 
Detailed Title 
A Phase 2, randomised, observer-blind, multi-
centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational 
vaccine when administered intramuscularly 
according to two different vaccine schedules in 
adults aged 40 to 80 years old.  
Co-ordinating author 
 (XPE Pharma & Science for 
GSK Biologicals) 
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eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
Investigational New Drug (IND) 
number 
16531 
EudraCT number 
2017-002941-31 
Detailed Title 
A Phase 2, randomised, observer-blind, multi-
centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational 
vaccine when administered intramuscularly 
according to two different vaccine schedules in 
adults aged 40 to 80 years old.  
Contributing authors 
(Amended 26 May 2020) 
• 
 (Clinical & 
Epidemiology Project Lead) 
• 
 (Senior Clinical Research & 
Development Lead) and 
 
(Clinical Research & Development Lead)  
• 
 
 (Study Statisticians)  
• 
 (Lead 
Statisticians)  
• 
 
(Science Writers)  
• 
 
 (Study Delivery Leads)  
• 
 (Aixial for GSK Biologicals) 
(Clinical Trials Supply Manager) 
• 
 (CLS Clinical Read-out 
Team Leader) 
• 
 
 (CLS Study Managers) 
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eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
Investigational New Drug (IND) 
number 
16531 
EudraCT number 
2017-002941-31 
Detailed Title 
A Phase 2, randomised, observer-blind, multi-
centre study to evaluate the safety, 
reactogenicity and immunogenicity of GSK 
Biologicals' GSK3277511A investigational 
vaccine when administered intramuscularly 
according to two different vaccine schedules in 
adults aged 40 to 80 years old.  
Contributing authors 
(Amended 26 May 2020) 
• 
 
(Clinical Safety Representatives) 
• 
 (Oversight Data Manager) 
• 
 (TCS for GSK Biologicals) 
and 
 (ICON for GSK 
Biological) (Study Data Managers) 
• 
 
 (Regulatory Affairs 
Representatives)  
• 
 (Global patents) 
• 
 (Vaccine Development 
Lead) 
GSK Biologicals’ Protocol DS v15.0 
© 2017 GSK group of companies or its licensor. 
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Protocol Amendment 3 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
IND number 
16531 
EudraCT number 
2017-002941-31  
Date of protocol amendment 
Amendment 3 Final: 26 May 2020 
Detailed Title  
A Phase 2, randomised, observer-blind, multi-centre 
study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals' 
GSK3277511A investigational vaccine when 
administered intramuscularly according to two 
different vaccine schedules in adults aged 40 to 80 
years old. 
Sponsor signatory 
Ashwani Kumar Arora 
Clinical & Epidemiology Project Lead 
Signature 
 
 
 
Date 
 
 
 
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Protocol Amendment 3 Rationale 
Amendment number: 
Amendment 3 
This amendment is considered substantial based on the criteria defined in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it significantly impacts the conduct or management of the trial. 
Rationale/background for changes:  
• 
This protocol amendment 3 outlines measures that may be applicable during 
special circumstances (e.g. COVID-19 pandemic). The purpose of the amendment 
is to protect participant’s welfare and safety, and as far as possible ensure the 
potential benefit to the participant and promote data integrity. 
However, if the study specific visit and procedures can be completed, then they should 
be completed according to the protocol, taking into account clinical judgment and local 
public health guidance to protect the safety of staff and subjects. 
Amended text is indicated in bold italics in the body of the protocol. Detailed 
description of the changes is provided in APPENDIX C. 
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Protocol Amendment 3 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.  
• 
To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals’ study vaccine and other study-related duties and functions as 
described in the protocol. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality 
Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the subject and/or the subject’s legally acceptable representative.  
• 
To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).  
• 
To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data. 
• 
That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational vaccine, 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 
207759 (NTHI MCAT-008) 
IND number  
16531 
EudraCT number 
2017-002941-31  
Date of protocol amendment 
Amendment 3 Final: 26 May 2020 
Detailed Title 
A Phase 2, randomised, observer-blind, multi-centre 
study to evaluate the safety, reactogenicity and 
immunogenicity of GSK Biologicals' 
GSK3277511A investigational vaccine when 
administered intramuscularly according to two 
different vaccine schedules in adults aged 40 to 80 
years old. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
name, function and title 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
2. Sponsor Medical Expert for the Study 
Refer to the local study contact information document. 
3. Sponsor Study Monitor 
Refer to the local study contact information document. 
4. Sponsor Study Contact for Reporting of a Serious Adverse Event 
GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocol 
Section 8.4.2. 
5. GSK Biologicals’ Central Safety Physician On-Call Contact information for 
Emergency Unblinding  
GSK Biologicals Central Safety Physician and Back-up Phone contact: refer to 
protocol Section 8.8.  
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SYNOPSIS 
(Amended 26 May 2020) 
Detailed Title 
A Phase 2, randomised, observer-blind, multi-centre study to 
evaluate the safety, reactogenicity and immunogenicity of 
GSK Biologicals' GSK3277511A investigational vaccine 
when administered intramuscularly according to two 
different vaccine schedules in adults aged 40 to 80 years old.  
Indication 
Active immunisation for the reduction of frequency of 
moderate and severe Acute Exacerbation of Chronic 
Obstructive Pulmonary Disease (AECOPD) in patients with 
a previous history of moderate or severe AECOPD.  
Rationale for the 
study and study 
design 
• 
Rationale for the study 
The purpose of this Phase 2 study is to evaluate two vaccine 
schedules of the investigational NTHi-Mcat vaccine. 
As the prevalence of COPD increases with age and as age 
has an influence on both the immunogenicity and 
reactogenicity of a vaccine, subjects 40–80 years old will be 
enrolled. As cigarette smoking is the most commonly 
encountered risk factor for COPD, adults with a smoking 
history of at least 10 pack-years will be selected in order to 
immunologically match the COPD population as much as 
possible. Literature data indeed suggest that alterations of the 
immune system start early on in smokers, before the COPD 
disease is recognised Barcelo, 2008; Droemann, 2005; 
Takanashi, 1999. 
Several formulations of a vaccine containing the NTHi 
antigens (10 or 30 µg) either non-adjuvanted or combined 
with different adjuvants (aluminium [Al], adjuvant system 
[AS]01E and AS04C) were already evaluated in two previous 
Phase 1 clinical trials (NTHI-002 in healthy adults aged 18 - 
40 years and NTHI-003 in current and former healthy 
smokers of 50-70 years old). The investigational vaccines 
were well-tolerated, with an acceptable safety and 
reactogenicity profile. These studies allowed the dose 
selection of the NTHi antigens (10 µg) and the adjuvant 
system (AS01E) evaluated for the first time in moderate and 
severe COPD patients aged 40-80 years in the Phase 2 study 
NTHI-004. 
The safety, reactogenicity and immunogenicity of different 
formulations of the NTHi-Mcat investigational vaccine have 
been evaluated in the Phase 1 study in healthy adults aged 
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18-40 years and in current and former smokers aged 50-70 
years (study NTHI MCAT-001). Based on results obtained 
up to 30 days post-Dose 2 from this study, the AS01E-
adjuvanted formulation containing 10 µg of NTHi proteins 
PD and PE-PilA and 3.3 µg of UspA2 has been selected for 
evaluation in the current NTHI MCAT-008 study. The 
current study will evaluate the impact of a 3rd dose 
(following a 0-2 month vaccination schedule), either given at 
6 months or at 12 months after the first dose. The primary 
aim is to assess the safety of the additional dose. We will 
also investigate how the two schedules improve the 
persistence of antibody response. 
• 
Rationale for the study design 
Previous studies in the COPD project have evaluated a 2-
dose vaccination schedule. The current study will evaluate 
the safety and immunogenicity of 3 doses of the 
investigational vaccine. Adults aged 40 to 80 years with a 
smoking history of at least 10 pack-years, will receive 2 
doses of the NTHi-Mcat investigational vaccine at 0 and 2 
months in both study arms. Following these 2 doses, one 
study arm will receive a 3rd dose of the investigational NTHi-
Mcat vaccine at 6 months and a placebo control at 12 months 
(Schedule 1) and the other study arm will receive a placebo 
control at 6 months and a 3rd dose of the investigational 
NTHi-Mcat vaccine at 12 months (Schedule 2). 
• 
Rationale for the use of placebo 
The placebo dose is included in the NTHI MCAT-008 study 
in order to preserve the blind in the evaluation of the two 
vaccination schedules.  
Objectives 
Primary 
• 
To evaluate the safety and reactogenicity profile of the 
NTHi-Mcat vaccine administered according to two 
vaccination schedules 
 
Secondary 
• 
To evaluate the long term safety profile. 
• 
To evaluate the humoral immunogenicity of the NTHi-
Mcat investigational vaccine. 
• 
To evaluate the cellular immunogenicity (CD4+ T cell 
response) of the NTHi-Mcat investigational vaccine. 
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Tertiary 
• 
To explore the T helper profile to the PD-, PE-, PilA-, 
UspA2 -specific CD4+/ CD8+ T cell responses.  
• 
To evaluate the cellular immunogenicity (CD8+ T cell 
response) of the NTHi-Mcat investigational vaccine.  
• 
To collect blood samples for assay 
development/validation and/or for additional evaluation 
of the immune responses to the investigational vaccine 
and to other potential pathogens involved in AECOPD.  
Study design 
• 
Experimental design: Phase II, observer-blind, 
randomised, multi-centric study with two parallel 
groups.  
• 
Duration of the study: for each subject enrolled, the 
study will last approximately 2 years from Visit 1 
(enrolment visit): 
− 
Epoch 001: Primary (Vaccination phase) starting at 
Visit 1 (Day 1) and ending at Visit 9 (Day 541). 
− 
Epoch 002: Long-term follow-up starting after Visit 
9 (Day 541) and ending at Visit 10 (Day 721). 
• 
Primary Completion Date: Visit 9 (Day 541). 
Refer to glossary of terms for the definition of PCD. 
• 
End of Study (EoS): Last testing results released of 
samples collected at Visit 10 (Day 721). 
Refer to glossary of terms for the definition of EoS. 
• 
Study groups: 
− 
Schedule 1: 100 planned subjects receiving three 
doses of the AS01E-adjuvanted GSK Biologicals' 
NTHi-Mcat investigational vaccine containing 10 
µg of PD, 10 µg of PE-PilA, and 3.3 µg of UspA2 
at Visit 1 (Day 1), Visit 3 (Day 61) and Visit 5 (Day 
181) and one dose of placebo at Visit 7 (Day 361). 
− 
Schedule 2: 100 planned subjects receiving three 
doses of the AS01E-adjuvanted GSK Biologicals' 
NTHi-Mcat investigational vaccine containing 10 
µg of PD, 10 µg of PE-PilA, and 3.3 µg of UspA2 
at Visit 1 (Day 1), Visit 3 (Day 61) and Visit 7 (Day 
361) and one dose of placebo at Visit 5 (Day 181). 
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Synopsis Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
Schedule 1 
100 
40 – 80 years 
x 
x 
Schedule 2 
100 
40 – 80 years 
x 
x 
Synopsis Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Groups 
 Schedule 1  
Schedule 2  
10-10-3/AS01E  
NTHi-Mcat 10-10-3  
x 
x 
AS01E  
x 
x 
Placebo  
Formulation buffer S9b  
x 
x 
 
 
• 
Vaccination schedule: at Visit 1 (Day 1), Visit 3 (Day 
61), Visit 5 (Day 181) and Visit 7 (Day 361). 
 
• 
Treatment allocation: Subjects will be allocated to a study 
group using a centralised randomisation system on 
internet (SBIR).  
• 
Blinding: observer-blind (Epoch 001) and open (Epoch 
002). 
Synopsis Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch 002 
open 
 
• 
Sampling schedule: 
− 
Blood samples for assessment of humoral 
immunogenicity will be collected from all subjects at 
Visit 1 (Day 1), Visit 4 (Day 91), Visit 5 (Day 181), 
Visit 6 (Day 211), Visit 7 (Day 361), Visit 8 (Day 
391), Visit 9 (Day 541) and Visit 10 (Day 721)*. 
− 
Blood samples for assessment of cell-mediated 
immunogenicity (CMI) will be collected from all 
subjects in the CMI sub-cohort at Visit 1 (Day 1), 
Visit 4 (Day 91), Visit 5 (Day 181), Visit 6 (Day 
211), Visit 7 (Day 361) and Visit 8 (Day 391). 
Refer to Section 5.6.18 for study procedures to be 
considered during special circumstances. 
• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF), 
Diary Cards and Phone contacts. 
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• 
Safety monitoring: Safety evaluations by the Safety 
Review Team (SRT) (blinded). Refer to section 8.10 for 
description of safety monitoring. 
Number of subjects 
Approximately 100 eligible adult subjects aged 40 to 80 years 
having a significant smoking history ( 10 pack-years) per 
study group (i.e. 200 subjects in total). 
Endpoints 
Primary 
• 
Solicited local and general symptoms. 
− 
Occurrence of each solicited local and general 
symptom (any and Grade 3) reported within 7 days 
(Day 1 – Day 7) after each vaccination, within each 
vaccination schedule.  
• 
Unsolicited adverse events.  
− 
Occurrence of each unsolicited AE reported within 30 
days (Day 1 – Day 30) after any vaccination, 
according to the Medical Dictionary for Regulatory 
Activities (MedDRA) classification, within each 
vaccination schedule.  
• 
Serious adverse events.  
− 
Occurrence of any serious adverse events reported 
from Day 1 (Visit 1) up to and including Day 541 
(Visit 9), within each vaccination schedule.  
• 
Potential Immune-mediated diseases (pIMDs).  
− 
Occurrence of pIMDs reported from Day 1 (Visit 1) 
up to and including Day 541 (Visit 9), within each 
vaccination schedule.  
 
Secondary 
• 
Serious Adverse Events. 
− 
Occurrence of any serious adverse events reported 
from Day 541 (Visit 9) up to and including Day 721 
(Visit 10), within each vaccination schedule.  
• 
Potential Immune-mediated diseases (pIMDs).  
− 
Occurrence of pIMDs reported from Day 541 (Visit 
9) up to and including Day 721 (Visit 10), within each 
vaccination schedule.  
• 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations, as measured by ELISA, at Day 1, Day 91, 
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Day 181, Day 211, Day 361, Day 391, Day 541 and Day 
721, within each vaccination schedule.  
• 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
seropositivity, as measured by ELISA, at Day 1, Day 91, 
Day 181, Day 211, Day 361, Day 391, Day 541 and Day 
721, within each vaccination schedule. 
 
• 
NTHi-specific and Mcat-specific cell-mediated immune 
responses as measured by flow cytometry ICS [frequency 
of specific CD4+ T-cells expressing two or more markers, 
such as interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α), and CD40 
ligand (CD40L)], at Day 1, Day 91, Day 181, Day 211, 
Day 361 and Day 391, in a sub-cohort of subjects and 
within each vaccination schedule. 
 
Tertiary 
• 
T helper profile of the specific CD4+ (CD8+) T cell 
response based on the expression of T helper 1, T helper 2 
and T helper 17 specific markers at Day 1, Day 91, Day 
181, Day 211, Day 361 and Day 391, within each 
vaccination schedule.  
• 
NTHi-specific and Mcat-specific cell-mediated immune 
responses as measured by flow cytometry ICS [frequency 
of specific CD8+ T-cells expressing two or more markers, 
such as interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α), and CD40 
ligand (CD40L)], at Day 1, Day 91, Day 181, Day 211, 
Day 361 and Day 391, in a sub-cohort of subjects and 
within each vaccination schedule.  
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 8 
SYNOPSIS ...................................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................... 22 
GLOSSARY OF TERMS ............................................................................................... 25 
1. 
INTRODUCTION .................................................................................................... 30 
1.1. 
Background ................................................................................................ 30 
1.1.1. 
COPD: an introduction ................................................................. 30 
1.1.2. 
Current management of AECOPD ............................................... 31 
1.1.3. 
GSK Biologicals’ NTHi-Mcat investigational vaccine .................... 31 
1.2. 
Rationale for the study and study design .................................................... 32 
1.2.1. 
Rationale for the study ................................................................. 32 
1.2.2. 
Rationale for the study design ...................................................... 33 
1.2.3. 
Rationale for the use of placebo .................................................. 33 
1.3. 
Benefit: Risk Assessment ........................................................................... 33 
1.3.1. 
Risk Assessment ......................................................................... 34 
1.3.2. 
Benefit Assessment ..................................................................... 34 
1.3.3. 
Overall Benefit: Risk Conclusion .................................................. 34 
2. 
OBJECTIVES ......................................................................................................... 35 
2.1. 
Primary objective ........................................................................................ 35 
2.2. 
Secondary objectives .................................................................................. 35 
2.3. 
Tertiary objectives ....................................................................................... 35 
3. 
STUDY DESIGN OVERVIEW ................................................................................ 36 
4. 
STUDY COHORT ................................................................................................... 38 
4.1. 
Number of subjects/centres ........................................................................ 38 
4.2. 
Inclusion criteria for enrolment .................................................................... 38 
4.3. 
Exclusion criteria for enrolment ................................................................... 39 
5. 
CONDUCT OF THE STUDY .................................................................................. 41 
5.1. 
Regulatory and ethical considerations, including the informed 
consent process.......................................................................................... 41 
5.2. 
Subject identification and randomisation ..................................................... 42 
5.2.1. 
Subject identification .................................................................... 42 
5.2.2. 
Randomisation of treatment ......................................................... 42 
5.2.2.1. 
Randomisation of supplies .......................................... 42 
5.2.2.2. 
Treatment allocation to the subject ............................. 42 
5.2.2.2.1. 
Study group allocation ............................ 42 
5.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 42 
5.3. 
Method of blinding ...................................................................................... 43 
5.4. 
General study aspects ................................................................................ 43 
5.5. 
Outline of study procedures ........................................................................ 44 
5.6. 
Detailed description of study procedures .................................................... 47 
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5.6.1. 
Informed consent ......................................................................... 47 
5.6.2. 
Check inclusion and exclusion criteria ......................................... 47 
5.6.3. 
Collect demographic data ............................................................ 47 
5.6.4. 
Medical history ............................................................................. 48 
5.6.5. 
Smoking status ............................................................................ 48 
5.6.6. 
Smoking exposure history ............................................................ 48 
5.6.7. 
Measure/record height and weight ............................................... 48 
5.6.8. 
Physical examination ................................................................... 48 
5.6.9. 
Urine Pregnancy test ................................................................... 49 
5.6.10. 
Check contraindications to vaccination ........................................ 49 
5.6.11. 
Assess pre-vaccination body temperature ................................... 49 
5.6.12. 
Study group and treatment number allocation .............................. 49 
5.6.13. 
Study Vaccine administration ....................................................... 49 
5.6.14. 
Sampling...................................................................................... 50 
5.6.14.1. Blood sampling for immune response 
assessments .............................................................. 50 
5.6.15. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions .................................................... 50 
5.6.16. 
Distribution of Subject Card ......................................................... 50 
5.6.17. 
Recording of AEs, SAEs, pregnancies and pIMDs ....................... 51 
5.6.18. 
Study procedures during special circumstances .......................... 51 
5.6.19. 
Study conclusion .......................................................................... 52 
5.7. 
Biological sample handling and analysis ..................................................... 52 
5.7.1. 
Use of specified study materials .................................................. 53 
5.7.2. 
Biological samples ....................................................................... 53 
5.7.3. 
Laboratory assays ....................................................................... 53 
5.7.4. 
Biological samples evaluation ...................................................... 55 
5.7.4.1. 
Immunological read-outs ............................................ 55 
5.7.5. 
Immunological correlates of protection ......................................... 55 
6. 
STUDY VACCINES AND ADMINISTRATION ........................................................ 56 
6.1. 
Description of study vaccines ...................................................................... 56 
6.2. 
Storage and handling of study vaccines ...................................................... 56 
6.3. 
Dosage and administration of study vaccines ............................................. 57 
6.4. 
Replacement of unusable vaccine doses .................................................... 57 
6.5. 
Contraindications to subsequent vaccination .............................................. 58 
6.6. 
Concomitant medications/products and concomitant vaccinations .............. 58 
6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 59 
6.6.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 59 
6.7. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 60 
7. 
HEALTH ECONOMICS .......................................................................................... 60 
8. 
SAFETY ................................................................................................................. 60 
8.1. 
Safety definitions ........................................................................................ 60 
8.1.1. 
Definition of an adverse event ...................................................... 60 
8.1.2. 
Definition of a serious adverse event ........................................... 61 
8.1.3. 
Solicited adverse events .............................................................. 62 
8.1.3.1. 
Solicited local (injection-site) adverse events .............. 62 
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8.1.3.2. 
Solicited general adverse events ................................ 63 
8.1.4. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ............................................................................ 63 
8.1.5. 
Adverse events of specific interest ............................................... 63 
8.1.5.1. 
Potential immune-mediated diseases ......................... 63 
8.2. 
Events or outcomes not qualifying as adverse events or serious 
adverse events ........................................................................................... 66 
8.2.1. 
Pregnancy ................................................................................... 66 
8.3. 
Detecting and recording adverse events, serious adverse events 
and pregnancies ......................................................................................... 67 
8.3.1. 
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies ..................................... 67 
8.3.2. 
Post-Study adverse events and serious adverse events .............. 69 
8.3.3. 
Evaluation of adverse events and serious adverse events ........... 69 
8.3.3.1. 
Active questioning to detect adverse events 
and serious adverse events ........................................ 69 
8.3.3.2. 
Assessment of adverse events ................................... 70 
8.3.3.2.1. 
Assessment of intensity .......................... 70 
8.3.3.2.2. 
Assessment of causality ......................... 71 
8.3.3.3. 
Assessment of outcomes............................................ 72 
8.3.3.4. 
Medically attended visits ............................................. 72 
8.4. 
Reporting of serious adverse events, pregnancies, and other events ......... 73 
8.4.1. 
Prompt reporting of serious adverse events, pregnancies, 
and other events to GSK Biologicals ............................................ 73 
8.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs ............................................................... 73 
8.4.3. 
Completion and transmission of SAE reports to GSK 
Biologicals ................................................................................... 74 
8.4.3.1. 
Back-up system in case the electronic 
reporting system does not work .................................. 74 
8.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals ................................................................................... 74 
8.4.5. 
Reporting of pIMDs to GSK Biologicals ........................................ 74 
8.4.6. 
Updating of SAE, pregnancy, and pIMD information after 
removal of write access to the subject’s eCRF ............................. 75 
8.4.7. 
Regulatory reporting requirements for serious adverse 
events .......................................................................................... 75 
8.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies ................................................................................................ 76 
8.5.1. 
Follow-up of adverse events and serious adverse events ............ 76 
8.5.1.1. 
Follow-up during the study .......................................... 76 
8.5.1.2. 
Follow-up after the subject is discharged from 
the study ..................................................................... 76 
8.5.2. 
Follow-up of pregnancies ............................................................. 76 
8.6. 
Treatment of adverse events ...................................................................... 77 
8.7. 
Unblinding ................................................................................................... 77 
8.8. 
Emergency unblinding ................................................................................ 77 
8.9. 
Subject card ................................................................................................ 78 
8.10. 
Safety monitoring ........................................................................................ 78 
8.10.1. 
Safety Review Team .................................................................... 78 
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9. 
SUBJECT COMPLETION AND WITHDRAWAL ..................................................... 79 
9.1. 
Subject completion ..................................................................................... 79 
9.2. 
Subject withdrawal ...................................................................................... 79 
9.2.1. 
Subject withdrawal from the study ............................................... 79 
9.2.2. 
Subject withdrawal from study vaccines ....................................... 80 
10. STATISTICAL METHODS ...................................................................................... 80 
10.1. 
Primary endpoints ....................................................................................... 80 
10.2. 
Secondary endpoints .................................................................................. 81 
10.3. 
Tertiary endpoint ......................................................................................... 81 
10.4. 
Determination of sample size ...................................................................... 81 
10.5. 
Cohorts for Analyses .................................................................................. 84 
10.5.1. 
Exposed set ................................................................................. 84 
10.5.2. 
Full Analysis Set .......................................................................... 84 
10.5.3. 
Per-protocol set for analysis of immunogenicity ........................... 84 
10.6. 
Derived and transformed data ..................................................................... 85 
10.7. 
Analysis of demographics ........................................................................... 86 
10.8. 
Analysis of safety ........................................................................................ 86 
10.9. 
Analysis of immunogenicity ......................................................................... 87 
10.9.1. 
Within groups assessment ........................................................... 87 
10.9.2. 
Cell-mediated immune response ................................................. 88 
10.10. Interpretation of analyses ............................................................................ 88 
10.11. Conduct of analyses ................................................................................... 88 
10.11.1. Sequence of analyses.................................................................. 88 
10.11.2. Statistical considerations for interim analyses .............................. 89 
11. ADMINISTRATIVE MATTERS ............................................................................... 89 
11.1. 
Electronic Case Report Form instructions ................................................... 89 
11.2. 
Study Monitoring by GSK Biologicals .......................................................... 89 
11.3. 
Record retention ......................................................................................... 90 
11.4. 
Quality assurance ....................................................................................... 91 
11.5. 
Posting of information on publicly available clinical trial registers and 
publication policy ........................................................................................ 91 
11.6. 
Provision of study results to investigators ................................................... 91 
11.7. 
Data Sharing ............................................................................................... 92 
12. COUNTRY SPECIFIC REQUIREMENTS ............................................................... 92 
13. REFERENCES ....................................................................................................... 93 
14. APPENDICES ........................................................................................................ 96 
 
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LIST OF TABLES 
PAGE 
Table 1 
Study groups and epochs foreseen in the study ..................................... 37 
Table 2 
Study groups and treatment foreseen in the study ................................. 37 
Table 3 
Blinding of study epochs ........................................................................ 37 
Table 4 
Sub-cohorts ............................................................................................ 38 
Table 5 
List of study procedures ......................................................................... 44 
Table 6 
Intervals between study visits ................................................................. 47 
Table 7 
Biological samples ................................................................................. 53 
Table 8 
Humoral Immunity (Antibody determination) ........................................... 54 
Table 9 
Cell-mediated Immunity (CMI) using flow cytometry ............................... 54 
Table 10 
Immunological read-outs ........................................................................ 55 
Table 11 
Study vaccines ....................................................................................... 56 
Table 12 
Dosage and administration ..................................................................... 57 
Table 13 
Solicited local adverse events ................................................................ 62 
Table 14 
Solicited general adverse events ............................................................ 63 
Table 15 
List of potential immune-mediated diseases ........................................... 64 
Table 16 
Reporting periods for collecting safety information ................................. 68 
Table 17 
Intensity scales for solicited symptoms ................................................... 70 
Table 18 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ................................................. 73 
Table 19 
Exact confidence interval for one proportion ........................................... 82 
Table 20 
Poisson probability to observe at least one event with rare 
frequency (μ) .......................................................................................... 83 
Table 21 
GSK Biologicals’ laboratories ................................................................. 97 
Table 22 
Outsourced laboratories ......................................................................... 97 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 36 
 
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LIST OF APPENDICES 
PAGE 
APPENDIX A LABORATORY ASSAYS ....................................................................... 96 
APPENDIX B CLINICAL LABORATORIES .................................................................. 97 
APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES TO THE 
PROTOCOL ........................................................................................... 98 
 
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LIST OF ABBREVIATIONS 
(Amended 26 May 2020) 
AE: 
Adverse Event 
AECOPD: 
Acute Exacerbation of COPD 
Al: 
Aluminium 
ANCOVA: 
Analysis of covariance 
AS01E: 
Adjuvant System 01E 
CD: 
Cluster of Differentiation 
CDC: 
Centers for Disease Control 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
CMI: 
Cell-Mediated Immunity 
COPD: 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CRDL: 
Clinical Research & Development Lead 
eCRF: 
electronic Case Report Form 
EDD: 
Estimated Date of Delivery 
EGA: 
Estimated Gestational Age 
ELISA: 
Enzyme-linked immunosorbent assay 
eTDF: 
Electronic Temperature excursion Decision Form 
EoS: 
End of Study 
ES: 
Exposed Set 
FAS: 
Full Analysis Set 
GCP: 
Good Clinical Practice 
GM: 
Geometric Mean 
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GMC: 
Geometric Mean Concentration  
GOLD: 
Global Initiative for Chronic Obstructive Lung Disease 
GSK: 
GlaxoSmithKline 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Conference on Harmonisation 
ICS: 
Intracellular Cytokine Staining 
IDMC: 
Independent Data Monitoring Committee 
IEC: 
Independent Ethics Committee 
IFN-γ: 
Interferon gamma 
IgG: 
Immunoglobulin G 
IL: 
Interleukin 
IM: 
Intramuscular 
IMP: 
Investigational Medicinal Product 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
LAR: 
Legally Acceptable Representative 
LMP: 
Last Menstrual Period 
LSLV: 
Last Subject Last Visit 
MACDP: 
Metropolitan Atlanta Congenital Defects Program 
MATEX: 
MATerial EXcellence 
Mcat: 
Moraxella catarrhalis 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mg: 
Milligram 
ml: 
Millilitre 
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NTHi: 
Non-typeable Haemophilus influenzae 
PBMC: 
Peripheral Blood Mononuclear Cell 
PCD: 
Primary Completion Date 
PD: 
Protein D  
PE: 
Protein E  
PilA: 
Type IV pili subunit  
pIMD: 
Potential Immune-Mediated Disease 
PPS: 
Per Protocol Set 
PT: 
Preferred Term 
SAE: 
Serious Adverse Event 
SAS: 
Statistical Analysis Software 
SBIR: 
Randomisation System on Internet 
SRT: 
Safety Review Team 
TNF-α: 
Tumour Necrosis Factor alpha 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 
UspA2: 
Ubiquitous surface protein A2  
WHO: 
World Health Organisation 
L: 
Microliter 
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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, 
• 
Combined estrogen and progesterone oral 
contraceptives, 
• 
Injectable progestogen, 
• 
Implants of etenogestrel or levonorgestrel, 
• 
Contraceptive vaginal ring, 
• 
Percutaneous contraceptive patches, 
• 
Intrauterine device or intrauterine system, 
• 
Male partner sterilisation prior to the female 
subject’s entry into the study, and this male is the 
sole partner for that subject, 
The information on the male sterility can come from 
the site personnel’s review of the subject’s medical 
records; or interview with the subject on her 
medical history. 
• 
Male condom combined with a vaginal spermicide 
(foam, gel, film, cream or suppository), and/or 
progesterone alone oral contraceptive. 
Adequate contraception does not apply to subjects of 
child bearing potential with same sex partners, or for 
subjects who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered 
related to the medicinal product.  
An adverse event (AE) can therefore be any 
unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new 
or exacerbated) temporally associated with the use of a 
medicinal product. For marketed medicinal products, 
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this also includes failure to produce expected benefits 
(i.e. lack of efficacy), abuse or misuse. 
Alcoholism: 
Alcoholism, also known as dependency on alcohol or 
alcohol addiction, is a chronic disease. The signs and 
symptoms of alcoholism include: 
• 
A strong craving for alcohol. 
• 
Continued use despite repeated physical, 
psychological, or interpersonal problems. 
• 
The inability to limit drinking. 
Blinding: 
A procedure in which one or more parties to the trial are 
kept unaware of the treatment assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
trial, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a serious adverse 
event. In an observer-blind study, the subject and the site 
and sponsor personnel involved in the clinical evaluation 
of the subjects are blinded while other study personnel 
may be aware of the treatment assignment (see Section 
5.3 for details on observer-blinded studies).  
Current smoker: 
A person who is currently smoking or who has stopped 
smoking within 6 months before study start.  
Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
End of Study  
(Synonym of End of Trial) 
For studies without collection of human biologicals 
samples or imaging data EoS is the Last Subject Last 
Visit (LSLV).  
For studies with collection of Human Biologicals 
Samples or imaging data, EoS is defined as the date of 
the last testing/reading released of the Human Biological 
Samples or imaging data, related to primary and 
secondary endpoints. EoS must be achieved no later than 
8 months after LSLV. 
Epoch: 
An epoch is a set of consecutive timepoints or a single 
timepoint from a single protocol. Epochs are defined to 
support a main purpose which is either to draw 
conclusions on subject participation or to draw a 
complete conclusion to define or precise the targeted 
label of the product. Supporting means that data 
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collected at the timepoints included in an epoch must be 
sufficient to fulfil the purpose of the epoch. 
Typical examples of epochs are screening, primary 
vaccinations, boosters, yearly immunogenicity follow-
ups, and surveillance periods for efficacy or safety. 
eTrack: 
GSK’s tracking tool for clinical trials. 
Evaluable: 
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the per-protocol analysis (see Sections 6.6.2 
and 10.5 for details on criteria for evaluability). 
Former smoker: 
A person who stopped smoking for at least 6 months at 
the time of study start.  
Immunological correlate 
of protection: 
The defined immune response above which there is a 
high likelihood of protection in the absence of any host 
factors that might increase susceptibility to the 
infectious agent. 
Investigational vaccine: 
(Synonym of 
Investigational Medicinal 
Product) 
A pharmaceutical form of an active ingredient being 
tested in a clinical trial, including a product with a 
marketing authorisation when used in a way different 
from the approved form, or when used for an 
unapproved indication, or when used to gain further 
information about an approved use.  
Menarche: 
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development 
and pubic hair growth. Menarche usually occurs within 
1-2 years of breast development, thelarche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non-
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue). 
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. 
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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 
(including cigarillos) should not be used to calculate 
pack-year history. 
Potential Immune-
Mediated Disease: 
Potential immune-mediated diseases (pIMDs) are a 
subset of AEs that include autoimmune diseases and 
other inflammatory and/or neurologic disorders of 
interest which may or may not have an autoimmune 
aetiology. 
Primary completion date: 
The date that the final subject was examined or received 
an intervention for the purpose of final collection of data 
for all primary outcomes, whether the clinical trial was 
concluded according to the pre-specified protocol or was 
terminated. 
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. 
Study vaccine/product 
Any investigational vaccine/product being tested and/or 
any authorized use of a vaccine/ product /placebo as a 
reference or administered concomitantly, in a clinical 
trial that evaluates the use of an investigational 
vaccine/product. 
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Sub-cohort: 
A group of subjects for whom specific study procedures 
are planned as compared to other subjects or a group of 
subjects who share a common characteristic (e.g. ages, 
vaccination schedule,…) at the time of enrolment. 
Subject: 
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient 
of the vaccine 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. 
Treatment number: 
A number identifying a treatment to a subject, according 
to treatment allocation. 
Unsolicited adverse event: 
Any AE reported in addition to those solicited during the 
clinical study. Also any ‘solicited’ symptom with onset 
outside the specified period of follow-up for solicited 
symptoms will be reported as an unsolicited adverse 
event. 
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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
COPD: an introduction 
Chronic Obstructive Pulmonary Disease (COPD), a common preventable disease, is 
characterised by persistent airflow limitation that is usually progressive. The airflow 
limitation is associated with an enhanced chronic inflammatory response in the airways 
and lungs to noxious particles of gases. The most important environmental risk factor for 
COPD is tobacco smoking, even though other factors, such as occupational exposure, 
may also contribute to the development of the disease [GOLD, 2017]. It is a multi-
component disease that manifests as an accelerated decline in lung function, with 
symptoms such as breathlessness on physical exertion, deteriorating health status and 
exacerbations. 
The prevalence of COPD is increasing. Worldwide, COPD (GOLD grade II and above) 
affects 10.1±4.8% of the population ≥40 years of age [Buist, 2007]. COPD is most 
prevalent in adults/elderly with a history of smoking [Mannino, 2002]. It is the fourth 
leading cause of chronic morbidity and mortality in the United States and the first in 
terms of disease burden in China. According to the World Health Organisation (WHO), 
COPD is expected to be the third cause of death worldwide by 2020 [Rabe, 2007]. 
Acute exacerbations and comorbidities contribute to the overall disease severity in 
individual COPD patients. An acute exacerbation of COPD (AECOPD) is defined as an 
acute event characterised by a worsening of the patient’s respiratory symptoms that is 
beyond normal day-to-day variations and leads to a change in medication [GOLD, 2017]. 
AECOPD additionally increase morbidity and mortality, lead to faster decline in lung 
function, poorer functional status, and have a significant impact on healthcare systems 
worldwide [Sapey, 2006]. Between 40-60% of medical expenditure for COPD is a direct 
consequence of AECOPD Cazzola, 2008. 
The lungs are known to be colonised with different strains of bacteria [Erb-Downward, 
2011; Wilkinson, 2017]. In COPD patients, acquisition of new bacterial strains is 
believed to be an important cause of AECOPD [Sethi, 2002]. Although estimates vary 
widely, Non-Typeable Haemophilus influenzae (NTHi) appears to be the main bacterial 
pathogen associated with AECOPD (11-38%), followed by Moraxella catarrhalis (Mcat) 
(3-25%) and Streptococcus pneumoniae (4-9%) [Alamoudi, 2007; Bandi, 2003; Beasley, 
2012; Hutchinson, 2007; Ko, 2007; Larsen, 2009; Murphy, 2005; Papi, 2006; Rosell, 
2005; Sethi, 2002; Sethi, 2008; Wilkinson, 2006]. A prospective, observational cohort 
study in patients with COPD aged 40-85 is ongoing to assess how changes in the COPD 
airway microbiome contribute to the incidence and severity of AECOPD [Bourne, 2014]. 
Molecular diagnostic and typing techniques are used to describe the dynamics of airway 
infection during AECOPD and stable disease, and associations with clinical outcome. 
These results will increase our understanding of the contribution of pathogens to 
AECOPD. 
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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 manage or treat COPD, some 
with a positive impact on the AECOPD rate. However, a need for further novel 
interventions remains because current approaches are not completely effective, even 
when targeted and used optimally. 
Prevention of AECOPD is an insufficiently addressed medical need today, despite 
existing preventative therapies (bronchodilators such as long-acting muscarinic 
antagonists, long-acting beta agonists, methylxanthines, corticosteroids, 
phosphodiesterase-4 inhibitors and combination drugs), and is thought to remain so in the 
10 years horizon.  
The use of antibiotics is recommended by several guidelines [American Thoracic Society 
and European Respiratory Society, 2004] as a standard treatment for COPD patients with 
AECOPD showing purulent sputum. However, as not all patients have confirmed 
bacterial-related exacerbations, there is an inappropriate use of antibiotics, leading to the 
spread of antibiotic-resistant bacteria [Daubin, 2008]. Infections with multidrug-resistant 
bacteria have been linked to increases in morbidity, length of hospitalisation, health care 
cost and mortality [Nseir, 2008]. 
There is currently no vaccine indicated for prevention of AECOPD, even though 
influenza and pneumococcal vaccines are routinely recommended to COPD patients. The 
availability of a vaccine for the prevention of bacterial AECOPD could contribute 
significantly to the current management of COPD, in terms of reducing the risk of 
bacterial exacerbations as well as the inappropriate use of antibiotics. 
1.1.3. 
GSK Biologicals’ NTHi-Mcat investigational vaccine 
GlaxoSmithKline (GSK) Biologicals is developing a new NTHi-Mcat investigational 
vaccine against diseases caused by NTHi and Mcat. The investigational vaccine that will 
be evaluated in the present study is an adjuvanted multi-component vaccine consisting of 
conserved surface proteins from NTHi and Mcat. Three NTHi proteins have been 
selected: Protein D (PD), as a free recombinant protein and Protein E (PE) and PilA 
protein, as a recombinant fusion protein named PE-PilA. The selected Mcat antigen is the 
UspA2. 
The target population of GSK NTHi-Mcat vaccine are COPD patients, which are often 
elderly, who are known to have a weakened immune response due to functional defects 
and altered frequencies of innate and adaptive immune cells, with impaired generation of 
long-term immune memory (immunosenescence) Weinberger, 2008. Moreover, the 
immune response of COPD patients has been suggested to be disturbed both locally and 
systemically. Using an adjuvant may help to induce a higher and longer-lasting immune 
response. 
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Please refer to the current Investigator Brochure for information regarding the pre-
clinical and clinical studies and the epidemiological information of the NTHi-Mcat 
investigational vaccine. 
1.2. 
Rationale for the study and study design 
1.2.1. 
Rationale for the study 
The purpose of this Phase 2 study is to evaluate two vaccine schedules of the 
investigational NTHi-Mcat vaccine. 
As the prevalence of COPD increases with age and as age has an influence on both the 
immunogenicity and reactogenicity of a vaccine, subjects 40–80 years old will be 
enrolled. As cigarette smoking is the most commonly encountered risk factor for COPD, 
adults with a smoking history of at least 10 pack-years will be selected in order to 
immunologically match the COPD population as much as possible. Literature data indeed 
suggest that alterations of the immune system start early on in smokers, before the COPD 
disease is recognised Barcelo, 2008; Droemann, 2005; Takanashi, 1999. 
Several formulations of a vaccine containing the NTHi antigens (10 or 30 µg) either non-
adjuvanted or combined with different adjuvants (aluminium [Al], adjuvant system 
[AS]01E and AS04C) were already evaluated in two previous Phase 1 clinical trials 
(NTHI-002 in healthy adults aged 18 - 40 years and NTHI-003 in current and former 
healthy smokers of 50-70 years old). The investigational vaccines were well-tolerated, 
with an acceptable safety and reactogenicity profile. These studies allowed the dose 
selection of the NTHi antigens (10 µg) and the adjuvant system (AS01E) evaluated for the 
first time in moderate and severe COPD patients aged 40-80 years in the Phase 2 study 
NTHI-004. 
The safety, reactogenicity and immunogenicity of different formulations of the NTHi-
Mcat investigational vaccine have been evaluated in the Phase 1 study in healthy adults 
aged 18-40 years and in current and former smokers aged 50-70 years (study NTHI 
MCAT-001). Based on results obtained up to 30 days post-Dose 2 from this study, the 
AS01E-adjuvanted formulation containing 10 µg of NTHi proteins PD and PE-PilA and 
3.3 µg of UspA2 has been selected for evaluation in the current NTHI MCAT-008 study. 
The current study will evaluate the impact of a 3rd dose (following a 0-2 month 
vaccination schedule), either given at 6 months or at 12 months after the first dose. The 
primary aim is to assess the safety of the 3rd dose. We will also investigate how these two 
schedules improve the persistence of antibody response.  
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1.2.2. 
Rationale for the study design 
Previous studies in the COPD project have evaluated a 2-dose vaccination schedule. The 
current study will evaluate the safety and immunogenicity of 3 doses of the 
investigational vaccine. Adults aged 40 to 80 years with a smoking history of at least 10 
pack-years, will receive 2 doses of the NTHi-Mcat investigational vaccine at 0 and 2 
months in both study arms. Following these 2 doses, one study arm will receive a dose of 
the investigational NTHi-Mcat vaccine at 6 months and a placebo at 12 months 
(Schedule 1) and the other study arm will receive a placebo at 6 months and a dose of the 
investigational NTHi-Mcat vaccine at 12 months (Schedule 2). 
1.2.3. 
Rationale for the use of placebo 
The placebo dose is included in the NTHI MCAT-008 study in order to preserve the blind 
in the evaluation of the two vaccination schedules.  
1.3. 
Benefit: Risk Assessment 
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of the NTHi-Mcat investigational vaccine. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol: 
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1.3.1. 
Risk Assessment 
Important 
Potential/Identified Risk 
Data/Rationale for Risk 
Mitigation Strategy 
NTHi-Mcat investigational vaccine 
Theoretical risk of acquiring 
a vaccine-induced 
autoimmune disease after 
vaccination 
No confirmed signals related 
to this potential risk have been 
identified during the preclinical 
and clinical programs so far. 
Close monitoring of potential 
immune-mediated diseases in 
clinical development programs 
using adjuvant systems. The 
potential risk for events of 
possible autoimmune aetiology 
to occur is mentioned in the 
Informed Consent Form (ICF). 
Study Procedures 
Risk of blood sampling 
Blood sampling associated 
risk of syncope, dizziness, 
infection at the site after or 
during venepuncture. 
Blood samples will be obtained 
by a trained professional and 
medical assistance will be 
available. 
The potential risk of feeling 
faint, or experiencing mild local 
pain, bruising, irritation or 
redness at the site where blood 
was taken, is mentioned in the 
ICF. The amount of blood to be 
taken for sampling will not be 
harmful to the subject’s health 
(see section 5.6.14). 
1.3.2. 
Benefit Assessment 
• 
Contribution to the process of developing of a vaccine against AECOPD. 
• 
Medical evaluations/assessments associated with this study (i.e. physical 
examination). 
1.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimise risks to subjects participating in this 
study, the potential and/or known risks identified in association with the candidate 
NTHi-Mcat vaccines are justified by the anticipated benefits that may be afforded to 
patients for the prevention of AECOPD. 
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2. 
OBJECTIVES 
2.1. 
Primary objective 
• 
To evaluate the safety and reactogenicity profile of the NTHi-Mcat vaccine 
administered according to two vaccination schedules 
Refer to Section 10.1 for the definition of the primary endpoints. 
2.2. 
Secondary objectives  
• 
To evaluate the long term safety profile.  
• 
To evaluate the humoral immunogenicity of the NTHi-Mcat investigational vaccine.  
• 
To evaluate the cellular immunogenicity (CD4+ T cell response) of the NTHi-Mcat 
investigational vaccine.  
Refer to Section 10.2 for the definition of the secondary endpoints. 
2.3. 
Tertiary objectives 
• 
To explore the T helper profile to the PD-, PE-, PilA-, UspA2 -specific CD4+/ CD8+ 
T cell responses. 
• 
To evaluate the cellular immunogenicity (CD8+ T cell response) of the NTHi-Mcat 
investigational vaccine.  
• 
To collect blood samples for assay development/validation and/or for additional 
evaluation of the immune responses to the investigational vaccine and to other 
potential pathogens involved in AECOPD.  
Refer to Section 10.3 for the definition of the tertiary endpoints and to section 10.11.1 for 
the reporting of tertiary endpoint results.  
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• 
Study groups: 
− 
Schedule 1 : Approximately 100 subjects receiving three doses of the AS01E-
adjuvanted GSK Biologicals' NTHi-Mcat investigational vaccine containing 10 
µg of PD, 10 µg of PE-PilA, and 3.3 µg of UspA2 at Visit 1 (Day 1), Visit 3 
(Day 61) and Visit 5 (Day 181) and one dose of placebo at Visit 7 (Day 361). 
− 
Schedule 2 : Approximately 100 subjects receiving three doses of the AS01E-
adjuvanted GSK Biologicals' NTHi-Mcat investigational vaccine containing 10 
µg of PD, 10 µg of PE-PilA, and 3.3 µg of UspA2 at Visit 1 (Day 1), Visit 3 
(Day 61) and Visit 7 (Day 361) and one dose of placebo at Visit 5 (Day 181). 
Table 1 
Study groups and epochs foreseen in the study 
Study groups 
Number of subjects 
Age (Min/Max) 
Epochs 
Epoch 001 
Epoch 002 
Schedule 1 
100 
40 – 80 years 
x 
x 
Schedule 2 
100 
40 – 80 years 
x 
x 
Table 2 
Study groups and treatment foreseen in the study 
Treatment name 
Vaccine/Product name 
Study Groups 
Schedule 1 
Schedule 2 
 10-10-3/AS01E  
NTHi-Mcat 10-10-3   
x 
x 
AS01E  
x 
x 
Placebo  
Formulation buffer S9b  
x 
x 
• 
Vaccination schedule: at Visit 1 (Day 1), Visit 3 (Day 61), Visit 5 (Day 181) and 
Visit 7 (Day 361).  
• 
Treatment allocation: Subjects will be allocated to a study group using a centralised 
randomisation system on internet (SBIR).  
• 
Blinding: observer-blind (Epoch 001) and open (Epoch 002). 
Table 3 
Blinding of study epochs 
Study Epochs 
Blinding 
Epoch 001 
observer-blind 
Epoch 002 
open 
• 
Sampling schedule:  
− 
Blood samples for assessment of humoral immunogenicity will be collected 
from all subjects at Visit 1 (Day 1), Visit 4 (Day 91), Visit 5 (Day 181), Visit 6 
(Day 211), Visit 7 (Day 361), Visit 8 (Day 391), Visit 9 (Day 541) and Visit 10 
(Day 721)*.  
− 
Blood samples for assessment of cell-mediated immunogenicity (CMI) will be 
collected from all subjects in the CMI sub-cohort at Visit 1 (Day 1), Visit 4 (Day 
91), Visit 5 (Day 181), Visit 6 (Day 211), Visit 7 (Day 361) and Visit 8 (Day 
391). 
Refer to Section 5.6.18 for study procedures to be considered during special 
circumstances. 
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• 
Type of study: self-contained. 
• 
Data collection: Electronic Case Report Form (eCRF), Diary Cards and Phone 
contacts. 
• 
Safety monitoring: Safety evaluations will be performed by the Safety Review Team 
(SRT) (blinded). Refer to Section 8.10 for description of safety monitoring. 
4. 
STUDY COHORT 
4.1. 
Number of subjects/centres 
This will be a multi-centre study. 
The target is to enrol 100 eligible adult subjects aged 40 to 80 years having a significant 
smoking history (≥ 10 pack-years) per study group (i.e. 200 subjects in total). Refer to 
Section 10.4 for a detailed description of the criteria used in the estimation of the sample 
size. 
Approximately 20% of the subjects (40 subjects in total) will be part of a sub-cohort 
for CMI analysis. An additional blood sample will be taken from these subjects at 
specified timepoints (Visits 1 [Day 1], 4 [Day 91], 5 [Day 181], 6 [Day 211], 7 [Day 361] 
and 8 [Day 391]). The CMI sub-cohort will be selected from sites able to process the 
blood samples according to GSK procedures for peripheral blood mononuclear cell 
(PBMC) preparation. 
Table 4 
Sub-cohorts 
Sub-cohort name 
Description 
Estimated number of subjects 
Sub-cohort for CMI 
At specific timepoints (Visit 1, 4, 5, 6, 7 and 8), 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) 
4.2. 
Inclusion criteria for enrolment 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity, regulatory acceptability of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
All subjects must satisfy ALL the following criteria at study entry: 
• 
Subjects who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the Diary Cards, completion of 
blood draws, return for follow-up visits). 
• 
Written informed consent obtained from the subject prior to performing any study 
specific procedure. 
• 
A male or female between, and including, 40 and 80 years of age at the time of the 
first vaccination. 
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• Current or former smoker with a cigarette smoking history of ≥ 10 pack-years.  
Please refer to the glossary of terms for the definitions of pack-years and of current 
and former smoker. 
• 
Female subjects of non-childbearing potential may be enrolled in the study.  
− 
Non-childbearing potential is defined as pre-menarche, current bilateral tubal 
ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause.  
Please refer to the glossary of terms for the definition of menarche and menopause. 
• Female subjects of childbearing potential may be enrolled in the study, if the subject: 
− 
has practiced adequate contraception for 30 days prior to vaccination, and 
− 
has a negative pregnancy test on the day of vaccination and 
− 
has agreed to continue adequate contraception during the entire treatment period 
and for 2 months after completion of the vaccination series. 
Please refer to the glossary of terms for the definition of adequate contraception. 
4.3. 
Exclusion criteria for enrolment 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity, regulatory acceptability of the study or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
The following criteria should be checked at the time of study entry. If ANY exclusion 
criterion applies, the subject must not be included in the study: 
• 
Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccines during the period starting 30 days before the first dose of study 
vaccines (Day -29 to Day 1), or planned use during the study period. 
• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe. 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting six 
months prior to the first vaccine dose. For corticosteroids, this will mean prednisone 
 20 mg/day, or equivalent. Inhaled and topical steroids are allowed. 
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first and ending 30 days after the 
last dose of vaccine administration, with the exception of any influenza or 
pneumococcal vaccine which may be administered ≥ 15 days preceding or following 
any study vaccine dose. 
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• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the subject has been or will be exposed to an investigational or a 
non-investigational vaccine/product (pharmaceutical product or device). 
• 
Previous vaccination with any vaccine containing NTHi and/or Mcat antigens.  
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required). 
• 
History of or current autoimmune disease. 
• 
History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine. 
• 
Acute disease and/or fever at the time of enrolment. 
− 
Fever is defined as temperature  37.5°C. The preferred location for measuring 
temperature in this study will be the oral cavity or the axilla. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever may be enrolled at the discretion of the investigator.  
• 
Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the first dose of study vaccine or planned administration 
during the study period. 
• 
Pregnant or lactating female. 
• 
Current alcoholism and/or drug abuse. 
Please refer to the glossary of terms for the definition of alcoholism. 
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions. 
• 
Diagnosed with a respiratory disorder (e.g. asthma, COPD, sarcoidosis, tuberculosis, 
bronchiectasis, lung fibrosis, pulmonary embolism, pneumothorax, or physician 
confirmed lung cancer).  
• 
Has significant disease (including significant neurological or psychological 
disorders), in the opinion of the investigator, likely to interfere with the study and/or 
likely to cause death within the study duration.  
• 
Malignancies within previous 5 years (excluding non-melanoma skin cancer) or 
lymphoproliferative disorders.  
• 
Any other condition that the investigator judges may interfere with study findings.  
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5. 
CONDUCT OF THE STUDY 
5.1. 
Regulatory and ethical considerations, including the 
informed consent process 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with the ICH Guideline for GCP, all 
applicable subject privacy requirements and the guiding principles of the Declaration of 
Helsinki.  
GSK will obtain favourable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. 
Conduct of the study includes, but is not limited to, the following: 
• 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
• 
Subject informed consent.  
• 
Investigator reporting requirements as stated in the protocol. 
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both. 
Freely given and written or witnessed/ thumb printed informed consent must be obtained 
from each subject, as appropriate, prior to participation in the study.  
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Clinical judgement, local regulations and requirements should guide the final 
structure and content of the local version of the ICF.  
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC. 
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5.2. 
Subject identification and randomisation 
5.2.1. 
Subject identification 
Subject identification numbers will be assigned sequentially to the subjects who have 
consented to participate in the study, according to the range of subject identification 
numbers allocated to each study centre. 
5.2.2. 
Randomisation of treatment 
5.2.2.1. 
Randomisation of supplies 
The randomisation of supplies within blocks will be performed at GSK Biologicals, using 
MATerial EXcellence (MATEX), a program developed for use in Statistical Analysis 
System (SAS®) (Cary, NC, USA) by GSK Biologicals. Entire blocks will be shipped to 
the study centres /warehouse(s). 
5.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose.  
5.2.2.2.1. Study group allocation 
The target will be to enrol approximately 200 eligible subjects who will be randomly 
assigned to two study groups in a (1:1) ratio (approximately 100 subjects in each group). 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomisation system on internet (SBIR).  
After obtaining the signed and dated ICF from the subject and having checked the 
eligibility of the subject, the site staff in charge of the vaccine administration will access 
SBIR. Upon providing the subject identification number, the randomisation system will 
determine the study group and will provide the treatment number to be used for 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, please refer to the SBIR user guide or the Study Procedures 
Manual (SPM) for specific instructions. 
5.2.2.2.2. Treatment number allocation for subsequent doses  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
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The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
5.3. 
Method of blinding  
As the investigational NTHi-Mcat vaccine in this study is of different appearance than 
the placebo and the investigational NTHi-Mcat vaccine will have to be reconstituted 
whereas the placebo does not, double-blinding is not feasible.  
Data of Epoch 1 will be collected in an observer-blind manner. By observer-blind, it is 
meant that during the course of the study, the vaccine recipient and those responsible for 
the evaluation of any study endpoint (e.g. safety, reactogenicity) will all be unaware of 
whether vaccine or placebo was administered.  
Data of Epoch 2 (long-term safety follow-up) will be collected in an open manner, as a 
clinical study report will be developed with all completed and cleaned data collected up 
to and including Visit 9 (Day 541 - Primary Completion Date). 
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 (e.g. study nurse) 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. 
5.4. 
General study aspects 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM. The SPM provides the investigator and the site 
personnel with administrative and detailed technical information that does not impact the 
safety of the subjects. 
 
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5.5. 
Outline of study procedures 
(Amended 26 May 2020) 
Table 5 
List of study procedures 
Epoch 
Epoch 001 
Epoch 
002 
Type of contact 
Visit 1 
Phone 
contact 
1 
Visit 2 Visit 3 
Phone 
contact 
2 
Visit 4 
Visit 5 
Phone 
contact 
3 
Visit 6 
Visit 7 
Phone 
contact 
4 
Visit 8 
Visit 9 Visit 10 i 
Timepoints 
Day 1 
Day 8 Day 31 Day 61 Day 68 Day 91 Day 181 Day 188 Day 211 Day 361 Day 368 Day 391 Day 541 Day 721 
h 
Sampling timepoints 
Pre-
Vacc I 
 
 
 
 
Post-
Vacc II 
Pre-Vacc 
III 
 
Post-
Vacc III 
Pre-
Vacc IV 
 
Post-
Vacc IV 
Post-
Vacc IV 
Post-
Vacc IV  
Informed consent  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion/exclusion criteria  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect demographic data  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Smoking exposure history (ATS-DLD-78A 
questionnaire) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measure/record height and weight  
● 
 
 
 
 
 
 
 
 
 
 
O a 
O a 
 
Physical examination  
● 
 
O a 
O a 
 
O a 
O a 
 
O a 
O a 
 
O a 
● 
● 
Urine pregnancy test b 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
 
Check contraindications to vaccination  
O 
 
 
O d 
 
 
O d 
 
 
O d 
 
 
 
 
Pre-vaccination body temperature  
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
 
Vaccines 
Study group and treatment number allocation  
O 
 
 
O 
 
 
O 
 
 
O 
 
 
 
 
Vaccine administration  
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
 
60 minutes post-injection assessment 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
 
Laboratory Assays 
Blood sampling for antibody determination (~20 
ml)  
● f  
 
 
 
 
● 
● f  
 
● 
● f  
 
● 
● 
●h 
Blood sampling for CMI response (~40 ml) c  
● f 
 
 
 
 
● 
● f  
 
● 
● f  
 
● 
 
 
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Epoch 
Epoch 001 
Epoch 
002 
Type of contact 
Visit 1 
Phone 
contact 
1 
Visit 2 Visit 3 
Phone 
contact 
2 
Visit 4 
Visit 5 
Phone 
contact 
3 
Visit 6 
Visit 7 
Phone 
contact 
4 
Visit 8 
Visit 9 Visit 10 i 
Timepoints 
Day 1 
Day 8 Day 31 Day 61 Day 68 Day 91 Day 181 Day 188 Day 211 Day 361 Day 368 Day 391 Day 541 Day 721 
h 
Sampling timepoints 
Pre-
Vacc I 
 
 
 
 
Post-
Vacc II 
Pre-Vacc 
III 
 
Post-
Vacc III 
Pre-
Vacc IV 
 
Post-
Vacc IV 
Post-
Vacc IV 
Post-
Vacc IV  
Safety assessments 
Distribution of Subject Card  
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distribution of Diary cards  
O 
 
 
O 
 
 
O 
 
 
O 
 
 
 
 
Return and review of Diary cards  
 
 
O 
 
 
O 
 
 
O 
 
 
O 
 
 
Diary card transcription  
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
Record any concomitant 
medications/vaccinations associated with an AE  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Record any intercurrent medical conditions e g 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of AEs e g 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs e g 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of pIMDs e  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of pregnancies e  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study Conclusion  
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
Note: The double-line border following Day 541 indicates the final analysis which will be performed on all data (i.e. data that are as clean as possible) obtained up to that timepoint.  
Vacc: vaccination.  
● is used to indicate a study procedure that requires documentation in the individual eCRF. 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF. 
a This procedure will be performed only if deemed necessary by the Investigator or delegate. 
b Only for women of childbearing potential.  
c  Only for subjects in the sub-cohort for CMI.  
d Refer to Section 6.5 for more details on study procedures for subjects meeting contraindications to subsequent vaccination before administration of vaccine Dose 2, 3 and 4.  
e  Please refer to Section 8.3 for recording periods of local and general solicited AEs, unsolicited AEs, SAEs, (S)AEs leading to study withdrawal, SAEs related to study 
vaccine(s)/product(s), intercurrent medical conditions, pIMDs and pregnancies.  
f Blood sampling must occur prior to vaccination. 
g. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs or SAEs (refer to Section 8.1 for safety 
definitions), and routine procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance with the time period set out in 
Table 16 
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h. The timepoints for Visit 10 and for blood sampling may change according to extended intervals. Refer to Section 5.6.18 for study procedures to be considered during 
special circumstances and Table 6 for details on visit intervals 
i Visit 10 may be a telephone contact during special circumstances. Refer to Section 5.6.18 for study procedures to be considered during special circumstances.  
 
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Whenever possible, the investigator should arrange study visits within the interval 
described in Table 6. 
Table 6 
Intervals between study visits  
(Amended 26 May 2020) 
Interval 
Optimal length of interval 
Allowed interval 
Visit 1  → Phone contact 1 
7 days 
7 - 9  days 
Visit 1  → Visit 2 
30 days 
30  - 45 days 
Visit 1  → Visit 3 
60 days 
60  - 75  days1 
Visit 3 →  Phone contact 2 
7 days 
7 - 9 days 
Visit 3  → Visit 4 
30 days 
30  - 45  days 1 
Visit 3 → Visit 5 
120 days 
120  - 150 days 1 
Visit 5 → Phone contact 3 
7 days 
7 - 9 days 
Visit 5  → Visit 6 
30 days 
30  - 45 days  1 
Visit 5 → Visit 7 
180 days 
180  – 210 days 1 
Visit 7  → Phone contact 4 
7 days 
7 – 9 days 
Visit 7 → Visit 8 
30 days 
30  – 45  days  1 
Visit 7 → Visit 9 
180 days 
180 – 210 days 1 
Visit 7 → Visit 10 
360 days 
360  – 390 days (+120 days 
under special 
circumstances)^1 
1 Subjects will not be eligible for inclusion in the per-protocol set (PPS) for analysis of immunogenicity if the study visit 
is performed outside this interval. 
^ Refer to Section 5.6.18 for study procedures to be considered during special circumstances. Impact on the 
per protocol set for immunogenicity will be determined on a case by case basis 
5.6. 
Detailed description of study procedures 
5.6.1. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 5.1 for the requirements on how to obtain 
informed consent. 
5.6.2. 
Check inclusion and exclusion criteria 
Check all inclusion and exclusion criteria as described in Sections 4.2 and 4.3 before 
enrolment.  
5.6.3. 
Collect demographic data 
Record demographic data such as year of birth, sex, race and ethnicity in the subject’s 
eCRF. 
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5.6.4. 
Medical history 
Obtain the subject’s medical history by interview and/or review of the subject’s medical 
records and record any pre-existing conditions or signs and/or symptoms present in a 
subject prior to the first study vaccination in the eCRF. 
5.6.5. 
Smoking status 
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. 
5.6.6. 
Smoking exposure history 
Smoking history will be obtained by means of a self-administered questionnaire (which 
will be part of the ATS-DLD-78A questionnaire) provided to the subjects, in which they 
will give answers about their smoking history, including duration (number of years) and 
number of cigarettes smoked. 
Please refer to the SPM for more details on questionnaire. 
From the information obtained via the questionnaire, calculate the pack-years using the 
following calculation (also refer to the glossary of terms for the definitions of pack-years) 
Please note that pipe and/or cigar use should not be used to calculate pack-year history: 
Total pack-years = Average no. cigarettes smoked / day x no. years of smoking 
20 
All data will be recorded in the subject’s eCRF. 
5.6.7. 
Measure/record height and weight 
Measure height and weight of the subject and record the data in the ‘Physical 
examination’ section of the eCRF. 
5.6.8. 
Physical examination 
At Visit 1, Visit 9 and Visit 10, 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 (including vital signs) at Visit 2 up to and including Visit 8 will be 
performed only if deemed necessary by the Investigator or delegate. 
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled within the allowed 
interval for this visit (see Table 6). 
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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.  
5.6.9. 
Urine Pregnancy test 
Female subjects of childbearing potential are to have a urine pregnancy test prior to any 
study vaccine administration. The study vaccine may only be administered if the urine 
pregnancy test is negative.  
Note: the urine pregnancy test must be performed even if the subject is menstruating at 
the time of the study visit. 
5.6.10. 
Check contraindications to vaccination 
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Section 6.5 for more details.  
5.6.11. 
Assess pre-vaccination body temperature 
The oral or axillary body temperature of all subjects needs to be measured prior to any 
study vaccine administration. If the subject has fever (fever is defined as temperature 
 37.5°C) on the day of vaccination, the vaccination visit will be rescheduled within the 
allowed interval for this visit (see Table 6). 
5.6.12. 
Study group and treatment number allocation 
Study group and treatment number allocation will be performed as described in Section 
5.2.2. The number of each administered treatment must be recorded in the eCRF. 
5.6.13. 
Study Vaccine administration 
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered intramuscularly (IM) preferably in the deltoid of the non-
dominant arm (refer to Section 6.3 for detailed description of the vaccine administration 
procedure). If the investigator or delegate determines that the subject’s health on the day 
of administration temporarily precludes vaccine administration, the visit will be 
rescheduled within the allowed interval for this visit (refer to Table 6). 
The subjects will be observed closely for at least 60 minutes following the administration 
of the vaccine, with appropriate medical treatment readily available in case of 
anaphylaxis. 
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5.6.14. 
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. 
5.6.14.1. 
Blood sampling for immune response assessments  
(Amended 26 May 2020) 
Blood samples will be taken during certain study visits as specified in Table 5 (List of 
Study Procedures). Blood sampling should occur prior to vaccine administration on days 
where vaccines are administered.   
Blood samples for humoral immunogenicity 
A volume of approximately 20 mL of whole blood should be drawn from all subjects for 
each analysis of humoral immune response at each pre-defined timepoint (Visit 1, Visit 4, 
Visit 5, Visit 6, Visit 7, Visit 8, Visit 9 and Visit 10)*. After whole blood processing into 
serum, serum samples should be kept at –20°C until shipment. Refer to the SPM and 
Central Laboratory manual for more details on sample storage conditions. 
* Refer to Section 5.6.18 for study procedures to be considered during special 
circumstances. 
Blood samples for CMI 
A volume of approximately 40 mL of whole blood should be drawn from all subjects 
included in the immunogenicity sub-cohort for analysis of cell-mediated immune (CMI) 
response at each pre-defined timepoint (Visit 1, Visit 4, Visit 5, Visit 6, Visit 7 and Visit 
8). The samples should be kept at room temperature and should be shipped as soon as 
possible (maximum 8 hours after whole blood collection) so that the CMI laboratory can 
start cell separation processing within 24 hours of collection. Refer to the SPM and 
Central Laboratory manual for more details on sample storage conditions. 
5.6.15. 
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 6.6. 
Intercurrent medical conditions must be checked and recorded in the eCRF as described 
in Section 6.7. 
5.6.16. 
Distribution of Subject Card 
For information regarding the Subject Card, please refer to Section 8.9. 
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5.6.17. 
Recording of AEs, SAEs, pregnancies and pIMDs 
(Amended 26 May 2020) 
• 
Refer to Section 8.3 for procedures for the investigator to record AEs, SAEs, 
pregnancies and pIMDs. Refer to Section 8.4 for guidelines and how to report SAE, 
pregnancy and pIMD reports to GSK Biologicals. Refer to the telephone script for 
more details on what should be collected during the Phone contacts. 
• 
The subjects will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.  
• 
At each vaccination visit, paper diary cards will be provided to the subject. The 
subject will be instructed to measure and record the oral or axillary body 
temperature, any solicited local/general (i.e. on the day of vaccination and during the 
next 6 days) or any unsolicited AEs (occurring on the day of vaccination and during 
the next 29 days after each vaccination). The subject will be instructed to return the 
completed diary card to the investigator at the next study visit. 
• 
Collect and verify completed diary cards during discussion with the subject on Visit 
2, Visit 4, Visit 6, and Visit 8. 
• 
Any unreturned diary cards will be sought from the subject through telephone call(s) 
or any other convenient procedure.  
• 
The investigator will transcribe the collected information into the eCRF in English. 
For Epoch 002, this includes the assessment of COVID-19 cases in accordance with 
the WHO definition. Refer to Section 5.6.18 and 8.3.1 for details.  
5.6.18. 
Study procedures during special circumstances 
(Amended 26 May 2020) 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled participants (still 
participating in the study) for Visit 10: 
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 6), then the interval may be extended 
up to a maximum length of 120 days (i.e. allowed interval for Visit 10 = 360 to 390 
days +120 days under special circumstances).  
• 
In case, a physical visit to the clinic is not possible in any circumstances even with 
the extended interval, safety follow-up may be made by a telephone call or other 
means of virtual contact, if appropriate. The telephone call/ mode of virtual 
contact will be considered equivalent to study conclusion visit. 
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5.6.19. 
Study conclusion 
The investigator will: 
• 
Review data collected to ensure accuracy and completeness 
• 
Complete the Study Conclusion screen in the eCRF. 
5.7. 
Biological sample handling and analysis 
Please refer to the SPM and Central Laboratory manual for details on biospecimen 
management (handling, storage and shipment). 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
• 
Collected samples will be used for protocol mandated research and purposes related 
to the improvement, development and quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these 
tests, the maintenance or improvement of these tests, the development of new test 
methods, as well as making sure that new tests are comparable to previous methods 
and work reliably. 
• 
It is also possible that future findings may make it desirable to use the samples 
acquired in this study for future research, not described in this protocol. Therefore, 
all subjects in countries where this is allowed will be asked to give a specific consent 
to allow GSK or a contracted partner to use the samples for future research. Future 
research will be subject to the laws and regulations in the respective countries and 
will only be performed once an independent Ethics Committee or Review Board has 
approved this research. 
Information on further investigations and their rationale can be obtained from GSK 
Biologicals.  
Any sample testing will be done in line with the consent of the individual subject.  
Refer also to the Investigator Agreement, where it is noted that the investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).  
Collected samples will be stored for a maximum of 20 years (counting from when the last 
subject performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the subject 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals. 
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5.7.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals and/or a central laboratory, it is 
MANDATORY that all clinical samples (including serum samples) be collected and 
stored exclusively using those materials in the appropriate manner. The use of other 
materials could result in the exclusion of the subject from the per-protocol analysis (See 
Section 10.5 for the definition of cohorts to be analysed). The investigator must ensure 
that his/her personnel and the laboratory(ies) under his/her supervision comply with this 
requirement. However, when GSK Biologicals and/or a central laboratory does not 
provide material for collecting and storing clinical samples, appropriate materials from 
the investigator’s site must be used. Refer to the Module on Clinical Trial Supplies in the 
SPM and to the Central Laboratory investigator manual. 
5.7.2. 
Biological samples 
(Amended 26 May 2020) 
Table 7 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Sub-cohort 
Blood for humoral immunogenicity 
20 
ml 
• 
Visit 1 (Day 1) 
• 
Visit 4 (Day 91) 
• 
Visit 5 (Day 181) 
• 
Visit 6 (Day 211) 
• 
Visit 7 (Day 361) 
• 
Visit 8 (Day 391) 
• 
Visit 9 (Day 541) 
• 
Visit 10 (Day 721)** 
All enrolled subjects 
Blood for CMI 
40 
ml 
• 
Visit 1 (Day 1) 
• 
Visit 4 (Day 91) 
• 
Visit 5 (Day 181) 
• 
Visit 6 (Day 211) 
• 
Visit 7 (Day 361) 
• 
Visit 8 (Day 391) 
Sub-cohort for CMI* 
*Refer to Section 4.1 for sub-cohort description. 
** Refer to Section 5.6.18 for study procedures to be considered during special circumstances and Table 6 for 
details on extended visit interval. 
5.7.3. 
Laboratory assays 
Please refer to APPENDIX A for a detailed description of the assays performed in the 
study. Please refer to APPENDIX B for the address of the clinical laboratories used for 
sample analysis. 
Humoral antibody responses  
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory or a 
GSK designated laboratory using qualified procedures. 
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Table 8 
Humoral Immunity (Antibody determination)  
System 
Component 
Method 
Kit / Manufacturer 
Unit* 
Cut-off* 
Laboratory 
SERUM 
anti-PilA antibody  
ELISA 
In house 
EU/mL  
8 
GSK 
Biologicals** 
or GSK 
designated 
laboratory 
anti-PE antibody  
16 
anti-PD antibody  
153 
anti-UspA2 antibody  
28 
EU/mL = ELISA unit per millilitre 
*Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of assay re-optimization, 
qualification, (re)validation or standardization). In this case, this will be documented in the clinical study report. 
**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany. 
Other assays may be developed and/or validated on blood samples with the aim to 
measure the immune response to any component of either the NTHi-Mcat investigational 
vaccines and/or to other respiratory pathogens. The research may include but is not 
limited to functional assays such as serum bactericidal activity assays against NTHi 
and/or Mcat. 
Cell-mediated immune responses  
CMI assays will be performed at GSK Biologicals or GSK designated laboratory using 
qualified procedures. 
Table 9 
Cell-mediated Immunity (CMI) using flow cytometry 
System 
Component Family 
Scale 
Method 
Unit 
Laboratory 
PBMCs 
Specific CD4+/CD8+ 
T-cells 
Quantitative 
Flow 
cytometry ICS 
Number of specific 
CD4+/CD8+ T-cells /106 
GSK Biologicals* 
or GSK designated 
laboratory 
PBMC = peripheral blood mononuclear cell; ICS = intracellular cytokine staining 
*GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany. 
Additional testing on peripheral blood mononuclear cells (PBMCs), such as, but not 
limited to, evaluation of NTHi and/or Mcat-specific memory B-cells, intracellular 
cytokine staining (ICS) testing using other bacterial antigens, may be done during the 
study or after study completion, should these data be required for accurate interpretation 
of the data and/ or for further research related to the investigational vaccine and/ or the 
disease, should such test(s) become available at GSK Biologicals’ laboratory or a 
laboratory designated by GSK Biologicals. 
Additional exploratory testing related to the vaccine and/or the disease under study may 
be performed on the samples within the framework of the study if deemed necessary for 
accurate interpretation of the data or should such assay(s) become available at GSK. 
These assays may not be represented in the objectives/endpoints of the study protocol. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
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5.7.4. 
Biological samples evaluation 
5.7.4.1. 
Immunological read-outs 
(Amended 26 May 2020) 
Table 10 
Immunological read-outs 
Blood sampling timepoint 
Sub-cohort 
Name 
No. subjects 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 1 (Day 1) 
Pre-Vacc I 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 4 (Day 91) 
Post-Vacc II 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 5 (Day 181) 
Pre-Vacc III 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 6 (Day 211) 
Post-Vacc III 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 7 (Day 361) 
Pre-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 8 (Day 391) 
Post-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort* 
~40 
Specific CD4+/CD8+ T-cells 
Visit 9 (Day 541) 
Post-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
Visit 10 (Day 
721)** 
Post-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
*Approximately 20% of the subjects in each group will be part of a sub-cohort for CMI analysis. 
** Refer to Section 5.6.18 for study procedures to be considered during special circumstances and Table 6 for 
details on extended visit interval. 
5.7.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigens used in the candidate vaccine. 
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6. 
STUDY VACCINES AND ADMINISTRATION 
6.1. 
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 vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained.  
The vaccines are labelled and packed according to applicable regulatory requirements. 
Table 11 
Study vaccines 
Treatment 
name 
Vaccine/ 
product name 
Formulation 
Presentation 
Volume to 
be 
administered 
Number of 
doses 
10-10-
3/AS01E 
NTHi-Mcat 10-10-3  
PD=10µg; PE-PilA=10µg; 
UspA2=3.3µg  
Freeze-dried 
antigens in 
monodose 
vial  
0.5 ml  
3 
AS01E  
MPL=25µg; QS21=25µg; 
Liposomes  
Liquid in 
monodose 
vial  
Placebo 
Formulation buffer 
S9b  
Na2HPO4=0.4mg; 
KH2PO4=56µg; 
NaCl=1,16mg; KCl=30µg; 
MgCl2=15µg  
Liquid in 
monodose 
vial  
0.5 ml  
1 
MPL = 3-O-desacyl-4′-monophosphoryl lipid A; QS-21 =  Quillaja saponaria Molina, fraction 21 (Licensed by GSK from 
Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA corporation). 
6.2. 
Storage and handling of study vaccines 
The study vaccines must be stored at the respective label storage temperature conditions 
in a safe and locked place. Access to the storage space should be limited to authorized 
study personnel. The storage conditions will be assessed during pre-study activities under 
the responsibility of the sponsor study contact. The storage temperature should be 
continuously monitored with calibrated (if not validated) temperature monitoring 
device(s) and recorded. Refer to the Module on Clinical Trial Supplies in the SPM for 
more details on storage of the study vaccines. 
Temperature excursions must be reported in degree Celsius. 
Any temperature excursion outside the range of 0.0 to +8.0C (for +2 to +8°C label 
storage condition) impacting investigational medicinal products (IMPs) must be reported 
in the appropriate (electronic) temperature excursion decision form ([e]TDF). The 
impacted IMPs must not be used and must be stored in quarantine at label temperature 
conditions until usage approval has been obtained from the sponsor. 
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In case of temperature excursion below +2.0°C down to 0.0°C impacting IMP(s) there is 
no need to report in (e)TDF, but adequate actions must be taken to restore the +2 to +8°C 
label storage temperature conditions. The impacted IMP(s) may still be administered, but 
the site should avoid re-occurrence of such temperature excursion. Refer to the Module 
on Clinical Trial Supplies in the SPM for more details on actions to take. 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
6.3. 
Dosage and administration of study vaccines 
Table 12 
Dosage and administration 
Type of contact 
and timepoint 
Study 
group 
Treatment 
name 
Volume to 
be 
administered 
Route 1 
Site 
Location Directionality2 Laterality3 
Visit 1 (Day 1) 
Schedule 1 10-10-3/AS01E 
0.5 ml 
IM 
Deltoid 
Upper 
Non-
dominant  
Schedule 2 
Visit 3 (Day 61) 
Schedule 1 10-10-3/AS01E 
0.5 ml 
IM 
Deltoid 
Upper 
Non-
dominant  
Schedule 2 
Visit 5 (Day 181) Schedule 1 10-10-3/AS01E 
0.5 ml 
IM 
Deltoid 
Upper 
Non-
dominant  
Schedule 2 
Placebo 
Visit 7 (Day 361) Schedule 1 
Placebo 
0.5 ml 
IM 
Deltoid 
Upper 
Non-
dominant  
Schedule 2  10-10-3/AS01E  
1 Intramuscular (IM) 
2 Directionality is a qualifier for further detailing the location of the vaccine administration (e.g. Upper, Lower) 
3 The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the non-
dominant arm, an injection in the dominant arm may be performed. 
The investigational NTHi-Mcat vaccine needs to be reconstituted. Please refer to the 
SPM for more detailed instructions on study vaccine preparation. 
6.4. 
Replacement of unusable vaccine doses 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomisation when applicable), at least 20 % additional vaccine doses will be 
supplied to replace those that are unusable.  
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomisation. 
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6.5. 
Contraindications to subsequent vaccination 
The following events constitute absolute contraindications to further administration of 
NTHi-Mcat vaccine. If any of these events occur during the study, the subject must not 
receive additional doses of vaccine but may continue other study procedures at the 
discretion of the investigator (see Section 8.5). 
• 
Anaphylaxis following the administration of vaccine. 
• 
Pregnancy (see Section 8.2.1).  
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).  
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
• 
Current auto-immune disease.  
• 
Malignancy (excluding non-melanotic skin cancer and carcinoma in situ of the 
cervix, if considered cured) or lymphoproliferative disorder. 
• 
Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, exposes the subject to unacceptable risk from subsequent 
vaccination. In such cases, the investigator should use his/her clinical judgement 
prior to administering the next dose of the vaccine. Refer to Section 8.1.5.1 for the 
definition of pIMDs. 
The following events constitute contraindications to administration of NTHi-Mcat 
vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (see Section 5.5), or the subject may be withdrawn at the 
discretion of the investigator (see Section 8.5).  
• 
Acute disease and/or fever at the time of vaccination.  
− 
Fever is defined as temperature  37.5°C. The preferred location for measuring 
temperature in this study will be the oral cavity or the axilla. 
− 
Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines at the discretion of the 
investigator. 
6.6. 
Concomitant medications/products and concomitant 
vaccinations 
At each study visit/contact, the investigator or delegate should question the subject about 
any medications/products taken and vaccinations received by the subject. 
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6.6.1. 
Recording of concomitant medications/products and 
concomitant vaccinations 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF. 
• 
All concomitant vaccines or medications or products, associated with an AE, except 
vitamins and dietary supplements, administered during the entire study period 
following the first dose of study vaccine (Day 1 to Day 721). 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring [fever is defined as 
temperature  37.5°C]. The preferred location for measuring temperature in this 
study will be the oral cavity or the axilla. 
• 
Any concomitant medications/products/vaccines listed in Section 6.6.2. 
• 
Any concomitant medications/products/vaccines relevant to a SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of a SAE/pIMD. In addition, concomitant medications relevant to SAEs 
and pIMD need to be recorded on the expedited Adverse Event report. 
6.6.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses 
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 10.5 for cohorts to be analysed. 
• 
Any investigational or non-registered product (drug or vaccine) other than the study 
vaccines used during the study period.  
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the study period. For corticosteroids, this will 
mean prednisone  20 mg/day, or equivalent. Inhaled and topical steroids are 
allowed. 
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 
• 
A vaccine not foreseen by the study protocol administered during the period starting 
30 days before the first dose and ending at 30 days after the last dose of vaccine 
administration*, with the exception of any influenza or pneumococcal vaccine which 
may be administered ≥ 15 days preceding or following any study vaccine dose. 
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* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organised by the public health authorities, outside the routine 
immunisation program, the time period described above can be reduced if necessary 
for that vaccine provided it is licensed and used according to its Summary of Product 
Characteristics (SmPC) or Prescribing Information and according to the local 
governmental recommendations and provided a written approval of the Sponsor is 
obtained. 
• 
Immunoglobulins and/or any blood products administered during the study period. 
• 
Drug and/or alcohol abuse. 
6.7. 
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses 
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition that may lead to 
elimination from per-protocol analyses. If it is the case, the condition(s) must be recorded 
in the eCRF. 
Subjects may be eliminated from the per-protocol cohort for immunogenicity if, during 
the study, they incur a condition that has the capability of altering their immune response 
or are confirmed to have an alteration of their initial immune status. 
7. 
HEALTH ECONOMICS 
Not applicable. 
8. 
SAFETY 
The investigator or site staff is/are responsible for the detection, documentation and 
reporting of events meeting the criteria and definition of an adverse event (AE) or serious 
adverse event (SAE) as provided in this protocol.  
Each subject will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious. 
8.1. 
Safety definitions 
8.1.1. 
Definition of an adverse event 
An AE is any untoward medical occurrence in a clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
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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: 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study 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 study vaccine administration. 
• 
Pre- or post-treatment events that occur as a result of protocol-mandated procedures 
(i.e. invasive procedures, modification of subject’s previous therapeutic regimen). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 8.1.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
Examples of an AE DO NOT include: 
• 
Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE. 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
• 
Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF. 
8.1.2. 
Definition of a serious adverse event  
A SAE is any untoward medical occurrence that: 
a. 
Results in death, 
b. Is life-threatening, 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe. 
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 
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that occur during hospitalisation are also considered AEs. If a complication prolongs 
hospitalisation or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalisation’ occurred or was necessary, the 
AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition (known or 
diagnosed prior to informed consent signature) that did not worsen from baseline is 
NOT considered an AE. 
d. Results in disability/incapacity, OR 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza like illness, and accidental trauma (e.g. sprained 
ankle) which may interfere or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study subject. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalisation. 
8.1.3. 
Solicited adverse events 
Solicited local and general AEs occurring during a 7-day follow-up period after each 
vaccination (i.e. the day of vaccination and the 6 subsequent days) and unsolicited AEs 
occurring during a 30-day follow-up period after each vaccination (i.e. the day of 
vaccination and the 29 subsequent days), will be reported via diary cards. In addition, 
subjects will be asked at Phone contacts if there were any safety concerns in the last 7 
days; this information will be recorded via the appropriate section of the eCRF. 
8.1.3.1. 
Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
Table 13 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
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8.1.3.2. 
Solicited general adverse events 
The following general AEs will be solicited: 
Table 14 
Solicited general adverse events 
Fatigue  
Fever  
Gastrointestinal  symptoms† 
Headache  
Myalgia  
Chills  
†Gastrointestinal symptoms include nausea, vomiting, diarrhoea and/or abdominal pain. 
Note: Subjects will be instructed to measure and record the oral or axillary body 
temperature in the evening. Should additional temperature measurements be performed at 
other times of day, subjects will be instructed to record the highest temperature in the 
diary card. 
8.1.4. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events  
In absence of diagnosis, abnormal laboratory findings (e.g. clinical chemistry, 
haematology, urinalysis) or other abnormal assessments that are judged by the 
investigator to be clinically significant will be recorded as AE or SAE if they meet the 
definition of an AE or SAE (refer to Sections 8.1.1 and 8.1.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline 
and significantly worsen following the start of the study will also be reported as AEs or 
SAEs.  
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
8.1.5. 
Adverse events of specific interest 
8.1.5.1. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 15. In case of further updates to the 
pIMDs list, the investigators will be notified in a written communication. No further 
protocol amendments will be released.  
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 15 
List of potential immune-mediated diseases  
Neuroinflammatory disorders 
Musculoskeletal disorders 
 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and 
paresis (e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants. 
• 
Acute disseminated 
encephalomyelitis, including 
site specific variants e.g.: 
non-infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic inflammatory 
demyelinating 
polyneuropathy,  
- 
Multifocal motor 
neuropathy  
- 
Polyneuropathies 
associated with 
monoclonal 
gammopathy. 
• 
Narcolepsy. 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), 
including: 
- 
Diffuse Scleroderma 
- 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis  
- 
Polymyositis  
• 
Anti-synthetase syndrome. 
• 
Rheumatoid Arthritis and 
associated conditions 
including:  
- 
Juvenile Idiopathic 
Arthritis 
- 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, 
including:  
- 
Ankylosing Spondylitis,  
- 
Reactive Arthritis 
(Reiter's Syndrome), 
- 
Undifferentiated 
Spondyloarthritis, 
- 
Psoriatic Arthritis, 
- 
Enteropathic arthritis. 
• 
Relapsing Polychondritis. 
• 
Mixed Connective Tissue 
disorder. 
• 
Gout. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localised Scleroderma 
(Morphoea). 
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Vasculitis 
 
Blood disorders 
 
Others 
• 
Large vessels vasculitis 
including:  
- 
Giant Cell Arteritis 
(Temporal Arteritis), 
- 
Takayasu's Arteritis.  
• 
Medium sized and/or small 
vessels vasculitis including:  
- 
Polyarteritis nodosa, 
- 
Kawasaki's disease,  
- 
Microscopic 
Polyangiitis,  
- 
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis),  
- 
Churg–Strauss 
syndrome (allergic 
granulomatous angiitis 
or eosinophilic 
granulomatosis with 
polyangiitis),  
- 
Buerger’s disease 
(thromboangiitis 
obliterans),  
- 
Necrotizing vasculitis 
(cutaneous or 
systemic),  
- 
anti-neutrophil 
cytoplasmic antibody 
(ANCA) positive 
vasculitis (type 
unspecified), 
- 
Henoch-Schonlein 
purpura (IgA vasculitis),  
- 
Behcet's syndrome, 
- 
Leukocytoclastic 
vasculitis. 
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic 
anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune glomerulonephritis 
including: 
- 
IgA nephropathy,  
- 
Glomerulonephritis 
rapidly progressive,  
- 
Membranous 
glomerulonephritis,  
- 
Membranoproliferative 
glomerulonephritis,  
- 
Mesangioproliferative 
glomerulonephritis.  
- 
Tubulointerstitial nephritis 
and uveitis syndrome. 
• 
Ocular autoimmune diseases 
including: 
- 
Autoimmune uveitis  
- 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
 
Liver disorders 
Gastrointestinal disorders 
 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing 
cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel disease, 
including: 
- 
Crohn’s disease,  
- 
Ulcerative colitis,  
- 
Microscopic colitis,  
- 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave's or Basedow’s disease. 
• 
Diabetes mellitus type I. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune 
syndrome. 
• 
Autoimmune hypophysitis. 
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as a pIMD. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely. 
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In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to the above 
diagnoses will be available to investigators at study start. 
8.2. 
Events or outcomes not qualifying as adverse events or 
serious adverse events 
8.2.1. 
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 8.4.1 and 8.4.3: 
• 
Spontaneous pregnancy loss, including: 
− 
spontaneous abortion (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA , 2006]. It is recognized that national 
regulations might be different. 
• 
Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life). 
• 
Any congenital anomaly or birth defect (as per [CDC MACDP] guidelines) 
identified in the offspring of a study subject (either during pregnancy, at birth or 
later) regardless of whether the foetus is delivered dead or alive. This includes 
anomalies identified by prenatal ultrasound, amniocentesis or examination of the 
products of conception after elective or spontaneous abortion. 
Furthermore, any SAE occurring as a result of a post-study pregnancy AND considered 
by the investigator to be reasonably related to the study vaccine will be reported to GSK 
Biologicals as described in Section 8.4.3. While the investigator is not obligated to 
actively seek this information from former study participants, he/she may learn of a 
pregnancy through spontaneous reporting. 
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8.3. 
Detecting and recording adverse events, serious adverse 
events and pregnancies 
8.3.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
(Amended 26 May 2020) 
All AEs starting within 30 days following administration of each dose of study vaccine 
(Day 1 to Day 30) must be recorded into the appropriate section of the eCRF, irrespective 
of intensity or whether or not they are considered vaccination-related. 
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end at the last study visit. See Section 8.4 for instructions on reporting of 
SAEs. 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine. 
For Epoch 002, this includes the assessment of COVID-19 cases in accordance with 
the current WHO definition. Cases should be categorised as AEs (unsolicited or AEs 
leading to withdrawal) or SAEs (refer to Section 8.1 for safety definitions), and routine 
procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs 
should be followed in accordance with the time period set out in Table 16. 
In addition to the above-mentioned reporting requirements and in order to fulfil 
international reporting obligations, SAEs that are related to study participation (i.e. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine will be collected and recorded from the 
time the subject consents to participate in the study until she/he is discharged from the 
study. 
The time period for collecting and recording pregnancies will begin at the first receipt of 
study vaccine and will end at last study visit. See section 8.4 for instructions on reporting 
of pregnancies. 
The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccine and will end at the last study visit. See section 8.4 for instructions on 
reporting of pIMDs. 
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 16. 
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Table 16 
Reporting periods for collecting safety information 
Event 
Visit 1 
Dose 1 
6 d 
post 
Dose 1 
29 d 
post 
Dose 1 
 
Visit 3 
Dose 2 
6 d 
post 
Dose 2 
29 d 
post 
Dose 2 
 
Visit 5  
Dose 3 
6 d 
post 
Dose 3 
29 d 
post 
Dose 3 
 
Visit 7 
Dose 4 
6 d 
post 
Dose 4 
29 d 
post 
Dose 4 
Study 
conclusi
on 
Timepoint 
Day 1 
Day 7 
Day 30 
 
Day 61 
Day 67 
Day 90 
 
Day 
181 
Day 
187 
Day 
210 
 
Day 
361 
Day 
367 
Day 
390 
Day 721 
Solicited local and 
general AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the 
study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs ** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to 
study participation  
or concurrent GSK 
medication/vaccine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions leading to 
exclusion per 
protocol** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* i.e. consent obtained. The double-bordered lines indicate timings of vaccination. 
** During Epoch 002, if a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as (S)AEs leading to withdrawal) or 
SAEs (refer to Section 8.1 for safety definitions), and routine procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be followed in 
accordance with the defined time period. 
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8.3.2. 
Post-Study adverse events and serious adverse events 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 16. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE at 
any time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study vaccine, the investigator will promptly notify the 
Study Contact for Reporting SAEs. 
8.3.3. 
Evaluation of adverse events and serious adverse events 
8.3.3.1. 
Active questioning to detect adverse events and serious adverse 
events 
As a consistent method of collecting AEs, the subject should be asked a non-leading 
question such as: 
‘Have you felt different in any way since receiving the vaccine or since the previous 
visit?’ 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE in the eCRF. The investigator is not allowed to send photocopies of the 
subject’s medical records to GSK Biologicals instead of appropriately completing the 
eCRF. However, there may be instances when copies of medical records for certain cases 
are requested by GSK Biologicals. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to GSK Biologicals. 
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms. 
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8.3.3.2. 
Assessment of adverse events 
8.3.3.2.1. Assessment of intensity  
The intensity of the following solicited AEs will be assessed as described: 
Table 17 
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 
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 
Myalgia 
0 
Normal  
 
1 
Mild: Myalgia that is easily tolerated 
 
2 
Moderate: Myalgia that interferes with normal activity 
 
3 
Severe: Myalgia that prevents normal activity 
Chills 
0 
None 
 
1 
Chills that are easily tolerated 
2 
Chills that interfere with normal activity 
3 
Chills that prevent normal activity 
*Fever is defined as temperature  37.5°C. The preferred location for measuring temperature in this study will be the 
oral cavity or the axilla. 
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
The maximum intensity of local injection site redness/swelling will be scored at GSK 
Biologicals as follows: 
0: < 20 mm diameter 
1:  20 mm to  50 mm diameter 
2: > 50 mm to  100 mm diameter 
3: > 100 mm diameter 
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Temperature (in this study preferred location to measure the temperature is oral cavity or 
axilla) will be scored at GSK Biologicals as follows: 
0: < 37.5°C 
1: 37.5°C to 37.9°C 
2: 38.0°C to 38.9°C 
3: ≥ 39.0°C 
The intensity of each AE and SAE should be assigned to one of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with 
normal everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities. Such an AE 
would, for example, prevent attendance at work/school and 
would necessitate the administration of corrective therapy.  
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 
3 is a category used for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets one of the pre-
defined outcomes as described in Section 8.1.2. 
8.3.3.2.2. Assessment of causality 
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement. In case of concomitant 
administration of multiple vaccines/products, if possible, the investigator should specify 
if the AE could be causally related to a specific vaccine/product administered (i.e. 
investigational, control/placebo or co-administered vaccine). When causal relationship to 
a specific vaccine(s)/product(s) cannot be determined the investigator should indicate the 
AE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study vaccine will be considered and investigated. The investigator will also consult the 
IB to determine his/her assessment. 
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the Expedited Adverse Events Report to GSK Biologicals. The 
investigator may change his/her opinion of causality in light of follow-up information and 
update the SAE information accordingly. The causality assessment is one of the criteria 
used when determining regulatory reporting requirements. 
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All solicited local (injection site) and general reactions will be considered causally related 
to vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
Is there a reasonable possibility that the AE may have been caused by the study vaccine? 
YES 
: 
There is a reasonable possibility that the study 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 8.1.2), additional 
examinations/tests will be performed by the investigator in order to determine ALL 
possible contributing factors for each SAE. 
Possible contributing factors include: 
• 
Medical history. 
• 
Other medication. 
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine, if applicable. 
• 
Erroneous administration. 
• 
Other cause (specify). 
8.3.3.3. 
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). 
8.3.3.4. 
Medically attended visits 
For each solicited and unsolicited symptom the subject experiences, the subject will be 
asked if he/she received medical attention defined as hospitalisation, or an otherwise 
unscheduled visit to or from medical personnel for any reason, including emergency 
room visits. This information will be recorded in the eCRF. 
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8.4. 
Reporting of serious adverse events, pregnancies, and 
other events 
8.4.1. 
Prompt reporting of serious adverse events, pregnancies, and 
other events to GSK Biologicals 
SAEs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 18, once the investigator determines that 
the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 8.3 will be reported promptly 
to GSK within the timeframes described in Table 18, once the investigator becomes 
aware of the pregnancy.  
pIMDs that occur in the time period defined in Section 8.3 will be reported promptly to 
GSK within the timeframes described in Table 18, once the investigator determines that 
the event meets the protocol definition of a pIMD. 
Table 18 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
Pregnancies 
2 weeks* 
electronic pregnancy report 
2 weeks* 
electronic pregnancy report 
pIMDs 
24 hours** ‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
* Timeframe allowed after receipt or awareness of the information. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD. 
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD. 
8.4.2. 
Contact information for reporting serious adverse events, 
pregnancies and pIMDs 
Study Contact for Reporting SAEs, pIMDs and pregnancies 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs, pIMDs and pregnancies 
24/24 hour and 7/7 day availability: 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax:
 
Email address:
 
Canadian sites only: 
Fax: 
 
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8.4.3. 
Completion and transmission of SAE reports to GSK Biologicals 
Once an investigator becomes aware that a SAE has occurred in a study subject, the 
investigator (or designate) must complete the information in the electronic Expedited 
Adverse Events Report WITHIN 24 HOURS. The report will always be completed as 
thoroughly as possible with all available details of the event. Even if the investigator does 
not have all information regarding a SAE, the report should still be completed within 24 
hours. Once additional relevant information is received, the report should be updated 
WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the SAE causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the SAE. 
8.4.3.1. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
8.4.4. 
Completion and transmission of pregnancy reports to GSK 
Biologicals 
Once the investigator becomes aware that a subject is pregnant, the investigator (or 
designate) must complete the required information onto the electronic pregnancy report 
WITHIN 2 WEEKS. 
Note: Conventionally, the estimated gestational age (EGA) of a pregnancy is dated from 
the first day of the last menstrual period (LMP) of the cycle in which a woman conceives. 
If the LMP is uncertain or unknown, dating of EGA and the estimated date of delivery 
(EDD) should be estimated by ultrasound examination and recorded in the pregnancy 
report. 
8.4.5. 
Reporting of pIMDs to GSK Biologicals 
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
designate) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
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event, in accordance with the pIMD standard questionnaire provided. Even if the 
investigator does not have all information regarding a pIMD, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD. 
Refer to Section 8.4.3.1 for back-up system in case the electronic reporting system does 
not work. 
8.4.6. 
Updating of SAE, pregnancy, and pIMD information after removal 
of write access to the subject’s eCRF 
When additional SAE, pregnancy or pIMD information is received after removal of the 
write access to the subject’s eCRF, new or updated information should be recorded on the 
appropriate paper report, with all changes signed and dated by the investigator. The 
updated report should be faxed to the Study Contact for Reporting SAEs (refer to the 
Sponsor Information) or to GSK Biologicals Clinical Safety and Pharmacovigilance 
department within the designated reporting time frames specified in Table 18. 
8.4.7. 
Regulatory reporting requirements for serious adverse events 
The investigator will promptly report all SAEs to GSK in accordance with the procedures 
detailed in Section 8.4.1. GSK Biologicals has a legal responsibility to promptly notify, 
as appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation. Prompt notification of SAEs by the 
investigator to the Study Contact for Reporting SAEs is essential so that legal obligations 
and ethical responsibilities towards the safety of other subjects are met. 
Investigator safety reports are prepared according to the current GSK policy and are 
forwarded to investigators as necessary. An investigator safety report is prepared for a 
SAE(s) that is both attributable to the study vaccine and unexpected. The purpose of the 
report is to fulfil specific regulatory and GCP requirements, regarding the product under 
investigation. 
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8.5. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
8.5.1. 
Follow-up of adverse events and serious adverse events  
8.5.1.1. 
Follow-up during the study 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject and provide additional relevant information on the subject’s condition to GSK 
Biologicals (within 24 hours for SAEs; refer to Table 18). 
All SAEs and pIMDs (serious or non-serious) documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the last visit of the subject. 
All AEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until 30 
days after the last vaccination. 
8.5.1.2. 
Follow-up after the subject is discharged from the study 
The investigator will follow subjects: 
• 
With SAEs, pIMDs (serious or non-serious), or subjects withdrawn from the study as 
a result of an AE, until the event has resolved, subsided, stabilised, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK Biologicals using a paper/ electronic 
Expedited Adverse Events Report and/or pregnancy report as applicable. 
GSK Biologicals may request that the investigator performs or arranges the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
subject dies during participation in the study or during a recognised follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
8.5.2. 
Follow-up of pregnancies 
Pregnant subjects will be followed to determine the outcome of the pregnancy. At the end 
of the pregnancy, whether full-term or premature, information on the status of the mother 
and child will be forwarded to GSK Biologicals using the electronic pregnancy report and 
the Expedited Adverse Events Report if applicable. Generally, the follow-up period 
doesn’t need to be longer than six to eight weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs for this study, if the pregnancy outcome is a 
SAE, it should always be reported as SAE. 
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8.6. 
Treatment of adverse events 
Treatment of any AE is at the sole discretion of the investigator and according to current 
good medical practice. Any medication administered for the treatment of a SAE / pIMDs 
should be recorded in Expedited Adverse Event Report of the subject’s eCRF (refer to 
Section 6.6). 
8.7. 
Unblinding 
GSK Biologicals’ policy (which incorporates ICH E2A guidance, EU Clinical Trial 
Directive and US Federal Regulations) is to unblind the report of any SAE which is 
unexpected and attributable/suspected to be attributable to the study vaccine, prior to 
regulatory reporting. The GSK Biologicals’ Central Safety Physician is responsible for 
unblinding the treatment assignment in accordance with the specified timeframes for 
expedited reporting of SAEs (refer to Section 8.4.1). 
8.8. 
Emergency unblinding 
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency, or in the event of a serious medical condition, when knowledge of 
the treatment is essential for the clinical management or welfare of the subject, as judged 
by the investigator. 
The emergency unblinding process consists of the automated system SBIR that allows the 
investigator to have unrestricted, immediate and direct access to the subject’s individual 
study treatment. 
The investigator has the option of contacting a GSK Biologicals’ On-call Central Safety 
Physician (or Backup) if he/she needs medical advice or needs the support of GSK to 
perform the unblinding (i.e. he/she cannot access the automated Internet-based system). 
Any emergency unblinding must be fully documented by using the Emergency 
Unblinding Documentation Form, which must be appropriately completed by the 
investigator and sent within 24 hours to GSK Biologicals. 
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GSK Biologicals’ Contact information for Emergency Unblinding 
24/24 hour and 7/7 day availability 
GSK Biologicals’ Central Safety Physician: 
Outside US/Canada: 
 (GSK Biologicals Central Safety Physician on-call) 
For US/Canada only: 
 (GSK Biologicals Central Safety Physician on-call) 
GSK Biologicals’ Central Safety Physician Back-up: 
Outside US/Canada: 
 
US/Canada only: 
 
Emergency Unblinding Documentation Form transmission: 
Outside US & Canada: 
Fax: 
 
US/Canada only: 
Fax: 
 
8.9. 
Subject card 
Study subjects must be provided with the address and telephone number of the main 
contact for information about the clinical study. 
The investigator (or designate) must therefore provide a “subject card” to each subject. In 
an emergency situation this card serves to inform the responsible attending physician that 
the subject is in a clinical study and that relevant information may be obtained by 
contacting the investigator. 
Subjects must be instructed to keep subject cards in their possession at all times during 
the study duration. 
8.10. 
Safety monitoring 
8.10.1. 
Safety Review Team 
The project’s SRT includes as core members the GSK Biologicals’ Central Safety 
Physician, Epidemiologist, the Clinical Research & Development Lead (CRDL), Clinical 
Regulatory Affairs representative and the Biostatistician of the project. The SRT is 
responsible for on-going safety monitoring (blinded) of the entire project and meets on a 
regular basis (at least once per year). Additional meetings will be convened as required 
for events requiring urgent review or ad hoc when significant new safety data becomes 
available as recommended. 
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9. 
SUBJECT COMPLETION AND WITHDRAWAL 
9.1. 
Subject completion 
A subject who returns for the concluding visit foreseen in the protocol is considered to 
have completed the study. 
9.2. 
Subject withdrawal 
Withdrawals will not be replaced. 
9.2.1. 
Subject withdrawal from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit foreseen in the protocol.  
All data collected until the date of withdrawal/last contact of the subject will be used for 
the analysis. 
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact. 
Investigators will make an attempt (3 telephone calls [once every 3 days] and a certified 
letter to the last known address) to contact those subjects who do not return for scheduled 
visits or follow-up.  
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw a subject from the study was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Unsolicited non-serious adverse event. 
• 
Solicited adverse event 
• 
Protocol violation (specify). 
• 
Consent withdrawal, not due to an adverse event*. 
• 
Moved from the study area. 
• 
Lost to follow-up. 
• 
Other (specify). 
*In case a subject is withdrawn from the study because he/she/the subject’s parent(s) has 
withdrawn consent, the investigator will document the reason for withdrawal of consent, 
if specified by the subject/subject’s parent(s), in the eCRF. 
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Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 8.5.1.2). 
9.2.2. 
Subject withdrawal from study vaccines 
A ‘withdrawal’ from the study vaccines refers to any subject who does not receive the 
complete treatment, i.e. when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccines may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(safety or immunogenicity) if planned in the study protocol.  
Information relative to premature discontinuation of the study vaccines will be 
documented on the Vaccine Administration screen of the eCRF. The investigator will 
document whether the decision to discontinue further vaccination/treatment was made by 
the subject himself/herself, or by the investigator, as well as which of the following 
possible reasons was responsible for withdrawal: 
• 
Serious adverse event. 
• 
Unsolicited non-serious adverse event. 
• 
Solicited adverse event 
• 
Not willing to be vaccinated 
• 
Other (specify). 
10. 
STATISTICAL METHODS 
10.1. 
Primary endpoints 
• 
Solicited local and general symptoms. 
− 
Occurrence of each solicited local and general symptom (any and Grade 3) 
reported within 7 days (Day 1 – Day 7) after each vaccination, within each 
vaccination schedule.  
• 
Unsolicited adverse events.  
− 
Occurrence of each unsolicited AE reported within 30 days (Day 1 – Day 30) 
after any vaccination, according to the Medical Dictionary for Regulatory 
Activities (MedDRA) classification, within each vaccination schedule.  
• 
Serious adverse events.  
− 
Occurrence of any serious adverse events reported from Day 1 (Visit 1) up to 
and including Day 541 (Visit 9), within each vaccination schedule. 
• 
Potential Immune-mediated diseases (pIMDs).  
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− 
Occurrence of pIMDs reported from Day 1 (Visit 1) up to and including Day 
541 (Visit 9), within each vaccination schedule. 
10.2. 
Secondary endpoints  
• 
Serious Adverse events  
− 
Occurrence of any serious adverse events reported from Day 541 (Visit 9) up to 
and including Day 721 (Visit 10), within each vaccination schedule.  
• 
Potential Immune-mediated diseases (pIMDs).  
− 
Occurrence of pIMDs reported from Day 541 (Visit 9) up to and including Day 
721 (Visit 10), within each vaccination schedule.  
• 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody concentrations, as measured by 
ELISA, at Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 
721, within each vaccination schedule.  
• 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 seropositivity, as measured by ELISA, 
at Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 541 and Day 721, 
within each vaccination schedule.  
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD4+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour 
necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 91, Day 
181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and within each 
vaccination schedule. 
10.3. 
Tertiary endpoint  
CMI: 
• 
T helper profile of the specific CD4+ (CD8+) T cell response based on the 
expression of T helper 1, T helper 2 and T helper 17 specific markers at Day 1, Day 
91, Day 181, Day 211, Day 361 and Day 391, within each vaccination schedule.  
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD8+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour 
necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 91, Day 
181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and within each 
vaccination schedule.  
10.4. 
Determination of sample size 
Primary objective 
In this study, a third injection will be given either at 6 months or at 12 months in order to 
verify the safety of the third dose. 
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Considering the sample size of 100 in each vaccination schedule, Table 19 illustrates the 
precision we can get on the percentage of subjects with grade 3 symptoms following a 
third vaccination. 
A sample size of 100 subjects allows a 2-sided 95% confidence interval with a width 
equal to 0.165 when the sample proportion is equal to 20%, using a simple asymptotic 
formula. 
Table 19 
Exact confidence interval for one proportion 
 
N=100 subjects 
N=90 subjects* 
% of subjects 
 with a symptom 
Exact 95% Confidence Interval (CI) 
Exact 95% Confidence Interval (CI) 
Lower Limit 
Upper limit 
Lower Limit 
Upper limit 
0 
0.0 
3.6 
0.0 
4.0 
5 
1.6 
11.3 
1.5 
11.7 
10 
4.9 
17.6 
4.7 
18.1 
15 
8.6 
23.5 
8.3 
24.1 
20 
12.7 
29.2 
12.3 
29.8 
25 
16.9 
34.7 
16.5 
35.2 
30 
21.2 
40.0 
20.8 
40.6 
35 
25.7 
45.2 
25.2 
45.8 
40 
30.3 
50.3 
29.8 
50.9 
45 
35.0 
55.3 
34.5 
55.8 
50 
39.8 
60.2 
39.3 
60.7 
55 
44.7 
65.0 
44.2 
65.5 
60 
49.7 
69.7 
49.1 
70.2 
65 
54.8 
74.3 
54.2 
74.8 
70 
60.0 
78.8 
59.4 
79.2 
75 
65.3 
83.1 
64.8 
83.5 
80 
70.8 
87.3 
70.2 
87.7 
Computation is done using PASS12. 
*Considering a 10% drop out rate. 
Table 19 gives confidence intervals for observed events for 90 to 100 subjects. 
Table 20 shows the probability to observe a rare adverse event (such as a rare serious AE) 
in the total study population (approximately 200 subjects). 
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Table 20 
Poisson probability to observe at least one event with rare 
frequency (μ) 
N 
μ 
μ*N 
p>0 
p≤0 
200 
0.01 
2.0 
0.87 
0.13 
200 
0.011 
2.2 
0.89 
0.11 
200 
0.012 
2.4 
0.91 
0.09 
200 
0.013 
2.6 
0.93 
0.07 
200 
0.014 
2.8 
0.94 
0.06 
200 
0.015 
3.0 
0.95 
0.05 
200 
0.016 
3.2 
0.96 
0.04 
200 
0.017 
3.4 
0.97 
0.03 
200 
0.018 
3.6 
0.97 
0.03 
200 
0.019 
3.8 
0.98 
0.02 
200 
0.02 
4.0 
0.98 
0.02 
200 
0.021 
4.2 
0.99 
0.01 
200 
0.022 
4.4 
0.99 
0.01 
200 
0.023 
4.6 
0.99 
0.01 
200 
0.024 
4.8 
0.99 
0.01 
200 
0.025 
5.0 
>0.99 
<0.01 
Computation is done using SAS 9.2 
Assuming 200 subjects exposed (100 subject in each arm), if the incidence to present a 
serious or severe event is 1.50%, the probability to observe at least 1 event would equal 
95%. This probability will be larger if the incidence is larger than 1.5%.  
In absence of event, we would assume either than the incidence is lower or that the false-
negative risk of an incidence equal or higher than 1.50% is 5% [Hanley, 1983]. 
Secondary objectives: 
Humoral immunogenicity after third dose 
The intent of this secondary objective is to evaluate the improvement of the persistence of 
antibody response at one month after a third injection. An increase in the antibody titres 
compared to the second dose is expected. 
Approximately a 10% drop out is expected for the third dose evaluation (given at 6 
months for one arm and at 12 months for the other arm) and thus 90 evaluable subjects 
are expected to be analysed for the humoral immunogenicity evaluation.  
A sample size of 90 evaluable subjects achieves 90% power to detect a difference of 
0.256 between the null hypothesis mean of 0.0 and the alternative hypothesis mean with a 
known standard deviation of 0.83 and with a significance level (alpha) of 0.05 using a 
one-sided one-sample t-test. 
CMI immunogenicity after third dose  
This second secondary objective aims to investigate on the cellular immunogenicity in a 
subset of 20 subjects per arm (40 subjects in total).  
CMI will be evaluated as frequency of CD4+ T-cells expressing at least two different 
markers, when stimulated by each antigen PD, PE, PilA and UspA2. 
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No inferential analysis is planned for CMI data and thus 40 subjects are considered to be 
sufficient for the purpose to report mean, median, min, max, Q1 and Q3 and represent 
them via boxplot. 
10.5. 
Cohorts for Analyses 
The following study cohorts will be evaluated. 
10.5.1. 
Exposed set 
The exposed set (ES) will include all subjects with at least 1 study vaccine administration 
documented, with respect to the vaccine actually administered: 
• 
A safety analysis based on the ES will include all subjects with at least one vaccine 
dose administered and who provided safety data. 
10.5.2. 
Full Analysis Set 
The full analysis set (FAS) will include all subjects with at least 1 study vaccine 
administration for whom immunogenicity data are available: 
• 
An immunogenicity analysis based on the FAS will include all vaccinated subjects 
for whom immunogenicity data are available. 
The FAS analysis will be performed per treatment as planned in the randomization. 
10.5.3. 
Per-protocol set for analysis of immunogenicity  
(Amended 26 May 2020) 
The per-protocol set (PPS) for immunogenicity will include all subjects in the FAS: 
• 
Who met all eligibility criteria. 
• 
For whom the administration of the vaccines was according to protocol. 
• 
Who complied with the vaccination schedule, as specified in Table 12 and Table 6. 
• 
Who received the study vaccines according to protocol procedures. 
• 
Who did not receive a concomitant medication/ product leading to elimination from 
the PPS (per-protocol) analysis (see Section 6.6.2) up to the 1 month post-Dose 4 
visit (Day 391). 
• 
Who did not present an intercurrent medical condition leading to elimination from 
the PPS analysis for immunogenicity (see Section 6.7), up to the 1 month 
post-Dose 4 visit (Day 391). 
• 
Who complied with the blood sample timings as specified in Table 10 and Table 6. 
• 
For whom post-vaccination immunogenicity results are available for at least 1 assay. 
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Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
10.6. 
Derived and transformed data 
Demography 
• 
For a given subject and a given demographic variable, missing measurement will not 
be replaced. 
Safety 
• 
For solicited symptoms, missing or unevaluable measurements will not be replaced. 
Therefore the analysis of the solicited symptoms based on the ES will include only 
subjects/doses with documented safety data (i.e., symptom screen/sheet completed). 
• 
For the unsolicited symptoms and concomitant medications/ products/ vaccinations, 
all vaccinated subjects will be considered and subjects who miss reporting 
symptoms/concomitant medications/ products/ vaccinations will be treated as 
subjects without unsolicited symptoms or concomitant medications/ products/ 
vaccinations, respectively. 
Immunogenicity 
• 
Calculation of the GMCs will be performed by taking the anti-logarithm in base 10 
(anti-log10) of the mean of the log10 concentration transformations. 
• 
Antibody concentrations below the assay cut-off will be given an arbitrary value of 
half the assay cut-off for the purpose of geometric mean concentration (GMC) 
calculation. 
• 
A seronegative subject is defined as a subject whose antibody concentration is below 
the assay cut-off value (i.e. the ELISA lower limit of quantification). 
• 
A seropositive subject is defined as a subject whose antibody concentration is greater 
than or equal to the assay cut-off value (i.e. the ELISA lower limit of quantification). 
• 
For a given subject and the analysis of a given immunogenicity measurement, 
missing or unevaluable measurements will not be replaced. 
CMI  
• 
The frequency of CD4+ or CD8+ T-cells producing two or more markers (such as 
interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), tumour necrosis factor 
alpha (TNF-α), upon in vitro stimulation with the antigen (induction condition) is 
calculated by adding an offset of 0.5 to the number of activated CD4+/CD8+ T cells 
(numerator) divided by the total number of CD4+/CD8+ T cells involved 
(denominator).  
• 
The frequency of antigen-specific CD4+ or CD8+ T-cells for each individual subject 
is calculated as the difference between the frequency of CD4+ or CD8+ T-cells 
producing at least 2 cytokines/markers among IFN-, IL-2, IL-13, IL-17, TNF- 
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and/or CD40L, upon in vitro stimulation with the antigen (induction condition) 
minus the frequency of CD4+ or CD8+ T-cells producing at least 2 cytokines upon 
in vitro stimulation in medium only (background condition). For descriptive statistics 
purposes, differences less or equal to zero (0) are imputed to 1.  
10.7. 
Analysis of demographics 
Demographic characteristics such as age at enrolment, sex, race, ethnicity and smoking 
status will be summarised by study group using descriptive statistics: 
• 
Frequency tables will be generated for categorical variable such as sex, race, 
ethnicity, age category, smoking status; 
• 
Mean, median, standard deviation, minimum and maximum will be provided for 
continuous data such as age. 
The distribution of subjects enrolled among the study sites will be tabulated as a whole 
and per study group. 
Withdrawal status will be summarised by group using descriptive statistics: 
• 
The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal; 
• 
The number of subjects enrolled into the study as well as the number of subjects 
excluded from PPS and FAS will be tabulated. 
No inferential analyses of demographic data are planned. 
10.8. 
Analysis of safety 
The analysis for safety will be performed on the ES. 
The number and percentage of subjects with at least one local solicited AE, with at least 
one general solicited AE and with any solicited AE during the 7-day follow-up period 
after each vaccination, will be tabulated with exact 95% confidence interval (CI), after 
each vaccination and overall by study group. The percentage of doses followed by at least 
one local solicited AE, by at least one general solicited AE and by any solicited AE will 
be tabulated overall by group with exact 95% CIs. The same computations will be done 
for Grade 3 solicited AEs.  
The number and percentage of subjects reporting each individual solicited local and 
general AE during the 7-day follow-up period will be tabulated with exact 95% CI after 
each vaccination and overall by vaccine schedule. The percentage of doses followed by 
each individual solicited local and general AE will be tabulated overall by group with 
exact 95% CIs. 
The same tabulation will be performed for Grade 3 AEs. 
For fever, additional analyses will be performed by 0.5°C increments. 
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All the unsolicited adverse events occurring within 30 days after each vaccination, judged 
either as probably related, possibly related, or not related to vaccination by the 
investigator, will be recorded.  
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 at least one unsolicited AE during 
the 30-day follow-up period after any study vaccination will be tabulated with its exact 
95% CI for each group and by MedDRA PT. Similar tabulation will be done for the 
percentage of doses, for Grade 3 unsolicited symptoms. 
The number of subjects who experienced any pIMD or any SAE from first vaccination 
up to 12 months post-Dose 4 will be reported. 
The number of subjects who experienced any SAE, death, pIMD or AE leading to 
study withdrawal, from first vaccination up to study conclusion, and any SAE related 
to study participation of concurrent GSK medication/ vaccination, during the entire 
study period, will be reported. 
In case of Pregnancy during the study, data follow-up and pregnancy outcomes will be 
described in detail. 
The percentage of subjects using concomitant medication/ product associated with an 
AE will be summarised per group for each study vaccination and overall study 
vaccination. 
10.9. 
Analysis of immunogenicity 
The analysis will be performed on the PPS at first line. If the percentage of vaccinated 
subjects with serological results excluded from the PPS is more than 10%, a second 
analysis will be performed on the FAS. 
10.9.1. 
Within groups assessment 
For each group and at each timepoint during which blood samples are collected for 
humoral immune response (at Day 1, Day 91, Day 181, Day 211, Day 361, Day 391, Day 
541 and Day 721), and for each component (PD, PE, PilA and UspA2), the following will 
be computed: 
• 
Seropositivity rate and associated 95% CI (See Table 8 for assay cut-off values). 
• 
GMCs and their 95% CIs. 
• 
Percentage of subjects with fold increase including 2-fold, 4-fold and 8-fold increase 
from baseline and associated 95% CI. 
The distribution of antibody concentrations will be displayed using Reverse Cumulative 
Curves. 
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The GMC ratios will be computed for each timepoint by using an ANCOVA model on 
the logarithm base10 transformation of the concentrations. This model will include the 
study group, country, age category (40 - 59 years or 60 - 80 years) and smoking status 
(current or former smokers) as factors and pre-Dose 1 concentration (as covariate). 
The difference in terms of seropositivity rate at each timepoint will be also evaluated, 
presenting point estimate and the 95% CIs at each time point.   
10.9.2. 
Cell-mediated immune response 
CMI induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting the 
frequencies (including mean, medium, minimum and maximum) of antigen-specific 
CD4+ /CD8+T cells per 106 cells. The specific CD4+/ CD8+T cells being identified as 
the CD4+/ CD8+ T cells expressing at least 2 different cytokines/activation markers 
among CD40 Ligand (CD40L), IL-2, TNF-, IFN- γ, IL-13 and IL-17 upon in vitro 
stimulation. A descriptive statistic (Min, Q1, Median, Q3 & Max) will be reported for 
each group at Day 1, Day 91, Day 181, Day 211, Day 361 and Day 391. 
10.10. 
Interpretation of analyses 
All safety and immunogenicity analyses are planned with the intention to estimate the 
safety and immune response after a third injection. No comparisons are planned for this 
study and if comparative analyses will be performed they will be done with alpha level of 
5% without alpha adjustment.  
10.11. 
Conduct of analyses 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report. 
10.11.1. 
Sequence of analyses 
• 
The analyses will be performed stepwise: 
− 
A final analysis of the primary epoch including all data from the two vaccination 
schedules up to and including Day 541 (Visit 9) will be performed in a first step. 
A complete clinical study report, containing all data of the primary epoch will be 
written and made available to the investigators at this stage. 
− 
Analyses conducted on the data collected during the follow- up epoch up to and 
including Day 721 (Visit 10) will be performed in a second step. 
An integrated clinical study report containing all data and analyses of the primary 
and follow-up epoch will be written and made available to the investigators. 
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10.11.2. 
Statistical considerations for interim analyses 
No interim analysis is planned for this study.  Data up to and including Day 541 (i.e. Visit 
9) are considered ‘final’ and completed data, while the remaining 6 months open label 
safety data are considered long-term safety follow-up. 
11. 
ADMINISTRATIVE MATTERS 
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality, public disclosure requirements and 
publications must be fulfilled.  
11.1. 
Electronic Case Report Form instructions 
A validated GSK defined electronic data collection tool will be used as the method for 
data collection.  
In all cases, subject initials will not be collected nor transmitted to GSK. Subject data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures. 
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction by the investigator or appropriately qualified designee. In all 
cases, the investigator remains accountable for the study data.  
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the study report is 
complete and approved by all parties. 
11.2. 
Study Monitoring by GSK Biologicals 
GSK will monitor the study to verify that, amongst other items, the:  
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol, any other 
study agreements, GCP and all applicable regulatory requirements.  
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits. 
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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 eCRF review and a Source Document 
Verification (SDV). By SDV we understand verifying eCRF entries by comparing them 
with the source data that will be made available by the investigator for this purpose.  
The Source Documentation Agreement Form describes the source data for the different 
data in the eCRF. This document should be completed and signed by the site monitor and 
investigator and should be filed in the investigator’s study file. Any data item for which 
the eCRF will serve as the source must be identified, agreed and documented in the 
source documentation agreement form.  
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures. 
11.3. 
Record retention 
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere) in a safe and 
secure location. The records must be easily accessible, when needed (e.g. audit or 
inspection), and must be available for review in conjunction with assessment of the 
facility, supporting systems, and staff. Where permitted by applicable laws/regulations or 
institutional policy, some or all of these records can be maintained in a validated format 
other than hard copy (e.g. microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure that an acceptable back-up of the reproductions exists and that 
there is an acceptable quality control procedure in place for making these reproductions. 
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by ICH GCP, any 
institutional requirements, applicable laws or regulations, or GSK standards/procedures, 
otherwise, the minimum retention period will default to 25 years after completion of the 
study report. 
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to archival at an off-site facility, transfer of 
ownership of the records in the event the investigator leaves the site.  
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11.4. 
Quality assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues. 
11.5. 
Posting of information on publicly available clinical trial 
registers and publication policy 
GSK assures that the key design elements of this protocol will be posted on the GSK 
website and in publicly accessible database(s) such as clinicaltrials.gov, in compliance 
with the current regulations. 
GSK also assures that results of this study will be posted on the GSK website and in 
publicly accessible regulatory registry(ies) within the required time-frame, in compliance 
with the current regulations. The minimal requirement is to have primary endpoint 
summary results disclosed at latest 12 months post primary completion date (PCD) and to 
have secondary endpoint disclosed at latest 12 months after the last subject last visit 
(LSLV) as described in the protocol. 
As per EU regulation, summaries of the results of GSK interventional studies (phase 1-4) 
in adult population conducted in at least one EU member state will be posted on publicly 
available EMA registers within 12 months of EoS (as defined in the protocol) in the 
concerned EU member state. However, where, for scientific reasons detailed in the 
protocol, it is not possible to submit a summary of the results within one year in the 
concerned EU member state, the summary of results shall be submitted as soon as it is 
available. In this case, the protocol shall specify when the results are going to be 
submitted, together with a justification.  
GSK also aims to publish the results of these studies in searchable, peer reviewed 
scientific literature and follows the guidance from the International Committee of 
Medical Journal Editors. 
11.6. 
Provision of study results to investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK Biologicals will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
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11.7. 
Data Sharing 
Under the framework of the SHARE initiative, results of GSK studies may be combined 
with non-GSK studies, to investigate further about the study product(s) and other 
product(s), and /or the disease/condition under investigation and related diseases and 
conditions. 
12. 
COUNTRY SPECIFIC REQUIREMENTS 
Explanatory statement concerning Gender Distribution (Article 7, paragraph 2 (12) 
of the German GCP ORDER) 
For this NTHI MCAT-008 study, there is no intention to conduct specific analyses 
investigating the relationship between gender and the safety and efficacy of the 
investigational NTHi-Mcat vaccine. Recruitment will include males and females. To not 
expose pregnant women and their foetuses/children to an early-phase investigational 
vaccine, females enrolled in this trial will either be of non-childbearing potential (i.e., 
have a current tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or be 
premenarchal or postmenopausal), or if she is of childbearing potential, she must practice 
adequate contraception for 30 days prior to the beginning of the administration of study 
treatment, have a negative pregnancy test and continue such precautions during the entire 
study treatment period and for 2 months after completion of the injection series (Refer to 
the study protocol, Section 4.2 “Inclusion criteria” and Section 4.3 “Exclusion criteria”). 
The recruitment will be closed to females who are pregnant or lactating. Similarly, 
patients becoming or deciding to become pregnant during the study must stop the study 
treatment administrations. 
The indication of the vaccine under investigation is to reduce the frequency of moderate 
and severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) in 
patients with a previous history of moderate or severe AECOPD. Historically, COPD was 
considered a disease of males. The past few decades have seen a shift in this paradigm. In 
the United States, between the periods of the First National Health and Nutrition 
Examination Survey (NHANES I) and NHANES III, the prevalence of spirometrically 
determined moderate COPD increased in women from 50.8 per 1000 to 58.2 per 1000, 
whereas the prevalence decreased in men from 108.1 per 1000 to 74.3 per 1000.3 Data 
from the National Health Interview Survey show that the self-reported prevalence of 
COPD in the United States was stable from 1998 through 2009 and has remained higher 
in women than in men. A similar trend is seen in other developed countries such as 
Canada, the Netherlands, and Australia [Aryal, 2013]. There are no reports of gender 
differences in the efficacy or safety outcomes for patients receiving the investigational 
NTHi-Mcat vaccine.  
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13. 
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; 
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American Thoracic Society and European Respiratory Society. Standards for the 
diagnosis and management of patients with COPD. 2004. New York, USA; Lausanne, 
Switzerland. Ref Type: Conference. 
Aryal S, Diaz-GuzmanN E, Mannino DM. COPD and gender differences: an update. 
Transl Res. 2013 Oct;162(4):208-18. 
Bandi V, Jakubowycz M, Kinyon C, et al. Infectious exacerbations of chronic obstructive 
pulmonary disease associated with respiratory viruses and non-typeable Haemophilus 
influenzae. FEMS Immunol Med Microbiol. 2003;37:69-75. 
Barcelo B, Pons J, Ferrer JM, et al. Phenotypic characterisation of T-lymphocytes in 
COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking. 
Eur Respir J 2008;31:555-562. 
Beasley V, Joshi PV, Singanayagam A, et al. Lung microbiology and exacerbations in 
COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:555-69. 
Bourne S, Cohet C, Kim V, et al. Acute Exacerbation and Respiratory Infections in 
COPD (AERIS): protocol for a prospective, observational cohort study. BMJ Open 2014 
Mar 7;4(3):e004546. 
Buist S, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of 
COPD (The BOLD Study): a population-based prevalence study. Lancet 
2007;370:741-50. 
Cazzola M, MacNee W, Martinez FJ, et al. Outcomes for COPD pharmacological trials: 
from lung function to biomarkers. Eur Respir J 2008;31:416-69. 
Centers for Disease Control and  Prevention Metropolitan Atlanta Congenital Defects 
Program (CDC MACDP) guidelines. Birth defects and genetic diseases branch 6-digit 
code for reportable congenital anomalies; 
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Daubin C, Parienti JJ, Vabret A, et al. Procalcitonin levels in acute exacerbation of 
COPD admitted in ICU: a prospective cohort study. BMC Infect Dis 2008;8:145. 
Droemann D, Goldmann T, Tiedje T, et al. Toll-like receptor 2 expression is decreased 
on alveolar macrophages in cigarette smokers and COPD patients. Resp Res 
2005;6:68-75. 
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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). From the Global 
Strategy for the diagnosis, management, and prevention of Chronic Obstructive 
Pulmonary Disease, updated 2017; http://www.goldcopd.org/. Last accessed: 16-
MAR-2017. 
Hanley JA, Lippman-Hand A. If nothing goes wrong, is everything all right? Interpreting 
zero numerators. JAMA 1983;249:1743-5. 
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. 
Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease 
surveillance-United States, 1971-2000. MMWR Surveill Summ 2002;51:1-16. 
Moris P, van der Most R, Leroux-Roels I, et al. H5N1 influenza vaccine formulated with 
AS03 A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin 
Immuno 2011; 31: 443-54. 
Murphy TF, Brauer AL, Grant BJ, et al. Moraxella catarrhalis in chronic obstructive 
pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med 
2005;172:195-9. 
Nseir S, Ader F. Prevalence and outcome of severe chronic obstructive pulmonary 
disease exacerbations caused by multidrug-resistant bacteria. Curr Opin Pulm Med 
2008;14:95-100. 
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. 
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Rabe KF, Hurd S, Anzueto, et al. Global Strategy for the Diagnosis, Management, and 
Prevention of Chronic Obstructive Pulmonary Disease. GOLD Executive Summary. Am J 
Respir Crit Care Med 2007;176:532-555. 
Rosell A, Monsó E, Soler N, et al. Microbiologic determinants of exacerbation in chronic 
obstructive pulmonary disease. Arch Intern Med 2005;165: 891-7. 
Sapey E, Stockley RA. COPD exacerbations 2: aetiology. Thorax 2006;61:250-8. 
Sethi S, Evans N, Grant BJ, et al. New strains of bacteria and exacerbations of chronic 
obstructive pulmonary disease. N Engl J Med 2002;347:465-71. 
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive 
pulmonary disease. N Engl J Med 2008;359:2355-65. 
Takanashi S, Hasegawa Y, Kanehira Y, et al. Interleukin-10 level in sputum is reduced in 
bronchial asthma, COPD and in smokers. Eur Respir J 1999;14:309-314. 
Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of Immune 
Responses to Vaccines in Elderly Persons. Clin Infect Dis 2008;46:1078-84. 
Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway 
bacterial and rhinoviral infection in exacerbations of COPD. Chest 2006;129:317-24. 
Wilkinson TMA, Aris E, Bourne S, et al. A prospective, observational cohort study of the 
seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD. 
Thorax. 2017 Apr 21. [Epub ahead of print].  
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14. 
APPENDICES 
APPENDIX A LABORATORY ASSAYS  
Humoral immunity  
Serological assays will be performed at GSK Biologicals’ laboratory or in a GSK 
designated laboratory using assays as described below and in Table 8. The cut-off and 
unit of these assays might be subject to change during the course of the study (e.g. in case 
of assay re-optimization, qualification, (re)validation or standardization). In this case, this 
will be documented in the clinical study report. 
Anti-PD antibodies 
Anti-PD antibodies will be determined using a validated ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The technical cut-off of the assay is 153 EU/mL. 
Anti-PE antibodies 
Anti-PE antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PE antibodies will be determined, using in-
house made reference serum. The technical cut-off of the assay is 16 EU/mL.  
Anti-PilA antibodies 
Anti-PilA antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PilA antibodies will be determined, using an 
in-house made reference serum. The technical cut-off of the assay is 8 EU/mL.  
Anti-UspA2 antibodies 
Anti-UspA2 antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-UspA2 antibodies will be determined, using 
an in-house made reference serum. The technical cut-off of the assay is 28 EU/mL.  
Cell-mediated immunity  
CMI assays will be performed at GSK Biologicals' laboratory or in a GSK designated 
laboratory using assays as described in Table 9. 
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/markers (such as IL-2, IL-13, IL-17, IFN-γ, TNF-α and CD40L) or selected 
combination of cytokines will be evaluated by flow cytometry. 
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APPENDIX B 
CLINICAL LABORATORIES  
Table 21 
GSK Biologicals’ laboratories 
Laboratory 
Address 
GSK Biological’s Clinical Laboratory Sciences, 
Rixensart 
Biospecimen Reception - B7/44 
Rue de l'Institut, 89 - B-1330 Rixensart – Belgium 
GSK Biological’s Clinical Laboratory Sciences, 
Wavre-Nord Noir Epine 
Avenue Fleming, 20 - B-1300 Wavre - Belgium 
GSK Vaccines GmbH 
Klinische Serologie, Clinical Laboratory 
Sciences 
Gebaeude Z26 
Emil-von-Behring Str. 76, Marburg 35041 - Germany 
Table 22 
Outsourced laboratories  
Laboratory 
Address 
CEVAC - University of Gent 
De Pintelaan, 185 Gent, Belgium 
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APPENDIX C AMENDMENTS AND ADMINISTRATIVE CHANGES 
TO THE PROTOCOL 
GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 1 
eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
IND number 
16531 
EudraCT number 
2017-002941-31 
Amendment number: 
Amendment 1 
Amendment date: 
24 July 2018 
Co-ordinating author: 
, XPE Pharma & Science for GSK 
Biologicals 
Rationale/background for changes:  
• 
The Medical Dictionary for Regulatory Activities (MedDRA) list with potential 
immune mediated diseases (pIMDs) has been recently updated with the addition of 
“gout” as musculoskeletal disorder of interest (including re-arrangement of some 
other diseases). The main reason for updating the pIMD list in the protocol is so 
that the investigator can appropriately follow Section 6.5 Contraindications to 
subsequent vaccination (Occurrence of a new pIMD or the exacerbation of an 
existing pIMD that, in the opinion of the investigator, exposes the subject to 
unacceptable risk from subsequent vaccination. In such cases, the investigator 
should use his/her clinical judgement prior to administering the next dose of the 
vaccine. Refer to Section 8.1.5.1 for the definition of pIMDs). 
• 
Table 6 - Interval between study visits, reports the “allowed interval” in the third 
column. Some of the intervals are marked with the superscript “1” indicating that  
“subjects will not be eligible for inclusion in the Per-Protocol Set (PPS) for 
analysis of immunogenicity if the study visit is performed outside of this interval” 
but  not all are marked correctly. Therefore, Table 6 is currently amended to make 
sure that all the appropriate intervals are marked with the superscript in alignment 
with the definition of the PPS for analysis of immunogenicity (i.e., subjects will be 
excluded if not compliant with either the vaccination schedule or the blood sample 
timings). 
• 
The list of contributors was updated. 
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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Cover page 
Contributing authors 
• 
 
 (Study Delivery Leads) 
• 
 
(Study Statisticians) 
• 
 (Lead 
Statisticians) 
• 
 (Senior Clinical Research & 
Development Lead) and 
 (Clinical 
Research & Development Lead ) 
• 
 
(Regulatory Affairs Representatives) 
Table 6 Intervals between study visits 
Interval 
Optimal length of interval 
Allowed interval 
Visit 1  → Phone contact 1 
7 days 
7 - 9  days 
Visit 1  → Visit 2 
30 days 
30  - 45 days  1 
Visit 1  → Visit 3 
60 days 
60  - 75  days1 
Visit 3 →  Phone contact 2 
7 days 
7 - 9 days 
Visit 3  → Visit 4 
30 days 
30  - 45  days 1 
Visit 3 → Visit 5 
120 days 
120  - 150 days1 
Visit 5 → Phone contact 3 
7 days 
7 - 9 days 
Visit 5  → Visit 6 
30 days 
30  - 45 days  1 
Visit 5 → Visit 7 
180 days 
180  – 210 days1 
Visit 7  → Phone contact 4 
7 days 
7 – 9 days 
Visit 7 → Visit 8 
30 days 
30  – 45  days  1 
Visit 7 → Visit 9 
180 days 
180 – 210 days1 
Visit 7 → Visit 10 
360 days 
360  – 390 days1 
1 Subjects will not be eligible for inclusion in the per-protocol set (PPS) for analysis of immunogenicity if the study visit 
is performed outside this interval. 
8.1.5.1. Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune aetiology. AEs that need to be recorded and 
reported as pIMDs include those listed in Table 15. In case of further updates to the 
pIMDs list, the investigators will be notified in a written communication.  
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Table 15 List of potential immune-mediated diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy)  
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, including 
Miller Fisher syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants: e.g. non-infectious 
encephalitis, encephalomyelitis, 
myelitis, myeloradiculoneuritis 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic syndrome  
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy and 
polyneuropathies associated with 
monoclonal gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus erythematosus 
and associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), including 
diffuse systemic form and 
CREST syndrome 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions including 
juvenile chronic arthritis and 
Still’s disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, reactive 
arthritis (Reiter's Syndrome) 
and undifferentiated 
spondyloarthritis  
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous 
skin diseases 
(including pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localised 
Scleroderma 
(Morphoea) 
Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis including: 
giant cell arteritis such as 
Takayasu's arteritis and temporal 
arteritis.  
• 
Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome (allergic 
granulomatous angiitis), Buerger’s 
disease (thromboangiitis 
obliterans), necrotizing vasculitis 
and anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic 
anemia 
• 
Autoimmune 
thrombocytopenia 
• 
Antiphospholipid 
syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic 
anaemia 
• 
Autoimmune 
neutropenia  
• 
Autoimmune 
pancytopenia 
• 
Autoimmune glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune diseases 
(including autoimmune uveitis and 
autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathySarco
idosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
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Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune cholangitis 
• 
Inflammatory Bowel disease, 
including Crohn’s disease, 
ulcerative colitis, microscopic 
colitis, ulcerative proctitis  
• 
Celiac disease 
• 
Autoimmune pancreatitis 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave's or Basedow’s disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular autoimmune 
syndrome 
• 
Autoimmune hypophysitis 
Neuroinflammatory disorders 
Musculoskeletal disorders 
 
Skin disorders 
• 
Cranial nerve neuropathy, 
including paralysis and 
paresis (e.g. Bell’s palsy). 
• 
Optic neuritis. 
• 
Multiple sclerosis. 
• 
Transverse myelitis. 
• 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants. 
• 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants e.g.: non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis. 
• 
Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome. 
• 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic 
inflammatory 
demyelinating 
polyneuropathy,  
- 
Multifocal motor 
neuropathy  
- 
Polyneuropathies 
associated with 
monoclonal 
gammopathy. 
• 
Narcolepsy. 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), 
including: 
- 
Diffuse Scleroderma 
- 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis  
- 
Polymyositis  
• 
Anti-synthetase syndrome. 
• 
Rheumatoid Arthritis and 
associated conditions 
including:  
- 
Juvenile Idiopathic 
Arthritis 
- 
Still’s disease. 
• 
Polymyalgia rheumatica. 
• 
Spondyloarthropathies, 
including:  
- 
Ankylosing Spondylitis,  
- 
Reactive Arthritis 
(Reiter's Syndrome), 
- 
Undifferentiated 
Spondyloarthritis, 
- 
Psoriatic Arthritis, 
- 
Enteropathic arthritis. 
• 
Relapsing Polychondritis. 
• 
Mixed Connective Tissue 
disorder. 
• 
Gout. 
• 
Psoriasis. 
• 
Vitiligo. 
• 
Erythema nodosum. 
• 
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis). 
• 
Lichen planus. 
• 
Sweet’s syndrome. 
• 
Localised Scleroderma 
(Morphoea). 
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Vasculitis 
 
Blood disorders 
 
Others 
• 
Large vessels vasculitis 
including:  
- 
Giant Cell Arteritis 
(Temporal Arteritis), 
- 
Takayasu's Arteritis.  
• 
Medium sized and/or 
small vessels vasculitis 
including:  
- 
Polyarteritis nodosa, 
- 
Kawasaki's disease,  
- 
Microscopic 
Polyangiitis,  
- 
Wegener's 
Granulomatosis 
(granulomatosis with 
polyangiitis),  
- 
Churg–Strauss 
syndrome (allergic 
granulomatous 
angiitis or 
eosinophilic 
granulomatosis with 
polyangiitis),  
- 
Buerger’s disease 
(thromboangiitis 
obliterans),  
- 
Necrotizing 
vasculitis (cutaneous 
or systemic),  
- 
anti-neutrophil 
cytoplasmic 
antibody (ANCA) 
positive vasculitis 
(type unspecified), 
- 
Henoch-Schonlein 
purpura (IgA 
vasculitis),  
- 
Behcet's syndrome, 
- 
Leukocytoclastic 
vasculitis. 
• 
Autoimmune hemolytic 
anemia. 
• 
Autoimmune 
thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic 
anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune glomerulonephritis 
including: 
- 
IgA nephropathy,  
- 
Glomerulonephritis rapidly 
progressive,  
- 
Membranous 
glomerulonephritis,  
- 
Membranoproliferative 
glomerulonephritis,  
- 
Mesangioproliferative 
glomerulonephritis.  
- 
Tubulointerstitial nephritis 
and uveitis syndrome. 
• 
Ocular autoimmune diseases 
including: 
- 
Autoimmune uveitis  
- 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
 
Liver disorders 
Gastrointestinal disorders 
 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing 
cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel disease, 
including: 
- 
Crohn’s disease,  
- 
Ulcerative colitis,  
- 
Microscopic colitis,  
- 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
• 
Grave's or Basedow’s disease. 
• 
Diabetes mellitus type I. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune 
syndrome. 
• 
Autoimmune hypophysitis. 
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10.5.3. Per-protocol set for analysis of immunogenicity 
The per-protocol set (PPS) for immunogenicity will include all subjects in the FAS: 
• 
Who complied with the vaccination schedule, as specified in Table 12 and Table 6. 
• 
Who complied with the blood sample timings as specified in Table 10 and Table 6. 
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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 2 
eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
IND number 
16531 
EudraCT number 
2017-002941-31 
Amendment number: 
Amendment 2 
Amendment date: 
24 July 2019 
Co-ordinating author: 
, GSK Biologicals 
Rationale/background for changes:  
• 
The coordinating and contributing authors (page 2) were updated to reflect the 
current team in this Amendment 2. 
• 
In Table 8 - Humoral Immunity (Antibody determination) (section 5.7.3 
Laboratory Assays - Humoral antibody responses, page 51) and in Humoral 
immunity subsection (Appendix A - Laboratory Assays, page 94), the new ELISA 
cut-offs were updated, as result of a recent assay qualification. 
• 
Some typos in the temperature scale reported in the protocol Assessment of 
intensity part (section 8.3.3.2.1, page 69) were corrected. 
• 
A new outsourced Laboratory (CEVAC) was identified for Cell Mediated 
Immunity (CMI) testing and this new Laboratory was added in the study protocol 
in Table 22 - Outsourced laboratories (Appendix B - Clinical Laboratories, page 
95). 
• 
The CMI testing limited to the CD8 measurement was downgraded from 
secondary to tertiary endpoint (Secondary and Tertiary objectives and endpoints, 
Synopsis, pages 9 and 13; Secondary and Tertiary objectives, sections 2.2 and 2.3 
respectively, page 34; Secondary and Tertiary endpoints, sections 10.2 and 10.3 
respectively, pages 79 and 80; Secondary objectives - CMI immunogenicity after 
third dose, section 10.4, page 82) because: 
− 
Alignment of endpoints with other COPD ongoing trials. 
− 
The assay for CD8+ T cells detection is currently not qualified and there is no 
plan to qualify it. 
• 
Clarification of the wording in section 10.6, Derived and transformed data – CMI 
(page 84). 
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Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Cover page 
• 
 (Study 
Statisticians)  
• 
 (Science Writer)  
• 
 (CLS Study Managers)  
• 
 (TCS for GSK Biologicals) and 
 (ICON for 
GSK Biological) (Study Data Managers)  
5.7.3  Laboratory assays 
Humoral antibody responses 
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory or a 
GSK designated laboratory using qualified procedures. 
Table 8 Humoral Immunity (Antibody determination) 
System 
Component 
Method 
Kit / Manufacturer 
Unit* 
Cut-off* 
Laboratory 
SERUM 
anti-PilA antibody  
ELISA 
In house 
EU/ml  
7 8 
GSK 
Biologicals** or 
GSK designated 
laboratory 
anti-PE antibody  
8 16 
anti-PD antibody  
153  
anti-UspA2 IgG 
antibody  
18 28 
EU/mL = ELISA unit per millilitre 
*Assay cut-off and unit might be subject to change during the course of the study (e.g. in case of assay re-optimization, 
qualification, (re)validation or standardization). In this case, this will be documented in the clinical study report. 
**GSK Biologicals laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; 
Marburg, Germany. 
8.3.3.2.1 
Assessment of intensity  
Temperature (in this study preferred location to measure the temperature is oral cavity or 
axilla) will be scored at GSK Biologicals as follows: 
0: < 37.5°C 
1: 37.5°C to 37.938.0°C 
2: 38.038.1°C to 38.939.0°C 
3: >≥39.0°C 
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Synopsis - objectives 
Secondary 
• 
To evaluate the long term safety profile. 
• 
To evaluate the humoral immunogenicity of the NTHi-Mcat investigational 
vaccine. 
• 
To evaluate the cellular immunogenicity (CD4+ T cell response) of the NTHi-
Mcat investigational vaccine. 
Tertiary 
• 
To evaluate the cellular immunogenicity (CD8+ T cell response) of the NTHi-
Mcat investigational vaccine. 
Synopsis – endpoints 
Secondary 
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD4+/CD8+ T-cells expressing two or 
more markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), 
tumour necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 
91, Day 181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and within 
each vaccination schedule. 
Tertiary 
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD8+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), 
tumour necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 
91, Day 181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and 
within each vaccination schedule. 
2  
OBJECTIVES 
2.2 
Secondary objectives 
• 
To evaluate the long term safety profile.  
• 
To evaluate the humoral immunogenicity of the NTHi-Mcat investigational vaccine.  
• 
To evaluate the cellular immunogenicity (CD4+ T cell response) of the NTHi-Mcat 
investigational vaccine.  
2.3 
Tertiary objectives 
• 
To evaluate the cellular immunogenicity (CD8+ T cell response) of the NTHi-Mcat 
investigational vaccine. 
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10 
STATISTICAL METHODS 
10.2 Secondary endpoints 
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD4+/CD8+ T-cells expressing two or 
more markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), 
tumour necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 
91, Day 181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and within 
each vaccination schedule. 
10.3 Tertiary endpoints 
CMI: 
• 
NTHi-specific and Mcat-specific cell-mediated immune responses as measured by 
flow cytometry ICS [frequency of specific CD8+ T-cells expressing two or more 
markers, such as interleukin (IL)-2, IL-13, IL-17, interferon gamma (IFN-γ), 
tumour necrosis factor alpha (TNF-α), and CD40 ligand (CD40L)], at Day 1, Day 
91, Day 181, Day 211, Day 361 and Day 391, in a sub-cohort of subjects and 
within each vaccination schedule. 
10.4 Determination of sample size 
Secondary objectives: 
CMI immunogenicity after third dose 
CMI will be evaluated as frequency of CD4+ T-cells and CD8+ T-cells expressing at 
least two of different markers, cytokines, and expressing at least one cytokine when 
stimulated by each antigen PD, PE, PilA and UspA2. 
10.6 Derived and transformed data 
CMI: 
The frequency of antigen-specific CD4+ or CD8+ T-cells for each individual subject is 
calculated as the difference between the frequency of CD4+ or CD8+ T-cells producing 
at least 2 cytokines/markers among IFN-, IL-2, IL-13, IL-17, TNF- and/or CD40L, 
upon in vitro stimulation with the antigen (induction condition) minus the frequency of 
CD4+ or CD8+ T-cells producing at least 2 cytokines upon in vitro stimulation in 
medium only (background condition). 
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APPENDIX A 
LABORATORY ASSAYS 
Humoral immunity  
Serological assays will be performed at GSK Biologicals’ laboratory or in a GSK 
designated laboratory using assays as described below and in Table 8. The cut-off and 
unit of these assays might be subject to change during the course of the study (e.g. in case 
of assay re-optimization, qualification, (re)validation or standardization). In this case, this 
will be documented in the clinical study report. 
Anti-PD antibodies 
Anti-PD antibodies will be determined using a validated ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PD antibodies will be determined, using 
in-house made reference serum. The technical cut-off of the assay is 153 EU/mL. 
Anti-PE antibodies 
Anti-PE antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PE antibodies will be determined, using in-
house made reference serum. The technical cut-off of the assay is 816 EU/mL.  
Anti-PilA antibodies 
Anti-PilA antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PilA antibodies will be determined, using an 
in-house made reference serum. The technical cut-off of the assay is 78 EU/mL.  
Anti-UspA2 antibodies 
Anti-UspA2 antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-UspA2 antibodies will be determined, using 
an in-house made reference serum. The technical cut-off of the assay is 1828 EU/mL.  
Cell-mediated immunity  
After PBMC stimulation with the relevant antigens, the frequency of CD4+ and/or CD8+ 
T-cells expressing selected set of cytokines/markers (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. 
APPENDIX B 
CLINICAL LABORATORIES  
Table 22 Outsourced laboratories  
Laboratory 
Address 
CEVAC - University of Gent 
De Pintelaan, 185 Gent, Belgium 
 
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GlaxoSmithKline Biologicals SA 
Vaccines R &D 
Protocol Amendment 3 
eTrack study number and 
Abbreviated Title 
207759 (NTHI MCAT-008) 
IND number 
16531 
EudraCT number 
2017-002941-31 
Amendment number: 
Amendment 3 
Amendment date: 
26 May 2020 
Co-ordinating author: 
, GSK Biologicals 
This amendment is considered substantial based on the criteria defined in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it significantly impacts the conduct or management of the trial. 
• 
Rationale/background for changes:  
• 
This protocol amendment 3 outlines measures that may be applicable during 
special circumstances (e.g. COVID-19 pandemic). The purpose of the amendment 
is to protect participant’s welfare and safety, and as far as possible ensure the 
potential benefit to the participant and promote data integrity. 
However, if the study specific visit and procedures can be completed, then they should 
be completed according to the protocol, taking into account clinical judgment and local 
public health guidance to protect the safety of staff and subjects. 
Amended text has been included in bold italics and deleted text in strikethrough in 
the following sections: 
Cover page: 
 (Science Writer) 
Contributing authors - 
 (Senior Clinical Research & Development Lead) 
and 
 (Clinical Research & Development Lead) 
• 
 (Study 
Statistician)  
• 
 (Lead Statistician)  
• 
 (Science Writer) 
• 
 (Study Delivery Lead) 
• 
 (CLS Study Manager) 
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• 
 (Clinical Safety Representatives) 
• 
 (TCS for GSK Biologicals) and 
 (ICON for GSK 
Biological) (Study Data Manager) 
• 
 (Regulatory Affairs 
Representative) 
Synopsis and Section 3: 
• 
Sampling schedule: 
− 
Blood samples for assessment of humoral immunogenicity will be collected 
from all subjects at Visit 1 (Day 1), Visit 4 (Day 91), Visit 5 (Day 181), Visit 6 
(Day 211), Visit 7 (Day 361), Visit 8 (Day 391), Visit 9 (Day 541) and Visit 10 
(Day 721)*. 
Refer to Section 5.6.18 for study procedures to be considered during special 
circumstances. 
List of abbreviations: 
COVID-19 
Coronavirus Disease 2019 
Section 5.5 Outline of study procedures: 
Table 5: List of study procedures 
Epoch 
Epoch 001 
Epoch 
002 
Type of contact Visit 
1 
Phone 
contact 
1 
Visit 
2 
Visit 
3 
Phone 
contact 
2 
Visit 
4 
Visit 
5 
Phone 
contact 
3 
Visit 
6 
Visit 
7 
Phone 
contact 
4 
Visit 
8 
Visit 
9 
Visit 
10 i 
Timepoints 
Day 
1 
Day 8 Day 
31 
Day 
61 Day 68 Day 
91 
Day 
181 
Day 
188 
Day 
211 
Day 
361 
Day 
368 
Day 
391 
Day 
541 
Day 
721 h 
Sampling 
timepoints 
Pre-
Vacc 
I 
 
 
 
 
Post-
Vacc 
II 
Pre-
Vacc 
III 
 
Post-
Vacc 
III 
Pre-
Vacc 
IV 
 
Post-
Vacc 
IV 
Post-
Vacc 
IV 
Post-
Vacc 
IV  
Blood sampling for 
antibody 
determination (~20 
ml)  
● f  
 
 
 
 
● 
● f  
 
● 
● f  
 
● 
● 
●h 
Record any 
intercurrent medical 
conditions e g 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of  
AEs e g 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs 
e g 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of pIMDs 
e g 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
g. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be 
reported as AEs or SAEs (refer to Section 8.1 for safety definitions), and routine procedures for recording, 
evaluation, follow-up, and reporting of AEs, and SAEs should be followed in accordance with the time period 
set out in Table 16 
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h. The timepoints for Visit 10 and for blood sampling may change according to extended intervals. Refer to 
Section 5.6.18 for study procedures to be considered during special circumstances and Table 6 for details on 
visit intervals 
i Visit 10 may be a telephone contact during special circumstances. Refer to Section 5.6.18 for study 
procedures to be considered during special circumstances. 
Table 6: Intervals between study visits 
Interval 
Optimal length of interval 
Allowed interval 
Visit 7 → Visit 10 
360 days 
360  – 390 days (+120 days 
under special 
circumstances)1 ^ 
^ Refer to Section 5.6.18 for study procedures to be considered during special circumstances. Impact on the 
per protocol set for immunogenicity will be determined on a case by case basis 
Section 5.6.14.1 Blood sampling for immune response assessments 
Blood samples for humoral immunogenicity 
A volume of approximately 20 mL of whole blood should be drawn from all subjects for 
each analysis of humoral immune response at each pre-defined timepoint (Visit 1, Visit 4, 
Visit 5, Visit 6, Visit 7, Visit 8, Visit 9 and Visit 10)*. After whole blood processing into 
serum, serum samples should be kept at –20°C until shipment. Refer to the SPM and 
Central Laboratory manual for more details on sample storage conditions. 
* Refer to Section 5.6.18 for study procedures to be considered during special 
circumstances. 
Section 5.6.17 Recording of AEs, SAEs, pregnancies and pIMDs 
For Epoch 002, this includes the assessment of COVID-19 cases in accordance with 
the WHO definition. Refer to Section 5.6.18 and 8.3.1 for details. 
Section 5.6.18 Study procedures during special circumstances 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, 
the following measures may be implemented for enrolled participants (still 
participating in the study) for Visit 10: 
• 
If despite best efforts it is not possible to collect the biological samples within the 
interval predefined in the protocol (see Table 6), then the interval may be extended 
up to a maximum length of 120 days (i.e. allowed interval for Visit 10 = 360 to 390 
days +120 days under special circumstances).  
• 
In case, a physical visit to the clinic is not possible in any circumstances even with 
the extended interval, safety follow-up may be made by a telephone call or other 
means of virtual contact, if appropriate. The telephone call/ mode of virtual 
contact will be considered equivalent to study conclusion visit. 
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Section 5.7.2 Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Sub-cohort 
Blood for humoral immunogenicity 
20 
ml 
• 
Visit 1 (Day 1) 
• 
Visit 4 (Day 91) 
• 
Visit 5 (Day 181) 
• 
Visit 6 (Day 211) 
• 
Visit 7 (Day 361) 
• 
Visit 8 (Day 391) 
• 
Visit 9 (Day 541) 
• 
Visit 10 (Day 721)** 
All enrolled subjects 
** Refer to Section 5.6.18 for study procedures to be considered during special circumstances and Table 6 for 
details on extended visit interval. 
Section 5.7.4.1 Immunological read-outs 
Blood sampling timepoint 
Sub-cohort 
Name 
No. subjects 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Day 9 Visit 9 
(Day 541) 
Post-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
Day 10 Visit 10 
(Day 721)** 
Post-Vacc IV 
All subjects 
~200 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
Refer to Section 5.6.18 for study procedures to be considered during special circumstances and Table 6 for 
details on extended visit interval 
Section 8.3.1 Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
For Epoch 002, this includes the assessment of COVID-19 cases in accordance with 
the WHO definition. Cases should be categorised as AEs (unsolicited or AEs leading to 
withdrawal) or SAEs (refer to Section 8.1 for safety definitions), and routine 
procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs 
should be followed in accordance with the time period set out in Table 16. 
Event 
Visi
t 1 
Dos
e 1 
6 d 
pos
t 
Dos
e 1 
29 
d 
pos
t 
Dos
e 1 
 Visit 3 
Dos
e 2 
6 d 
po
st 
Do
se 
2 
29 d 
post 
Dose 
2 
 
Visi
t 5  
Dos
e 3 
6 d 
pos
t 
Dos
e 3 
29 d 
pos
t 
Dos
e 3 
 
Visi
t 7 
Dos
e 4 
6 d 
pos
t 
Dos
e 4 
29 d 
pos
t 
Dos
e 4 
Stud
y 
conc
lusio
n 
Timepoint 
Day 1 Day 
7 
Day 
30 
 
Day 
61 
Day 
67 
Day 
90 
 
Day 
181 
Day 
187 
Day 
210 
 
Day 
361 
Day 
367 
Day 
390 
Day 
721 
AEs/SAEs 
leading to 
withdrawal 
from the 
study** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs ** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent 
medical 
conditions 
leading to 
exclusion 
per 
protocol ** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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** During Epoch 002, if a diagnosis of COVID-19 is made in accordance with the current WHO case definition, 
cases should be reported as (S)AEs leading to withdrawal) or SAEs (refer to Section 8.1 for safety definitions), 
and routine procedures for recording, evaluation, follow-up, and reporting of AEs, and SAEs should be 
followed in accordance with the defined time period 
Section 10.5.3 Per-protocol set for analysis of immunogenicity 
Impact on the per protocol set for immunogenicity will be determined on a case by case 
basis. 
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