Immunogenicity and Safety Study of GSK's Investigational Vaccine (GSK3277511A) When Administered in Healthy Smokers and Ex-smokers Following Receipt of Shingrix Vaccine
Phase: PHASE2
Conditions: Respiratory Disorders
Sponsor: GlaxoSmithKline

CONFIDENTIAL 
209538 (NTHI MCAT-009) 
Protocol Amendment 1 Final 
18-MAY-2020 
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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut, 89 
1330 Rixensart, Belgium 
Primary Study vaccine 
• 
GSK’s non-typeable Haemophilus influenzae 
(NTHi) and Moraxella catarrhalis (Mcat) multi-
antigen vaccine consisting of 3 conserved surface 
proteins (PD, PE and PilA) from Haemophilus 
influenzae and one conserved surface protein 
(UspA2) from Mcat (GSK3277511A) adjuvanted 
with AS01E 
Other Study vaccine 
• 
GSK’s herpes zoster subunit (HZ/su) (Shingrix) 
vaccine (GSK1437173A), also called VZV 
gE/AS01B vaccine 
eTrack study number and 
abbreviated title 
209538 (NTHI MCAT-009)  
Investigational New Drug 
(IND) number 
016531 
EudraCT number 
2018-002977-24  
Date of protocol 
Final Version 1: 03 December 2018 
Date of protocol 
amendment/administrative 
change 
Administrative Change 1 Final: 14 December 2018 
Amendment 1 Final: 18 May 2020 
Title  
(Amended 18 May 2020) 
Immunogenicity and safety study of GSK’s 
investigational vaccine (GSK3277511A) when 
administered in healthy smokers and ex-smokers 
following receipt of Shingrix vaccine.  
Detailed Title 
(Amended 18 May 2020) 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine.  
Co-ordinating author(s) 
 (XPE Pharma & Science for GSK) 
Contributing authors 
• 
 (Clinical & Epidemiology 
Project Lead) 
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Protocol Amendment 1 Final 
18-MAY-2020 
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eTrack study number and 
abbreviated title 
209538 (NTHI MCAT-009) 
Investigational New Drug 
(IND) number 
016531 
EudraCT number 
2018-002977-24 
Detailed Title 
(Amended 18 May 2020) 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine. 
Contributing authors 
(Contd.) 
• 
 (Clinical Research & Development 
Lead) 
• 
 (Study Delivery Lead)  
• 
 (Lead Statistician) 
• 
 (Study 
Statisticians) (Amended 18 May 2020) 
• 
 (Clinical Safety 
Representative) 
• 
 (Clinical Safety 
Representative) 
• 
 (CLS Clinical Read-out 
Team Leader) 
• 
 (CLS Study Manager) 
• 
 (Oversight 
Data Managers) (Amended 18 May 2020) 
• 
 (Clinical 
Trials Supply Managers) (Amended 18 May 
2020) 
• 
 (Regulatory Affairs 
Representative) 
• 
 (Global Patents) 
• 
 (Lead Science Writer) 
• 
 (Science Writer) 
GSK Biologicals’ Protocol DS v 16.0 
© 2018 GSK group of companies or its licensor. 
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Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
Abbreviated Title 
209538 (NTHI MCAT-009)  
IND number 
016531 
EudraCT number 
2018-002977-24  
Date of protocol 
amendment/administrative 
change 
Amendment 1 Final: 18 May 2020 
Detailed Title 
(Amended 18 May 2020) 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine. 
Sponsor signatory 
Ashwani Kumar Arora 
Clinical & Epidemiology Project Lead 
Signature 
 
 
 
Date 
 
 
 
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Protocol Amendment 1 Final 
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Protocol Amendment 1 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(s)/product(s) and other study-related duties and 
functions as described in the protocol. 
• To supervise any individual or party to whom I have delegated trial-related duties and 
functions conducted at the trial site. 
• To ensure that any individual or party to whom I have delegated trial-related duties 
and functions conducted at the trial site are qualified to perform those trial-related 
duties and functions. 
• 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. 
• To have control of all essential documents and records generated under my 
responsibility before, during, and after the trial. 
• 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(s)/product(s), 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. 
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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 1 year following completion of the study.  
• Agree that GSK Biologicals may disclose any information 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 
209538 (NTHI MCAT-009)  
IND number  
016531  
EudraCT number 
2018-002977-24 
Date of protocol 
amendment/administrative 
change 
Amendment 1 Final: 18 May 2020 
Detailed Title 
(Amended 18 May 2020) 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers 
aged 50 to 80 years following receipt of Shingrix 
vaccine. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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Sponsor Information 
1. Sponsor 
GlaxoSmithKline Biologicals SA 
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 (SAE) 
GSK Biologicals’ Central Back-up Study Contact for Reporting SAEs: refer to 
protocol Section 12.5.9.3  
Study Contact for Reporting SAEs: refer to the local study contact information 
document. 
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 8.5.4.1. 
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PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES TABLE 
Table 1 
Document history 
Document 
Date 
Amendment 1 
18-MAY-2020 
Administrative Change 1 
14-DEC-2018 
Original Protocol 
03-DEC-2018 
Amendment 1 18 May 2020 
Overall Rationale for the Amendment 1  
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. 
The current analysis of the primary objective is planned on the per-protocol population. 
The use of the per protocol defined windows for vaccination and blood draws minimizes 
potential variability within the data for statistical comparisons. The planned analysis 
would test at least 1 geometric mean concentration (GMC) ratio (Sh_NTHi-Mcat over 
NTHi-Mcat) among anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 
in all time-lags under investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. To 
control the type I error below 2.5% (one-sided), a sequential procedure -is planned in the 
protocol. Starting from the 6-months lag, the 3-months NI will be tested only if the 6-
months NI will be demonstrated, while the 1-month NI will be tested only if the 6-months 
and 3-months NI will be both demonstrated. The expected sample size would allow to 
reach 80% of power. 
The study started on 23 Apr 2019. At the time of writing, group Sh_NTHi-Mcat_1 and 
control group NTHi-Mcat have completed the vaccination schedule and the blood draw 
as dictated by the study protocol, whereas the less advanced groups (Sh_NTHi-Mcat_3 
and Sh_NTHi-Mcat_6) are either due to receive the study vaccine or to undergo a blood 
draw. In accordance with the safety measures applied for COVID-19 containment in the 
Countries where the study is conducted, a number of study visits are unlikely to occur as 
planned. This is expected to impact 2 of the study groups (Sh_NTHi-Mcat_3 and 
Sh_NTHi-Mcat_6), for which the visits to collect data for primary endpoint are likely to 
occur while COVID-19 containment measures are in place.  
This protocol amendment 1 includes a modified primary objective, should the Sh-NTHI-
Mcat_6 or the Sh-NTHI-Mcat_3 and Sh_NTHi-Mcat_3 groups not meet the per-protocol 
defined sample size.  To complement this modified primary analysis, a descriptive 
analysis where the 95% confidence intervals around the geometric mean concentration 
(GMC) ratio will be presented for any group not meeting the per protocol sample size 
using all available data. The descriptive analysis may be used to support the interval 
between Shingrix and NTHi-Mcat vaccines administration for the planned NTHi-Mcat 
Phase III studies. 
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This protocol amendment 1 also outlines measures (e.g. for safety monitoring) that may 
be applicable during special circumstances, like COVID-19 pandemic, in order 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. 
In addition, provisions relating to specific reporting of serious adverse events and serious 
adverse reactions, in accordance with Article R1123-54 and Article R1123-46 of the 
French Public Health Code, are incorporated into the "Requirements for France” Section 
of this Protocol Amendment, in order to fulfill the commitment taken with French Health 
Authority. 
Amended text is indicated in bold italics in the body of the protocol. 
Table 2 
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
To swap the identifiers “short title” 
and “Detailed Title”. 
Identifiers need to be corrected 
 
Contributing authors 
Addition of new team members  
To reflect changes in the Team and 
contributions to the protocol 
amendment 
Sponsor signature page 
To change the identifier “short title” 
to “Detailed Title”.  
The detailed title is presented on 
this page and the identifier needs to 
be corrected. 
Investigator signature page 
To change the identifier “short title” 
to “Detailed Title”.  
The detailed title is presented on 
this page and the identifier needs to 
be corrected. 
Section 1 Synopsis; Objectives and 
endpoints 
Modification of the primary objective 
in case the per-protocol sample size 
for 1 (or more) of the 4 study groups 
is not reached, including addition of 
footnote and update of subsequent 
footnote referencing. 
To add a modified primary objective 
to be applied in case the per-
protocol sample size for 1 (or more) 
of the 4 study groups is not reached. 
This is necessary because the 
current analysis of the primary 
objective is planned on the per-
protocol population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned.  
Section 2 Schedule of Activities 
(SoA) – Table 3 and Table 4 
Addition of footnotes:  
• 11 to add information related to 
the diagnosis of COVID-19 per 
the WHO case definition and to 
clarify that routine study 
procedures and timeframes for 
reporting of AEs / SAEs should 
be followed; and,  
• 12 to add information regarding 
alternatives to study contacts 
To provide a reference to the WHO 
case definition for COVID-19, and to 
clarify that recording of AEs 
(unsolicited AEs or AEs leading to 
withdrawal) or SAEs should be 
aligned with routine procedures for 
the detection, reporting and 
recording of AEs or SAEs and 
timeframes set out in the protocol. 
And, to add information regarding 
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Section # and Name 
Description of Change 
Brief Rationale 
due to special circumstances 
(e.g. COVID-19 pandemic) 
alternatives to study contacts due to 
special circumstances (e.g. COVID-
19 pandemic) 
Section 4 Objective(s) and 
endpoint(s); Table 6 Objectives and 
endpoints 
Modification of the primary objective 
in case the per-protocol sample size 
for 1 (or more) of the 4 study groups 
is not reached, including addition of 
footnote and update of subsequent 
footnote referencing. 
To add a modified primary objective 
to be applied in case the per-
protocol sample size for 1 (or more) 
of the 4 study groups is not reached. 
This is necessary because the 
current analysis of the primary 
objective is planned on the per-
protocol population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned.  
Section 7.5.2 Concomitant 
medications/products/vaccines that 
may lead to the elimination of a 
subject from per-protocol analyses 
Correction of typographical error  
To correct a minor typographical 
error to improve readability 
Section 8 Study assessments and 
procedures  
Addition of a subsection (Section 
8.1) outlining study procedures 
during special circumstances (e.g. 
COVID-19 pandemic). (Subsequent 
Level 2 and Level 3 heading 
numbering updated.) 
To propose alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
can be sent back by conventional 
mail, etc.. 
Section 8.3.2.1 Blood sampling for 
immunogenicity assessment / Table 
10 and Table 11 
Addition of a footnote to clarify study 
procedures in special circumstances 
To highlight alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
can be sent back by conventional 
mail, etc.. 
Section 8.3.3.1 Humoral antibody 
responses 
Correction of typographical error  
To correct a minor typographical 
error to improve readability 
Section 8.3.4.1 Immunological read-
outs Table 14 
Addition of a footnote to clarify study 
procedures in special circumstances 
To highlight alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
can be sent back by conventional 
mail, etc.. 
Section 8.4 Safety assessments 
Addition of a sentence to clarify 
reference for case definition and 
recording of COVID-19 cases 
To note that diagnosis of COVID-19 
should be aligned with WHO case 
definition, and routine procedures as 
outlined in the study protocol for 
detection, recording and follow-up of 
AEs/SAEs should be followed 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.4.2 Time period and 
frequency for collecting AE and 
serious adverse event (SAE) 
information (and Table 15 and Table 
16) 
Addition of footnotes to clarify 
reference for case definition and 
recording of COVID-19 cases 
To note that diagnosis of COVID-19 
should be aligned with WHO case 
definition, and routine procedures as 
outlined in the study protocol for 
detection, recording and follow-up of 
AEs/SAEs should be followed 
Section 10.1.1 Hypotheses related 
to primary and secondary objectives 
Modification of the hypotheses 
related to the primary objective in 
case the per-protocol sample size 
for 1 (or more) of the 4 study groups 
is not reached. 
To include the hypothesis related to 
the modified primary objective to be 
applied in case the per-protocol 
sample size for 1 (or more) of the 4 
study groups is not reached. This is 
necessary because the current 
analysis of the primary objective is 
planned on the per-protocol 
population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned. This is expected to impact 
1 or 2 study groups depending on 
the ongoing viability of visits.  
Section 10.1.2 Sample size 
calculation 
Modification of the sample size 
calculation related to the primary 
objective in case the per-protocol 
sample size for 1 (or more) of the 4 
study groups is not reached. 
To include the sample size 
calculation related to the modified 
primary objective to be applied in 
case the per-protocol sample size 
for 1 (or more) of the 4 study groups 
is not reached. This is necessary 
because the current analysis of the 
primary objective is planned on the 
per-protocol population but, due to 
the containment measures for 
COVID-19 applied in the countries 
where the study is conducted, a 
number of study visits are unlikely to 
occur as planned. This is expected 
to impact 1 or 2 study groups 
depending on the ongoing viability 
of visits.  
Section 10.3.4 Immunogenicity 
analyses 
Modification of the primary objective 
and detail related to the statistical 
analyses to be applied in case the 
per-protocol sample size for 1 (or 
more) of the 4 study groups is not 
reached. 
To include the planned 
immunogenicity analyses in case 
the per-protocol sample size for 1 
(or more) of the 4 study groups is 
not reached. This is necessary 
because the current analysis of the 
primary objective is planned on the 
per-protocol population but, due to 
the containment measures for 
COVID-19 applied in the countries 
where the study is conducted, a 
number of study visits are unlikely to 
occur as planned. This is expected 
to impact 1 or 2 study groups 
depending on the ongoing viability 
of visits. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.1.1 List of abbreviations 
Addition of COVID-19 and definition 
To include a new abbreviation and 
corresponding definition used in the 
protocol 
Section 12.4.5 Committees 
Structure 
Addition of “No additional 
information” 
To complete an empty section 
Section 12.7.3 Requirements for 
France 
Addition of specific provisions 
relating to specific reporting of 
serious adverse events and serious 
adverse reactions in accordance 
with Article R1123-54 and Article 
R1123-46 of the French Public 
Health Code. 
To fulfil a commitment with the 
French Health Authority (ANSM), 
whereby GSK agreed that the term 
“issue” included: 
• suspicions of unexpected serious 
adverse reactions (SUSAR) 
occurring in France and outside the 
national territory; 
• expected serious adverse 
reactions and serious adverse 
events occurring in France; 
• new facts and urgent security 
measures. 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 7 
1. 
SYNOPSIS ............................................................................................................. 21 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 25 
3. 
INTRODUCTION .................................................................................................... 32 
3.1. 
Study rationale ............................................................................................ 32 
3.2. 
Background ................................................................................................ 32 
3.2.1. 
COPD: an introduction ................................................................. 32 
3.2.2. 
Current management of AECOPD ............................................... 33 
3.2.3. 
GSK Biologicals’ NTHi-Mcat investigational vaccine .................... 33 
3.2.4. 
GSK Biologicals’ Shingrix vaccine................................................ 34 
3.2.5. 
Sequential administration of AS01 adjuvant vaccines .................. 34 
3.3. 
Benefit/Risk assessment ............................................................................. 35 
3.3.1. 
Risk assessment .......................................................................... 35 
3.3.2. 
Benefit assessment ..................................................................... 36 
3.3.3. 
Overall Benefit: Risk conclusion ................................................... 36 
4. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 37 
5. 
STUDY DESIGN .................................................................................................... 40 
5.1. 
Scientific rationale for study design ............................................................. 40 
5.2. 
Overall design ............................................................................................. 41 
5.3. 
Number of subjects ..................................................................................... 44 
5.3.1. 
Cell-mediated immune response: sub-cohort ............................... 44 
5.4. 
Subject and study completion ..................................................................... 44 
6. 
STUDY POPULATION ........................................................................................... 45 
6.1. 
Inclusion criteria for enrolment .................................................................... 45 
6.2. 
Exclusion criteria for enrolment ................................................................... 45 
6.2.1. 
Medical conditions ....................................................................... 46 
6.2.2. 
Prior/concomitant therapy ............................................................ 46 
6.2.3. 
Prior/concurrent clinical study experience .................................... 47 
6.2.4. 
Other exclusions .......................................................................... 47 
6.3. 
Criteria for temporary delay for enrolment and vaccination ......................... 48 
7. 
TREATMENTS ....................................................................................................... 48 
7.1. 
Treatments administered ............................................................................ 48 
7.2. 
Method of treatment assignment ................................................................. 49 
7.2.1. 
Subject identification .................................................................... 49 
7.2.2. 
Randomization of treatment ......................................................... 49 
7.2.2.1. 
Randomization of supplies .......................................... 49 
7.2.2.2. 
Treatment allocation to the subject ............................. 49 
7.2.2.2.1. 
Study group and treatment 
number allocation ................................... 49 
7.2.2.2.2. 
Treatment number allocation for 
subsequent doses .................................. 50 
7.3. 
Blinding and unblinding ............................................................................... 50 
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7.4. 
Handling, storage and replacement of study vaccines ................................ 50 
7.4.1. 
Storage and handling of study vaccines ....................................... 50 
7.4.2. 
Replacement of unusable vaccines.............................................. 51 
7.5. 
Concomitant medications/products and concomitant vaccinations .............. 51 
7.5.1. 
Recording of concomitant medications/products and 
concomitant vaccinations ............................................................. 51 
7.5.2. 
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses ............ 52 
7.6. 
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses ............................................................. 53 
7.7. 
Contraindications to subsequent vaccination .............................................. 53 
7.8. 
Treatment after completion of the study ...................................................... 53 
7.9. 
Screen and baseline failures ....................................................................... 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 54 
8.1. 
Study procedures during special circumstances ......................................... 54 
8.2. 
General study aspects ................................................................................ 55 
8.3. 
Pre-vaccination procedures ........................................................................ 55 
8.3.1. 
Informed consent ......................................................................... 55 
8.3.2. 
Check inclusion and exclusion criteria ......................................... 55 
8.3.3. 
Collection of demographic data .................................................... 55 
8.3.4. 
Medical history ............................................................................. 55 
8.3.5. 
Smoking status ............................................................................ 55 
8.3.6. 
Smoking exposure history ............................................................ 56 
8.3.7. 
Measure/record height and weight ............................................... 56 
8.3.8. 
Physical examination ................................................................... 56 
8.3.9. 
Urine pregnancy test .................................................................... 56 
8.3.10. 
Previous vaccination .................................................................... 57 
8.3.11. 
Check contraindications to vaccination ........................................ 57 
8.3.12. 
Pre-vaccination body temperature ............................................... 57 
8.3.13. 
Distribution of Subject Card ......................................................... 57 
8.3.14. 
Study group and treatment number allocation .............................. 57 
8.3.15. 
Study vaccine administration ....................................................... 57 
8.4. 
Immunogenicity assessments ..................................................................... 58 
8.4.1. 
Use of specified study materials .................................................. 58 
8.4.2. 
Biological samples ....................................................................... 59 
8.4.2.1. 
Blood sampling for immunogenicity 
assessments .............................................................. 59 
8.4.3. 
Laboratory assays ....................................................................... 60 
8.4.3.1. 
Humoral antibody responses ...................................... 60 
8.4.3.2. 
Cell-mediated immune response ................................ 61 
8.4.4. 
Biological samples evaluation ...................................................... 62 
8.4.4.1. 
Immunological read-outs ............................................ 62 
8.4.5. 
Immunological correlates of protection ......................................... 63 
8.5. 
Safety Assessments ................................................................................... 63 
8.5.1. 
Safety definitions ......................................................................... 63 
8.5.2. 
Time period and frequency for collecting AE and serious 
adverse event (SAE) information ................................................. 63 
8.5.3. 
Method of detecting AEs and SAEs ............................................. 67 
8.5.4. 
Reporting of serious adverse events, pregnancies, and 
other events ................................................................................. 67 
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8.5.4.1. 
Contact information for reporting of serious 
adverse events (SAEs), pIMDs and 
pregnancies ................................................................ 68 
8.5.4.2. 
Regulatory reporting requirements for SAEs .............. 68 
8.5.5. 
Follow-up of AEs and SAEs ......................................................... 68 
8.5.6. 
Treatment of adverse events ....................................................... 69 
8.5.7. 
Subject card ................................................................................. 69 
8.6. 
Holding rules and safety monitoring ............................................................ 69 
8.7. 
Genetic research (pharmacogenetics) ........................................................ 69 
8.8. 
Biomarkers and pharmacogenomics ........................................................... 69 
8.9. 
Economic assessment ................................................................................ 69 
9. 
DISCONTINUATION CRITERIA ............................................................................. 70 
9.1. 
Discontinuation from the study .................................................................... 70 
9.2. 
Discontinuation of study vaccines ............................................................... 71 
9.3. 
Lost to follow-up.......................................................................................... 71 
10. STATISTICAL CONSIDERATIONS ........................................................................ 72 
10.1. 
Sample size determination .......................................................................... 72 
10.1.1. 
Hypotheses related to primary and secondary objectives ............ 72 
10.1.2. 
Sample size calculation ............................................................... 73 
10.2. 
Populations for analyses ............................................................................. 74 
10.3. 
Statistical analyses ..................................................................................... 74 
10.3.1. 
Subjects disposition ..................................................................... 74 
10.3.2. 
Demography and baseline characteristics analyses ..................... 74 
10.3.3. 
Efficacy analyses ......................................................................... 75 
10.3.4. 
Immunogenicity analyses ............................................................. 75 
10.3.5. 
Safety analyses ........................................................................... 77 
10.3.6. 
Other analyses ............................................................................ 77 
10.3.7. 
Interim analyses ........................................................................... 77 
10.4. 
Sequence of analyses................................................................................. 78 
11. REFERENCES ....................................................................................................... 79 
12. APPENDICES ........................................................................................................ 82 
12.1. 
Appendix 1: Abbreviations, glossary of terms and trademarks .................... 82 
12.1.1. 
List of abbreviations ..................................................................... 82 
12.1.2. 
Glossary of terms ......................................................................... 85 
12.1.3. 
Trademarks ................................................................................. 90 
12.2. 
Appendix 2: Clinical laboratory tests ........................................................... 91 
12.2.1. 
Laboratory assays: immune response ......................................... 91 
12.2.1.1. Humoral immunity ...................................................... 91 
12.2.1.2. Cell-mediated immunity .............................................. 91 
12.3. 
Appendix 3: Clinical laboratories ................................................................. 92 
12.4. 
Appendix 4: Study governance considerations ........................................... 93 
12.4.1. 
Regulatory and ethical considerations ......................................... 93 
12.4.2. 
Financial disclosure ..................................................................... 93 
12.4.3. 
Informed consent process ............................................................ 94 
12.4.4. 
Data protection ............................................................................ 94 
12.4.5. 
Committees structure ................................................................... 94 
12.4.6. 
Publication policy ......................................................................... 94 
12.4.7. 
Dissemination of clinical study data ............................................. 95 
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12.4.8. 
Data quality assurance ................................................................ 96 
12.4.9. 
Source documents ....................................................................... 96 
12.4.10. Study and site closure.................................................................. 97 
12.5. 
Appendix 5: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 98 
12.5.1. 
Definition of AE ............................................................................ 98 
12.5.1.1. AE Definition............................................................... 98 
12.5.1.2. Events Meeting the AE Definition ............................... 98 
12.5.1.3. Events NOT Meeting the AE Definition ....................... 99 
12.5.2. 
Definition of SAE .......................................................................... 99 
12.5.3. 
Solicited adverse events ............................................................ 100 
12.5.4. 
Unsolicited adverse events ........................................................ 100 
12.5.5. 
Adverse events of special interest (AESIs) ................................ 101 
12.5.5.1. Potential immune-mediated diseases ....................... 101 
12.5.5.2. Other adverse events of special interest ................... 104 
12.5.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events .......................................................................... 104 
12.5.7. 
Events or outcomes not qualifying as adverse events or 
serious adverse events .............................................................. 104 
12.5.7.1. Pregnancy ................................................................ 104 
12.5.8. 
Detecting and recording adverse events, serious adverse 
events and pregnancies ............................................................. 105 
12.5.8.1. Time period for detecting and recording 
adverse events, serious adverse events and 
pregnancies .............................................................. 106 
12.5.8.2. Evaluation of adverse events and serious 
adverse events ......................................................... 107 
12.5.8.2.1. Active questioning to detect 
adverse events and serious 
adverse events ..................................... 107 
12.5.8.2.2. Assessment of adverse events ............. 107 
12.5.8.2.3. Medically attended visits ....................... 110 
12.5.9. 
Reporting of serious adverse events, pregnancies, and 
other events ............................................................................... 111 
12.5.9.1. Prompt reporting of serious adverse events, 
pregnancies, and other events to GSK 
Biologicals ................................................................ 111 
12.5.9.2. SAEs requiring expedited reporting to GSK 
Biologicals ................................................................ 111 
12.5.9.3. Back-up system in case the electronic 
reporting system does not work ................................ 111 
12.5.9.4. Completion and transmission of pregnancy 
reports to GSK Biologicals ........................................ 112 
12.5.9.5. Reporting of pIMDs to GSK Biologicals .................... 112 
12.5.10. Updating of SAE, pregnancy, and AESI information after 
removal of write access to the subject’s eCRF ........................... 112 
12.5.11. Follow-up of adverse events, serious adverse events, and 
pregnancies ............................................................................... 113 
12.5.11.1. Follow-up of adverse events and serious 
adverse events ......................................................... 113 
12.5.11.1.1. Follow-up during the study .................... 113 
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12.5.11.1.2. Follow-up after the subject is 
discharged from the study .................... 113 
12.5.11.2. Follow-up of pregnancies.......................................... 113 
12.6. 
Appendix 6: Contraceptive guidance and collection of pregnancy 
information ................................................................................................ 114 
12.6.1. 
Definitions .................................................................................. 114 
12.6.1.1. Woman of Childbearing Potential (WOCBP) ............. 114 
12.6.1.1.1. Women in the following categories 
are not considered WOCBP .................. 114 
12.6.2. 
Contraception guidance ............................................................. 114 
12.6.3. 
Collection of pregnancy information ........................................... 115 
12.6.3.1. Male subjects with partners who become 
pregnant ................................................................... 115 
12.6.3.2. Female subjects who become pregnant ................... 116 
12.7. 
Appendix 7: Country-specific requirements ............................................... 117 
12.7.1. 
Requirements for Estonia .......................................................... 117 
12.7.2. 
Requirements for Finland ........................................................... 117 
12.7.3. 
Requirements for France ........................................................... 117 
12.7.4. 
Requirements for Italy ................................................................ 122 
12.7.5. 
Requirements for Spain ............................................................. 122 
12.8. 
Appendix 8: Protocol Amendment/Administrative change history .............. 123 
 
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LIST OF TABLES 
PAGE 
Table 1 
Document history ..................................................................................... 8 
Table 2 
List of main changes in the protocol and their rationale ............................ 9 
Table 3 
Schedule of Activities: Sh_NTHi-Mcat groups (Amended 18 May 
2020) ...................................................................................................... 26 
Table 4 
Schedule of Activities: NTHi-Mcat group (Amended 18 May 
2020) ...................................................................................................... 28 
Table 5 
Intervals between study visits ................................................................. 30 
Table 6 
Study objectives and endpoints .............................................................. 37 
Table 7 
Study groups, treatment and epochs foreseen in the study .................... 42 
Table 8 
Sub-cohorts ............................................................................................ 44 
Table 9 
Treatments administered ........................................................................ 48 
Table 10 
Blood sampling for humoral immunogenicity .......................................... 59 
Table 11 
Blood sampling for CMI .......................................................................... 60 
Table 12 
Humoral immunity (antibody determination) ........................................... 61 
Table 13 
CMI using flow cytometry ....................................................................... 61 
Table 14 
Immunological read-outs ........................................................................ 62 
Table 15 
Reporting periods for collecting safety information: Sh_NTHi-
Mcat groups (Amended 18 May 2020) ................................................... 64 
Table 16 
Reporting periods for collecting safety information: NTHi-Mcat 
group (Amended 18 May 2020) .............................................................. 66 
Table 17 
Timeframes for submitting serious adverse event, pregnancy and 
other events reports to GSK Biologicals ................................................. 67 
Table 18 
Contact information for reporting of serious adverse events 
(SAEs), pIMD and pregnancies .............................................................. 68 
Table 19 
GSK Biologicals’ laboratories ................................................................. 92 
Table 20 
Outsourced laboratories ......................................................................... 92 
Table 21 
Solicited local adverse events .............................................................. 100 
Table 22 
Solicited general adverse events .......................................................... 100 
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Table 23 
List of potential immune-mediated diseases (pIMDs) ........................... 102 
Table 24 
Intensity scales for solicited symptoms ................................................. 108 
Table 25 
Highly Effective Contraceptive Methods ............................................... 115 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 41 
 
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1. 
SYNOPSIS 
Indication: Active immunization to reduce exacerbations of chronic obstructive 
pulmonary disease (COPD) in patients with a history of exacerbations. The population of 
this study will include healthy smokers and ex-smokers aged 50 to 80 years of age 
(YOA) which will be used as a proxy for the COPD population. 
Rationale: The NTHI MCAT-009 study will provide information regarding the 
sequential administration of two vaccines adjuvanted with AS01. Specifically, whether a 
specific time window is required between two different vaccines containing the same 
AS01 components. The population of this study will include healthy smokers and ex-
smokers aged 50 to 80 years of age (YOA) which will be used as a proxy for the COPD 
population. 
Objectives and Endpoints: (Amended 18 May 2020) 
Objectives 
Endpoints 
Primary 
Confirmatory 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine versus the humoral 
immune response 1 month after Dose 2 of GSK 
Biologicals' NTHi-Mcat investigational vaccine 
alone.  
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above 
a limit of 0.667 for all anti-PD, anti-PE, anti-PilA, 
anti-UspA2.  
• 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 of 
NTHi-Mcat vaccine in the Sh_NTHi-Mcat groups 
(Day 181; Day 241; Day 331) compared to 
antibody concentrations 1 month after Dose 2 in 
the NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 group:2 
Confirmatory 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 of 
GSK Biologicals' NTHi-Mcat investigational vaccine 
when administered 1 or 3 months after Shingrix 
vaccine versus the humoral immune response 1 
month after Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% 
confidence interval (CI) of the geometric mean 
concentration (GMC) ratio (Sh_NTHi-
Mcat/NTHi-Mcat) is above a limit of 0.667 for 
all anti-PD, anti-PE, anti-PilA, anti-UspA2 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 
of NTHi-Mcat vaccine in the Sh_NTHi-Mcat_3 
group (Day 241) and Sh_NTHi-Mcat_1 group 
(Day 181) compared to antibody 
concentrations 1 month after Dose 2 in the 
NTHi-Mcat group (Day 91).1 
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Objectives 
Endpoints 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups:3 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after 
Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine when administered 1 
month after Shingrix vaccine versus the 
humoral immune response 1 month after 
Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above a 
limit of 0.667 for all anti-PD, anti-PE, anti-PilA, anti-
UspA2.  
Humoral immune response  
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations 1 month after Dose 2 of NTHi-Mcat 
vaccine in the Sh_NTHi-Mcat_1 group (Day 181) 
compared to antibody concentrations 1 month after 
Dose 2 in the NTHi-Mcat group (Day 91).1 
Secondary 
Descriptive 
• 
To evaluate the safety and reactogenicity profile 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered 
alone.  
• 
Solicited local and general adverse events (AEs)  
− 
Occurrence of each solicited local and general 
adverse event (AE), reported during a 7-day 
follow- up period (i.e. day of vaccination and 6 
subsequent days) after Dose 1 and after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine, in all subjects in all groups.  
• 
Unsolicited AEs  
− 
Occurrence of any unsolicited AEs, reported 
during a 30-day follow- up period (i.e. day of 
vaccination and 29 subsequent days) after Dose 
1 and after Dose 2 of GSK Biologicals' NTHi-
Mcat investigational vaccine, in all subjects in all 
groups.  
 
• 
Serious AEs  
− 
Occurrence of any SAE reported from first 
vaccination (Day 1) to Day 331 in all subjects in 
all groups. 
− 
Occurrence of any SAE, reported from Day 331 
to Day 661 in all subjects in all groups.  
− 
Potential immune-mediate diseases (pIMD)  
− 
Occurrence of any pIMD, reported from first 
vaccination (Day 1) to Day 331 in all subjects in 
all groups.  
− 
Occurrence of any pIMD, reported from Day 331 
to Day 661 in all subjects in all groups.   
Descriptive 
• 
To describe the humoral immune response of 
GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered 
alone.  
• 
Humoral response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations and seropositivity in all 
subjects before Dose 1 (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in 
the NTHi-Mcat group), and 1 month after Dose 2 
of NTHi-Mcat vaccine (Day 181; Day 241; Day 
331 in the Sh_NTHi-Mcat groups and Day 91 in 
the NTHi-Mcat group).1,4 
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Objectives 
Endpoints 
Descriptive 
• 
To describe the cell mediated immune (CMI) 
response (CD4+ T-cells) of GSK Biologicals’ 
NTHi-Mcat investigational vaccine when 
administered 1 or 3 or 6 months after Shingrix 
vaccine or when NTHi-Mcat is administered 
alone, in the CMI response sub-cohort. 
• 
CMI response 
− 
NTHi-specific and Mcat-specific CMI responses 
as measured by flow cytometry ICS (frequency of 
specific CD4+ T-cells expressing at least 2 
different markers among CD40 ligand (CD40L), 
interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α) 
upon in vitro stimulation) before Dose 1 (Day 91; 
Day 151; Day 241 in the Sh_NTHi-Mcat groups 
and Day 1 in the NTHi-Mcat group), and 1 month 
after Dose 2 of NTHi-Mcat vaccine (Day 181; 
Day 241; Day 331 in the Sh_NTHi-Mcat groups 
and Day 91 in the NTHi-Mcat group) in the CMI 
response sub-cohort.1 
Tertiary 
Descriptive 
• 
To describe the CMI response (CD8+ T-cells) of 
GSK Biologicals’ NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when NTHi-Mcat is 
administered alone, in the CMI response sub-
cohort.  
• 
To explore the T-helper profile of the PD-, PE-, 
PilA-, UspA2-specific CD4+/ CD8+ T cell 
responses. 
• 
CMI response  
− 
NTHi-specific and Mcat-specific CMI responses 
as measured by flow cytometry ICS (frequency of 
specific CD8+ T-cells expressing at least 2 
different markers among CD40L,IL-2, IL-13, IL-
17, IFN-γ, TNF-α upon in vitro stimulation) before 
Dose 1 (Day 91; Day 151; Day 241 in the 
Sh_NTHi-Mcat groups and Day 1 in the NTHi-
Mcat group), and 1 month after Dose 2 of NTHi-
Mcat vaccine (Day 181; Day 241; Day 331 in the 
Sh_NTHi-Mcat groups and Day 91 in the NTHi-
Mcat group) in the CMI response sub-cohort.1  
• 
T-helper profile  
− 
T-helper profile of the specific T-cell response in 
T-helper 1, T-helper 2 and T-helper 17 based on 
the specific expression of respectively IFN- γ, IL-
13 and IL-17 before Dose 1 of the NTHi-Mcat 
investigational vaccine (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in 
the NTHi-Mcat group), and 1 month after Dose 2 
of NTHi-Mcat investigational vaccine (Day 181; 
Day 241; Day 331 in the Sh_NTHi-Mcat groups 
and Day 91 in the NTHi-Mcat group) in the CMI 
sub-cohort. Frequencies of specific CD4+/CD8+ 
T cells per 106 cells expressing combinations of 
cytokines/activation markers will be explored.1 
1 Given the different intervals between vaccines, the label for study visits or contacts varies between treatment groups. 
Please refer to the study design diagram. 
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 group will be presented 
with all available data. The descriptive analysis may be used to support the interval between Shingrix and 
NTHi-Mcat vaccines administration  
3 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 
groups will be presented with all available data. The descriptive analysis may be used to support the 
interval between Shingrix and NTHi-Mcat vaccines administration  
4 Cut-off for seropositivity will be the lower limit of quantification (LLOQ) of the assay. 
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Overall Design: 
A Phase IIA, randomized, open-label, active controlled, multi-centric study with 4 
parallel groups (Synopsis Figure 1). Target enrolment is approximately 540 eligible 
subjects using a 1:1:1:1 randomization ratio (approximately 135 subjects in each of the 
following groups Sh_NTHi-Mcat_1, Sh_NTHi-Mcat_3, Sh_NTHi-Mcat_6, and NTHi-
Mcat). For each subject, the study will last approximately 22 months from Day 1 to study 
completion (Day 661). 
Synopsis Figure 1: Study design 
 
BS C = blood sample for cell-mediated immune response; BS H = blood sample for humoral immune responses/assay 
development from all subjects; C= Call; D = Day; mth(s) = month(s); NA = not applicable; NM = NTHi-Mcat 
vaccination; RAND = randomization; S = Safety; Sh = Shingrix vaccination; V = Visit 
Notes: 
1. Groups: Sh_NTHi-Mcat_1 (NTHi-Mcat vaccine administered 1 month after Shingrix vaccine) 
2. Groups: Sh_NTHi-Mcat_3 (NTHi-Mcat vaccine administered 3 months after Shingrix vaccine) 
3. Groups: Sh_NTHi-Mcat_6 (NTHi-Mcat vaccine administered 6 months after Shingrix vaccine) 
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4. Subjects randomized to the NTHi-Mcat control group will receive the first NTHi-Mcat vaccination at Visit 1 (Day 1) 
and the second NTHi-Mcat vaccination at Visit 3 (Day 61) 
5. Blood sample for cell-mediated immune response will be taken from approximately 60 subjects (~15 subjects in each 
group) 
6. Solicited local and general adverse events reported during a 7-day follow-up period after Dose 1 and after Dose 2 of 
NTHi-Mcat vaccine, and unsolicited adverse events reported during a 30-day follow-up period after Dose 1 and 
after Dose 2 of NTHi-Mcat vaccine will be collected 
7. Safety follow-up 
2. 
SCHEDULE OF ACTIVITIES (SOA) 
An outline of the study procedures to be performed is provided in Table 3 and Table 4. 
 
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Table 3 
Schedule of Activities: Sh_NTHi-Mcat groups (Amended 18 May 2020) 
 
Epoch 001 
Epoch 002 
Contact type and contact 
timepoint by study group 
Sh_NTHi-Mcat_1  
V1_1 
D1  
V2_1 
D61  
V3_1 
D91  
C1_1 
D98  
V4_1 
D121  
V5_1 
D151  
C2_1 
D158  
V6_1 
D181  
C3_1 
D331  
N/A 
V7_1 
D511  
C4_1 
D661  
Sh_NTHi-Mcat_3  
V1_3 D1  
V2_3 
D61  
V3_3  
D151  
C1_3 
D158  
V4_3 
D181  
V5_312 
D211  
C2_3 
D218  
V6_312 
D241  
C3_3 
D331  
C4_3 
D391  
V7_312 
D571  
C5_3 
D661  
Sh_NTHi-Mcat_6  
V1_6  
D1  
V2_6 
D61  
V3_612 
D241  
C1_6 
D248  
V4_612 
D271  
V5_612 
D301  
C2_6 
D308  
V6_612 
D331  
N/A 
C3_6 
D481  
V7_612 
D661  
N/A 
Sampling timepoint (vaccinations) 
Sh1 
Sh2 
NM1 
 
 
NM2 
 
 
 
 
 
 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
Check inclusion / exclusion criteria  
● 
 
 
 
 
 
 
 
 
 
 
 
Collect demographic data  
● 
 
 
 
 
 
 
 
 
 
 
 
Record previous vaccination data 
● 
 
 
 
 
 
 
 
 
 
 
 
Measure record height and weight  
● 
 
 
 
 
 
 
 
 
 
 
 
Physical examination1  
● 
O 
O 
 
 
O 
 
O 
 
 
O 
 
Smoking status  
● 
 
 
 
 
 
 
 
 
 
 
 
Smoking exposure history (ATS-DLD-78A 
questionnaire) 
● 
 
 
 
 
 
 
 
 
 
 
 
Vaccines 
 
 
 
 
 
 
 
 
 
 
 
 
Study group and treatment number allocation  
● 
 
 
 
 
 
 
 
 
 
 
 
Treatment number allocation for subsequent doses2  
O 
O 
O 
 
 
O 
 
 
 
 
 
 
Vaccine administration (Sh_NTHi-Mcat groups)3  
● 
● 
● 
 
 
● 
 
 
 
 
 
 
Recording of administered treatment number  
● 
● 
● 
 
 
● 
 
 
 
 
 
 
Clinical specimens for laboratory assays 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for antibody determination (~10 ml)  
 
 
●4 
 
 
 
 
● 
 
 
 
 
Blood sampling for CMI response (~40 ml)5  
 
 
●4 
 
 
 
 
● 
 
 
 
 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
● 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6  
● 
● 
● 
 
 
● 
 
 
 
 
 
 
Check contraindications and warnings and 
precautions to vaccination  
O 
O 
O 
 
 
O 
 
 
 
 
 
 
Pre-vaccination body temperature  
● 
● 
● 
 
 
● 
 
 
 
 
 
 
Record any concomitant medication/vaccination10 
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Record any intercurrent medical conditions10 
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Distribution of subject card 
O 
 
 
 
 
 
 
 
 
 
 
 
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Epoch 001 
Epoch 002 
Contact type and contact 
timepoint by study group 
Sh_NTHi-Mcat_1  
V1_1 
D1  
V2_1 
D61  
V3_1 
D91  
C1_1 
D98  
V4_1 
D121  
V5_1 
D151  
C2_1 
D158  
V6_1 
D181  
C3_1 
D331  
N/A 
V7_1 
D511  
C4_1 
D661  
Sh_NTHi-Mcat_3  
V1_3 D1  
V2_3 
D61  
V3_3  
D151  
C1_3 
D158  
V4_3 
D181  
V5_312 
D211  
C2_3 
D218  
V6_312 
D241  
C3_3 
D331  
C4_3 
D391  
V7_312 
D571  
C5_3 
D661  
Sh_NTHi-Mcat_6  
V1_6  
D1  
V2_6 
D61  
V3_612 
D241  
C1_6 
D248  
V4_612 
D271  
V5_612 
D301  
C2_6 
D308  
V6_612 
D331  
N/A 
C3_6 
D481  
V7_612 
D661  
N/A 
Sampling timepoint (vaccinations) 
Sh1 
Sh2 
NM1 
 
 
NM2 
 
 
 
 
 
 
Distribution of diary cards  
 
 
O 
 
 
O 
 
 
 
 
 
 
Return of diary cards  
 
 
 
 
O 
 
 
O 
 
 
 
 
Diary card transcription by investigator or delegate  
 
 
 
 
● 
 
 
● 
 
 
 
 
Recording of solicited AEs  
 
 
● 
● 
 
● 
● 
 
 
 
 
 
Recording of unsolicited AEs11 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
 
Recording of AEs leading to withdrawal11 
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Recording of SAEs11 and pregnancies  
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Recording of SAEs related to study participation, or to 
a concurrent GSK medication/vaccine  
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Recording of pIMDs 
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Study conclusion  
 
 
 
 
 
 
 
 
 
 
●9 
●7 
Note: The double-line borders indicate analyses which will be performed on all data obtained up to those time points. 
● is used to indicate a study procedure that requires documentation in the individual eCRF; O is used to indicate a study procedure that does not require documentation in the 
individual eCRF. 
AEs = adverse events; C = Call; CMI = cell-mediated immune response; D = Day; eCRF = electronic case report form; N/A = not applicable; NM = NTHi-Mcat; pIMDs = potential 
immune-mediated diseases; SAEs = serious adverse events; Sh = Shingrix; V = Visit 
1 Complete physical examination including vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate).  
2 Treatment number allocation with randomization at Visit 1 (Day 1) for all treatment groups. Treatment number allocation without randomization at Visit 2 (Day 61), Visit 3 (Day 91; 
Day 151; Day 241) and, Visit 5 (Day 151; Day 211; Day 301) for Sh_NTHi-Mcat treatment groups (Table 3) and at Visit 3 (Day 61) for NTHi-Mcat treatment group (Table 4).  
3 Vaccinations should be given in the same arm (both Shingrix and NTHi-Mcat vaccinations). 
4 Blood sampling must occur prior to vaccination.  
5 Only for subjects in the sub-cohort for CMI (refer to Section 5.3.1 for details regarding the sub-cohort). 
6. A urine pregnancy test will be performed only for women of childbearing potential. 
7. Applicable for Sh_NTHi-Mcat_1 and Sh_NTHi-Mcat_3 study groups. 
8. Applicable for Sh_NTHi-Mcat_3 and Sh_NTHi-Mcat_6 study groups. 
9. Applicable for Sh_NTHi-Mcat_6 study group. 
10. All concomitant medications/vaccinations and intercurrent medical conditions up to 1 month post Dose 2 of NTHi-MCat vaccine and all concomitant medications/vaccinations and 
intercurrent medical conditions associated with SAEs and pIMDs for the entire study period. 
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11. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (unsolicited AEs, AEs leading to withdrawal) 
or SAEs (refer to Section 12.5 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 15 
12. Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
Table 4 
Schedule of Activities: NTHi-Mcat group (Amended 18 May 2020) 
Epoch 
Epoch 001  
Epoch 002 
Type of contact 
V1  
C1  
V2  
V3  
C2  
V4  
C3  
C4  
V5  
C5  
Time points 
D1  
D8  
D31  
D61  
D68  
D91  
D241  
D331  
D4219  
D661  
Sampling time points 
NM 1 
 
 
NM 2 
 
 
 
 
 
 
Informed consent  
● 
 
 
 
 
 
 
 
 
 
Check inclusion / exclusion criteria  
● 
 
 
 
 
 
 
 
 
 
Collect demographic data  
● 
 
 
 
 
 
 
 
 
 
Record previous vaccination data 
● 
 
 
 
 
 
 
 
 
 
Measure record height and weight  
● 
 
 
 
 
 
 
 
 
 
Physical examination1  
● 
 
 
O 
 
O 
 
 
O 
 
Smoking status  
● 
 
 
 
 
 
 
 
 
 
Smoking exposure history (ATS-DLD-78A questionnaire) 
● 
 
 
 
 
 
 
 
 
 
Vaccines  
Study group and treatment number allocation  
● 
 
 
 
 
 
 
 
 
 
Treatment number allocation for subsequent doses2  
O 
 
 
O 
 
 
 
 
 
 
Vaccine administration (NTHi-Mcat group)3  
● 
 
 
● 
 
 
 
 
 
 
Recording of administered treatment number  
● 
 
 
● 
 
 
 
 
 
 
Clinical specimens for laboratory assays 
Blood sampling for antibody determination (~10 ml) 
●4 
 
 
 
 
● 
 
 
 
 
Blood sampling for CMI response (~40 ml)5 
●4 
 
 
 
 
● 
 
 
 
 
Safety assessments 
Medical history  
● 
 
 
 
 
 
 
 
 
 
Urine pregnancy test6 
● 
 
 
● 
 
 
 
 
 
 
Check contraindications and warnings and precautions to 
vaccination  
O 
 
 
O 
 
 
 
 
 
 
Pre-vaccination body temperature  
● 
 
 
● 
 
 
 
 
 
 
Record any concomitant medication/vaccination7  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Record any intercurrent medical conditions7 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
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Epoch 
Epoch 001  
Epoch 002 
Type of contact 
V1  
C1  
V2  
V3  
C2  
V4  
C3  
C4  
V5  
C5  
Time points 
D1  
D8  
D31  
D61  
D68  
D91  
D241  
D331  
D4219  
D661  
Sampling time points 
NM 1 
 
 
NM 2 
 
 
 
 
 
 
Distribution of subject card 
O 
 
 
 
 
 
 
 
 
 
Distribution of diary cards  
O 
 
 
O 
 
 
 
 
 
 
Return of diary cards  
 
 
O 
 
 
O 
 
 
 
 
Diary card transcription by investigator or delegate  
 
 
● 
 
 
● 
 
 
 
 
Recording of solicited AEs  
● 
● 
 
● 
● 
 
 
 
 
 
Recording of unsolicited AEs 
● 
● 
● 
● 
● 
● 
 
 
 
 
Recording of AEs leading to withdrawal8 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs8 and pregnancies  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs related to study participation, or to a 
concurrent GSK medication/vaccine  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of pIMDs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Study conclusion  
 
 
 
 
 
 
 
 
 
● 
Note: The double-line borders indicate analyses which will be performed on all data obtained up to those time points. 
● is used to indicate a study procedure that requires documentation in the individual eCRF; O is used to indicate a study procedure that does not require documentation in the 
individual eCRF. 
AEs = adverse events; C = Call; D = Day; eCRF = electronic case report form; NM = NTHi-Mcat; pIMDs = potential immune-mediated diseases; SAEs = serious adverse 
events; V = Visit; Vacc = vaccination 
1 Complete physical examination including vital signs (systolic/diastolic blood pressure, heart rate, respiratory rate).  
2 Treatment number allocation with randomization at Visit 1 (Day 1) for all treatment groups. Treatment number allocation without randomization at Visit 2 (Day 61), Visit 3 (Day 91; 
Day 151; Day 241), Visit 5 (Day 151; Day 211; Day 301) for Sh_NTHi-Mcat treatment groups (Table 3) and at Visit 3 (Day 61) for NTHi-Mcat treatment group (Table 4).  
3 Vaccinations should be given in the same arm  
4 Blood sampling must occur prior to vaccination.  
5 Only for subjects in the sub-cohort for CMI (refer to Section 5.3.1 for details regarding the sub-cohort). 
6 A urine pregnancy test will be performed only for women of childbearing potential. 
7. All concomitant medications/vaccinations and intercurrent medical conditions up to 1 month post Dose 2 of NTHi-MCat vaccine and all concomitant medications/vaccinations and 
intercurrent medical conditions associated with SAEs and pIMDs for the entire study period  
8. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (AEs leading to withdrawal) or SAEs (refer to 
Section 12.5 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 15 
9. Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
 
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Whenever possible, the investigator should arrange study visits within the intervals 
described in Table 5. 
Table 5 
Intervals between study visits 
Treatment groups 
Interval1,2 
Optimal length of 
interval3 
Allowed interval 
Sh_NTHi-Mcat_11 
V1_1 (D1) → 
V2_1 (D61) 
60 days  
60 – 80 days4 
V2_1 (D61) → 
V3_1 (D91) 
30 days  
30 – 50 days4 
V3_1 (D91) → 
C1_1 (D98) 
7 days  
7 – 11 days 
V3_1 (D91) → 
V4_1 (D121) 
30 days  
30 – 45 days 
V3_1 (D91) → 
V5_1 (D151) 
60 days  
60 – 75 days4 
V5_1 (D151) → 
C2_1 (D158) 
7 days  
7 – 11 days 
V5_1 (D151) → 
V6_1 (D181) 
30 days  
30 – 45 days4 
V5_1 (D151) → 
C3_1 (D331) 
180 days  
180 – 210 days 
V5_1 (D151) → 
V7_1 (D511) 
360 days  
360 – 390 days 
V5_1 (D151) → 
C4_1 (D661) 
510 days  
510 – 540 days 
Sh_NTHi-Mcat_31 
V1_3 (D1) → 
V2_3 (D61) 
60 days  
60 – 804 
V2_3 (D61) → 
V3_3 (D151) 
90 days  
90 – 110 days4 
V3_3 (D151) → 
C1_3 (D158) 
7 days  
7 – 11 days 
V3_3 (D151) → 
V4_3 (D181) 
30 days  
30 – 45 days 
V3_3 (D151) → 
V5_3 (D211) 
60 days  
60 – 75 days4 
V5_3 (D211) → 
C2_3 (D218) 
7 days  
7 – 11 days 
V5_3 (D211) → 
V6_3 (D241) 
30 days  
30 – 45 days4 
V5_3 (D211) → 
C3_3 (D331) 
120 days  
120 – 150 days 
V5_3 (D211) → 
C4_3 (D391) 
180 days  
180 – 210 days 
V5_3 (D211) → 
V7_3 (D571) 
360 days  
360 – 390 days 
V5_3 (D211) → 
C5_3 (D661) 
450 days  
450 – 480 days 
Sh_NTHi-Mcat_61 
V1_6 (D1) → 
V2_6 (D61) 
60 days  
60 – 80 days4 
V2_6 (D61) → 
V3_6 (D241) 
180 days  
180 – 200 days4 
V3_6 (D241) → 
C1_6 (D248) 
7 days  
7 – 11 days 
V3_6 (D241) → 
V4_6 (D271) 
30 days  
30 – 45 days 
V3_6 (D241) → 
V5_6 (D301) 
60 days  
60 – 75 days4 
V5_6 (D301) → 
C2_6 (D308) 
7 days  
7 – 11 days 
V5_6 (D301) → 
V6_6 (D331) 
30 days  
30 – 45 days4 
V5_6 (D301) → 
C3_6 (D481) 
180 days  
180 – 210 days 
V5_6 (D301) → 
V7_6 (D661) 
360 days  
360 – 390 days 
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Treatment groups 
Interval1,2 
Optimal length of 
interval3 
Allowed interval 
NTHi-Mcat2 
V1 (D1) → 
C1 (D8) 
7 days  
7 – 11 days 
V1 (D1) → 
V2 (D31) 
30 days  
30 – 45 days 
V1 (D1) → 
V3 (D61) 
60 days  
60 – 75 days4 
V3 (D61) → 
C2 (D68) 
7 days  
7 – 11 days 
V3 (D61) → 
V4 (D91) 
30 days  
30 – 45 days4 
V3 (D61) → 
C3 (D241) 
180 days  
180 – 210 days 
V3 (D61) → 
C4 (D331) 
270 days  
270 – 300 days 
V3 (D61) → 
V5 (D421) 
360 days  
360 – 390 days 
V3 (D61) → 
C5 (D661) 
600 days  
600 – 630 days 
D = Day; Sh = Shingrix; V = Visit 
1. In the Sh_NTHi-Mcat groups, after Day 1 (Visit 1_1; Visit 1_3; Visit 1_6) and Day 61 (Visit 2_1; Visit 2_3; Visit 2_6), 
the date of Dose 1 (Visit 3_1, Visit 3_3, or Visit 3_6) or Dose 2 (Visit 5_1, Visit 5_3, or Visit 5_6) of the NTHi-Mcat 
investigational vaccine, respectively, is used as the reference date to define the interval between study 
visits/contacts. 
2. In the NTHi-Mcat groups, the date of Dose 1 (Visit 1) or Dose 2 (Visit 3) of the NTHi-Mcat investigational vaccine, 
respectively, is used as the reference date to define the interval between study visits/contacts. 
3. Whenever possible the investigator should arrange study visits within this interval. 
4. 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 
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3. 
INTRODUCTION 
3.1. 
Study rationale 
The NTHI MCAT-009 study will provide information regarding the sequential 
administration of two vaccines adjuvanted with AS01. Specifically, whether a specific 
time window is required between two different vaccines containing the same AS01 
components. The population of this study will include healthy smokers and ex-smokers 
aged 50 to 80 years of age (YOA) which will be used as a proxy for the COPD 
population. 
3.2. 
Background 
3.2.1. 
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 Organization (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 characterized by a worsening of the patient’s respiratory symptoms that is 
beyond normal day-to-day variations and leads to a change in medication [GOLD, 2017]. 
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 colonized with different strains of bacteria [Erb-Downward, 
2011; Wilkinson, 2017]. In COPD patients, acquisition of new bacterial strains of a 
pathogenic bacterial species 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%) 
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[Alamoudi, 2007; Bandi, 2003; Beasley, 2012; Hutchinson, 2007; Ko, 2007; Larsen, 
2009; Murphy, 2005; Papi, 2006; Rosell, 2005; Sethi, 2002; Sethi, 2008; Wilkinson, 
2006].  
3.2.2. 
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 hospitalization, 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. 
3.2.3. 
GSK Biologicals’ NTHi-Mcat investigational vaccine 
GlaxoSmithKline (GSK) Biologicals is developing a new NTHi-Mcat investigational 
vaccine targeting NTHi and Mcat with the aim of reducing the frequency of 
exacerbations in patients with a history of COPD. 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 type IV 
pili subunit (PilA) protein, as a recombinant fusion protein named PE-PilA. The selected 
Mcat antigen is the ubiquitous surface protein A2 (UspA2). 
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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 the NTHI 
MCAT-001 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 
study.  
The adjuvant system AS01E was developed at GSK Biologicals, and contains 25 µg of the 
immunostimulants MPL (3-O-desacyl-4’-monophosphoryl lipid A) and 25 µg of QS21 
(Quillaja saponaria Molina, fraction 21; Antigenics, New York, NY, US) formulated in 
combination with liposomes. MPL is a chemically detoxified form of the parent 
lipopolysaccharide from the gram negative bacterium Salmonella minnesota. QS21 is a 
natural saponin molecule (triterpene glycoside) obtained from the tree bark of Quillaja 
saponaria Molina. 
The use of an adjuvant may help to induce a higher and longer-lasting immune response 
in the target population of GSK NTHi-Mcat vaccine; i.e., COPD patients who are often 
elderly and 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.  
3.2.4. 
GSK Biologicals’ Shingrix vaccine 
Shingrix (Zoster Vaccine Recombinant, Adjuvanted) is approved in the US and in the EU 
for use in adults 50 years and older for the prevention of HZ (shingles). Shingrix is 
administered as a 2-dose vaccine series (0.5 ml each) as an intramuscular injection. The 
second dose should be administered anytime between 2 and 6 months after the first dose 
(refer to Table 5 for optimal (60 days) and allowed intervals (60–80 days) applicable for 
this study). 
The vaccine consists of VZV glycoprotein E (gE) and an adjuvant. The adjuvant system 
AS01B is used in combination with the gE antigen. AS01B and the above-mentioned 
AS01E consist of the same components, only the quantities differ. AS01B contains double 
the amount (50 µg) of the immunostimulants MPL (3-O-desacyl-4’-monophosphoryl 
lipid A) and double the amount (50 µg) of QS21 (Quillaja saponaria Molina, fraction 21; 
Antigenics, New York, NY, US) formulated in combination with liposomes.  
3.2.5. 
Sequential administration of AS01 adjuvant vaccines 
While substantial data are available to evaluate the safety and immunogenicity of 
sequential administration of the same AS01-adjuvanted vaccines, evaluation of sequential 
administration of different AS01-adjuvanted vaccines has not been performed to date.  
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Available evidence with the RTS,S malaria (up to 4 doses) and HZ candidate vaccines (2 
doses) indicates that these AS01-adjuvanted vaccines have a clinically acceptable safety 
profile, and a positive-benefit–risk ratio, supported by a recent meta-analysis of clinical 
trials of newly adjuvanted vaccines including AS01 in children, which did not identify 
any safety concerns [Stassijns, 2016; Didierlaurent, 2017].  
Limited clinical trial data are available from subjects who have received multiple 
administrations of vaccines containing different adjuvanted components. A total of 15 
subjects received Shingrix and Flu-Ad (flu vaccine adjuvanted with MF59) in the studies 
Zoster-006 and Zoster-022 [Cunningham, 2018]. The majority of the subjects received 
Flu-Ad more than one year after the last dose of Shingrix. From the analysis of the safety 
listings associated, no specific safety signals were detected for these subjects. 
The purpose of this study is to demonstrate the non-inferiority (NI) of the humoral 
immune response 1 month after Dose 2 of GSK Biologicals' non-typeable Haemophilus 
influenzae (NTHi) and Moraxella catarrhalis (Mcat) vaccine adjuvanted with AS01E, 
when administered after vaccination with the AS01-adjuvanted Shingrix vaccine (refer to 
Section 3.1). 
3.3. 
Benefit/Risk assessment 
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of NTHi-Mcat investigational vaccine. 
Please refer to the Prescribing Information for information regarding the summary 
potential risks and benefits of Shingrix. 
The following section outlines the risk assessment and mitigation strategy for this study 
protocol:  
3.3.1. 
Risk assessment 
Important/Potential/Identified/Risk of 
Clinical Significance 
Summary of 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 clinical 
program. Available clinical data 
do not highlight any concern. 
Close monitoring of potential 
immune-mediated diseases 
(pIMDs) as per study protocol. 
The potential risk of events of 
possible autoimmune aetiology 
occurring is mentioned in the 
ICF. In addition, the ICF advises 
subjects to contact the study 
doctor or the study staff 
immediately, should they get any 
symptoms that they feel may be 
serious. 
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Important/Potential/Identified/Risk of 
Clinical Significance 
Summary of Data/Rationale 
for Risk.  
Mitigation Strategy  
Shingrix 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 clinical 
program. Available clinical data 
do not highlight any concern. 
Close monitoring of pIMDs as 
per study protocol. 
The potential risk of events of 
possible autoimmune aetiology 
occurring is mentioned in the 
ICF. In addition, the ICF advises 
subjects to contact the study 
doctor or the study staff 
immediately, should they get any 
symptoms that they feel may be 
serious. 
Study procedures 
Risk of blood sampling. 
Blood sampling associated risk 
of syncope, dizziness, infection 
at the site after or during 
venipuncture. 
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 
2 and Section 8.4.2.1). 
3.3.2. 
Benefit assessment 
• 
Contribution to the process of developing of a vaccine against AECOPD. 
• 
Provision of relevant information regarding whether a specific time window is 
required between two different vaccines containing the same AS01 components. 
• 
Medical evaluations/assessments associated with study procedures (i.e. physical 
examination). 
3.3.3. 
Overall Benefit: Risk conclusion 
Taking into account the measures taken to minimize risks to subjects participating in this 
study, the potential and/or known risks identified in association with study vaccines 
(Shingrix and NTHi-Mcat) and study procedures, the study vaccines are justified by the 
anticipated benefits that may be afforded to patients for the prevention of HZ and 
AECOPD when the 2 vaccine series are sequentially administered with a 1, 3 or 6 month 
spacing. 
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4. 
OBJECTIVE(S) AND ENDPOINT(S)  
(Amended 18 May 2020) 
Table 6 
Study objectives and endpoints  
Objectives 
Endpoints 
Primary 
Confirmatory 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine versus the humoral 
immune response 1 month after Dose 2 of GSK 
Biologicals' NTHi-Mcat investigational vaccine 
alone.  
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above 
a limit of 0.667 for all anti-PD, anti-PE, anti-PilA, 
anti-UspA2.  
• 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 of 
NTHi-Mcat vaccine in the Sh_NTHi-Mcat groups 
(Day 181; Day 241; Day 331) compared to 
antibody concentrations 1 month after Dose 2 in 
the NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 group:2 
Confirmatory 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 of 
GSK Biologicals' NTHi-Mcat investigational vaccine 
when administered 1 or 3 months after Shingrix 
vaccine versus the humoral immune response 1 
month after Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% 
confidence interval (CI) of the geometric mean 
concentration (GMC) ratio (Sh_NTHi-
Mcat/NTHi-Mcat) is above a limit of 0.667 for 
all anti-PD, anti-PE, anti-PilA, anti-UspA2 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 
of NTHi-Mcat vaccine in the Sh_NTHi-Mcat_3 
group (Day 241) and Sh_NTHi-Mcat_1 group 
(Day 181) compared to antibody 
concentrations 1 month after Dose 2 in the 
NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups:2 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after 
Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine when administered 1 
month after Shingrix vaccine versus the 
humoral immune response 1 month after 
Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Humoral immune response  
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations 1 month after Dose 2 of NTHi-Mcat 
vaccine in the Sh_NTHi-Mcat_1 group (Day 181) 
compared to antibody concentrations 1 month after 
Dose 2 in the NTHi-Mcat group (Day 91).1 
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Objectives 
Endpoints 
Criterion: 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above a 
limit of 0.667 for all anti-PD, anti-PE, anti-PilA, anti-
UspA2.  
Secondary 
Descriptive 
• 
To evaluate the safety and reactogenicity profile 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered 
alone.  
• 
Solicited local and general adverse events (AEs)  
− 
Occurrence of each solicited local and general 
adverse event (AE), reported during a 7-day 
follow- up period (i.e. day of vaccination and 6 
subsequent days) after Dose 1 and after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine, in all subjects in all groups.  
• 
Unsolicited AEs  
− 
Occurrence of any unsolicited AEs, reported 
during a 30-day follow- up period (i.e. day of 
vaccination and 29 subsequent days) after Dose 
1 and after Dose 2 of GSK Biologicals' NTHi-
Mcat investigational vaccine, in all subjects in all 
groups.  
 
• 
Serious AEs  
− 
Occurrence of any SAE reported from first 
vaccination (Day 1) to Day 331 in all subjects in 
all groups. 
− 
Occurrence of any SAE, reported from Day 331 
to Day 661 in all subjects in all groups.  
− 
Potential immune-mediate diseases (pIMD)  
− 
Occurrence of any pIMD, reported from first 
vaccination (Day 1) to Day 331 in all subjects in 
all groups.  
− 
Occurrence of any pIMD, reported from Day 331 
to Day 661 in all subjects in all groups.   
Descriptive 
• 
To describe the humoral immune response of 
GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered 
alone.  
• 
Humoral response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations and seropositivity in all 
subjects before Dose 1 (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in 
the NTHi-Mcat group), and 1 month after Dose 2 
of NTHi-Mcat vaccine (Day 181; Day 241; Day 
331 in the Sh_NTHi-Mcat groups and Day 91 in 
the NTHi-Mcat group).1,4 
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Objectives 
Endpoints 
Descriptive 
• 
To describe the cell mediated immune (CMI) 
response (CD4+ T-cells) of GSK Biologicals’ 
NTHi-Mcat investigational vaccine when 
administered 1 or 3 or 6 months after Shingrix 
vaccine or when NTHi-Mcat is administered 
alone, in the CMI response sub-cohort. 
• 
CMI response 
− 
NTHi-specific and Mcat-specific CMI responses 
as measured by flow cytometry ICS (frequency of 
specific CD4+ T-cells expressing at least 2 
different markers among CD40 ligand (CD40L), 
interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α) 
upon in vitro stimulation) before Dose 1 (Day 91; 
Day 151; Day 241 in the Sh_NTHi-Mcat groups 
and Day 1 in the NTHi-Mcat group), and 1 month 
after Dose 2 of NTHi-Mcat vaccine (Day 181; 
Day 241; Day 331 in the Sh_NTHi-Mcat groups 
and Day 91 in the NTHi-Mcat group) in the CMI 
response sub-cohort.1,5 
Tertiary 
Descriptive 
• 
To describe the CMI response (CD8+ T-cells) of 
GSK Biologicals’ NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when NTHi-Mcat is 
administered alone, in the CMI response sub-
cohort.  
• 
To explore the T-helper profile of the PD-, PE-, 
PilA-, UspA2-specific CD4+/ CD8+ T cell 
responses. 
• 
CMI response  
− 
NTHi-specific and Mcat-specific CMI responses 
as measured by flow cytometry ICS (frequency of 
specific CD8+ T-cells expressing at least 2 
different markers among CD40L,IL-2, IL-13, IL-
17, IFN-γ, TNF-α upon in vitro stimulation) before 
Dose 1 (Day 91; Day 151; Day 241 in the 
Sh_NTHi-Mcat groups and Day 1 in the NTHi-
Mcat group), and 1 month after Dose 2 of NTHi-
Mcat vaccine (Day 181; Day 241; Day 331 in the 
Sh_NTHi-Mcat groups and Day 91 in the NTHi-
Mcat group) in the CMI response sub-cohort.1,4  
• 
T-helper profile  
− 
T-helper profile of the specific T-cell response in 
T-helper 1, T-helper 2 and T-helper 17 based on 
the specific expression of respectively IFN- γ, IL-
13 and IL-17 before Dose 1 of the NTHi-Mcat 
investigational vaccine (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in 
the NTHi-Mcat group), and 1 month after Dose 2 
of NTHi-Mcat investigational vaccine (Day 181; 
Day 241; Day 331 in the Sh_NTHi-Mcat groups 
and Day 91 in the NTHi-Mcat group) in the CMI 
sub-cohort. Frequencies of specific CD4+/CD8+ 
T cells per 106 cells expressing combinations of 
cytokines/activation markers will be explored.1 
1 Given the different intervals between vaccines, the label for study visits or contacts varies between treatment groups. 
Please refer to the study design diagram. 
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 group will be presented 
with all available data. The descriptive analysis may be used to support the interval between Shingrix and 
NTHi-Mcat vaccines administration  
3 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 
groups will be presented with all available data. The descriptive analysis may be used to support the 
interval between Shingrix and NTHi-Mcat vaccines administration 
4 Cut-off for seropositivity will be the lower limit of quantification (LLOQ) of the assay. 
5 Refer to Section 5.3.1 for details regarding the CMI response sub-cohort. 
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5. 
STUDY DESIGN  
5.1. 
Scientific rationale for study design 
Previous studies in the COPD project have evaluated a 2-dose vaccination schedule in an 
age range from 40 to 80 years in both healthy subjects either current or former smokers, 
and COPD patients. The current Phase IIA randomized, open-label study (NTHI MCAT-
009), will assess the impact on immunogenicity and safety of the sequential 
administration of Shingrix and the NTHi-Mcat vaccine. Subjects will be given the 
licensed Shingrix vaccine at the approved 2-dose schedule. At 1, 3 or 6 months after the 
second Shingrix vaccine, these subjects will receive the NTHi-Mcat vaccine (2 doses, 2 
months apart) (Sh_NTHi-Mcat_1, Sh_NTHi-Mcat_3, Sh_NTHi-Mcat_6 treatment 
groups). Subjects in the control group will be given the NTHi-Mcat vaccine (2 doses, 2 
months apart) alone. 
The primary objective of this study is to demonstrate non-inferiority (NI) of the humoral 
immune response of the NTHi-Mcat vaccine at 1, 3 or 6 months after the Shingrix 
vaccine as compared to the NTHi-Mcat vaccine immune response when prior Shingrix 
has not been received. Secondary objectives include the evaluation of CMI response after 
the NTHi-Mcat investigational vaccine in a sub-cohort of approximately 60 subjects, and 
the evaluation of the safety and reactogenicity profile of the NTHi-Mcat vaccine in all 
subjects. 
Shingrix is recommended in the US and in some European countries and based on current 
data it is anticipated that the vaccine will provide a broad coverage of protection for 
vaccinated individuals aged 50 years-plus. The planned study population for future 
COPD efficacy trials includes adults with COPD aged 40 years-plus which has 
considerable overlap with the Shingrix target population. The current study will enroll 
adults aged 50 to 80 years. As cigarette smoking is the most commonly encountered risk 
factor for COPD, current and former smokers with a smoking history of at least 10 pack-
years will be enrolled in order to immunologically represent the COPD population as 
much as possible. Data suggest that alterations to the immune system start early on in 
smokers, before the COPD disease is detected [Barcelo, 2008; Droemann, 2005; 
Takanashi 1999]. 
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5.2. 
Overall design 
Figure 1 
Study design overview 
 
BS C = blood sample for cell-mediated immune response; BS H = blood sample for humoral immune responses/assay 
development from all subjects; C= Call; D = Day; mth(s) = month(s); NA = not applicable; NM = NTHi-Mcat 
vaccination; RAND = randomization; S = Safety; Sh = Shingrix vaccination; V = Visit 
Notes: 
1. Groups: Sh_NTHi-Mcat_1 (NTHi-Mcat vaccine administered 1 month after Shingrix vaccine) 
2. Groups: Sh_NTHi-Mcat_3 (NTHi-Mcat vaccine administered 3 months after Shingrix vaccine) 
3. Groups: Sh_NTHi-Mcat_6 (NTHi-Mcat vaccine administered 6 months after Shingrix vaccine) 
4. Subjects randomized to the NTHi-Mcat control group will receive the first NTHi-Mcat vaccination at Visit 1 (Day 1) 
and the second NTHi-Mcat vaccination at Visit 3 (Day 61) 
5. Blood sample for cell-mediated immune response will be taken from approximately 60 subjects ( ~15 subjects in each 
group. Refer to Section 5.3.1 for details of the CMI sub-cohort  
6. Solicited local and general adverse events reported during a 7-day follow-up period after Dose 1 and after Dose 2 of 
NTHi-Mcat vaccine, and unsolicited adverse events reported during a 30-day follow-up period after Dose 1 and 
after Dose 2 of NTHi-Mcat vaccine will be collected 
7. Safety follow-up 
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Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the schedule of activities (Section 2), are essential and 
required for study conduct.  
• 
Type of study: self-contained. 
• 
Experimental design: Phase IIA , open-label, randomized, controlled, multi-centric, 
study with 4 parallel groups.  
• 
Duration of the study: For each subject, the study will last approximately 22 
months from Day 1 to study completion (Day 661). 
− 
Epoch 001: Primary starting at Day 1 and ending at Day 331. 
− 
Epoch 002: Long-term follow-up starting from Day 331 until the end of the 
study (Day 661). 
Note: Given the intervals between vaccine schedules, the timepoint for study visits 
or contacts varies between treatment groups (refer to Figure 1). 
• 
Primary completion date (PCD): PCD will be 1 month post-Dose 2 of the NTHi-
Mcat investigational vaccine (Day 331, based on Sh_NTHi-Mcat_6 treatment 
group). 
Refer to section 12.1.2 for the definition of PCD. 
• 
End of Study (EoS): Last subject last visit (Day 661). 
Refer to section 12.1.2 for the definition of EoS. 
• 
Study groups: Approximately 540 eligible subjects who will be randomly assigned 
to 4 study groups in a (1: 1: 1: 1) ratio (approximately 135 subjects in each group): 
Sh_NTHi-Mcat_1, Sh_NTHi-Mcat_3, Sh_NTHi-Mcat_6, NTHi-Mcat. Please refer 
to Section 10.1 for details related to the determination of sample size. 
Table 7 
Study groups, treatment and epochs foreseen in the study 
Study Groups 
Number 
of 
subjects 
Age 
(Min-Max) 
Treatment name 
Epochs 
(Blinding) 
Epoch 001 
(open-label) 
Epoch 002 
(open-label) 
Sh_NTHi-Mcat_1  
135 
50 – 80 years 
Shingrix / NTHi-Mcat 
●  
●  
Sh_NTHi-Mcat_3  
135 
50 – 80 years 
Shingrix / NTHi-Mcat 
●  
●  
Sh_NTHi-Mcat_6  
135 
50 – 80 years 
Shingrix / NTHi-Mcat 
●  
●  
NTHi-Mcat  
135 
50 – 80 years 
NTHi-Mcat 
●  
●  
Sh = Shingrix 
• 
Control: active control. 
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• 
Vaccination schedule(s):  
− 
Sh_NTHi-Mcat_1: 2 doses of GSK Biologicals’ Shingrix vaccine at Day 1, Day 
61 and, following a 1 month gap, 2 doses of GSK Biological’s NTHi-Mcat 
investigational vaccine at Day 91, and Day 151. 
− 
Sh_NTHi-Mcat_3: 2 doses of GSK Biologicals’ Shingrix vaccine at Day 1, Day 
61 and, following a 3 month gap, 2 doses of GSK Biological’s NTHi-Mcat 
investigational vaccine at Day 151 and Day 211.  
− 
Sh_NTHi-Mcat_6: 2 doses of GSK Biologicals’ Shingrix vaccine at Day 1, Day 
61 and, following a 6 month gap, 2 doses of GSK Biological’s NTHi-Mcat 
investigational vaccine at Day 241 and Day 301. 
− 
NTHi-Mcat: 2 doses of GSK Biological’s NTHi-Mcat investigational vaccine 
at Day 1 and Day 61.  
Note: Please refer to Figure 1 for Visit / Contact number. 
• 
Treatment allocation: Subjects will be allocated to a study group using an 
automated, electronic System Built for Internet Randomization (SBIR). 
• 
Blinding: open-label. 
Note: Due to the reactogenicity of the Shingrix vaccine it is not possible to mask 
with placebo. 
• 
Sampling schedule: Blood samples for the assessment of humoral immunogenicity 
will be collected from all subjects in all study groups. In addition, blood samples for 
the assessment of cell-mediated immune (CMI) response will be collected from 
subjects in the CMI sub-cohort (refer to Section 5.3.1 for details of the CMI sub-
cohort). Blood samples will be collected at the following timepoints: 
− 
Sh_NTHi-Mcat_1 at Day 91 (Visit 3_1) and Day 181 (Visit 6_1) 
− 
Sh_NTHi-Mcat_3 at Day 151 (Visit 3_3) and Day 241 (Visit 6_3) 
− 
Sh_NTHi-Mcat_6 at Day 241 (Visit 3_6) and Day 331 (Visit 6_6) 
− 
NTHi-Mcat at Day 1 (Visit 1) and Day 91 (Visit 4). 
• 
Data collection: Electronic Case Report Form (eCRF). Telephone contact. Solicited 
and unsolicited symptoms will be collected using a subject Diary (paper Diary 
[pDiary]).  
• 
Safety monitoring: All subjects will undergo a general physical examination 
(including vital signs) at Day 1 (Visit 1_1; Visit 1_3; Visit 1_6 in the Sh_NTHi-Mcat 
groups and Visit 1 in the NTHi-Mcat group), and also during subsequent clinic visits 
following the NTHi-Mcat vaccination if deemed necessary by the Investigator or 
delegate. Subjects will be observed for at least 60 minutes after each NTHi-Mcat 
vaccination for any immediate reactions. Solicited local and general AEs occurring 
during a 7-day follow-up period after each NTHi-Mcat 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 NTHi-Mcat vaccination (i.e. the day of vaccination 
and the 29 subsequent days), will be reported via diary cards. In addition, subjects 
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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. Finally, 
safety assessments will be performed during each clinic visit and safety follow-up 
calls to collect information on AEs leading to withdrawal, serious adverse events 
(SAEs), SAEs related to study participation or to a concurrent GSK 
medication/vaccine, pregnancies, pIMDs, throughout the study period. 
5.3. 
Number of subjects  
Healthy smokers and former smokers aged 50 to 80 years will be enrolled in this study. 
A maximum of approximately 540 subjects (135 subjects per study group) will be 
randomized such that approximately 432 evaluable subjects complete the study (refer to 
Section 10.1 for a detailed description of the criteria used in the estimation of the sample 
size).  
Withdrawals will not be replaced. 
5.3.1. 
Cell-mediated immune response: sub-cohort 
Approximately 60 subjects in total will be part of a sub-cohort for CMI analysis (Table 
8). An additional blood sample will be taken from these subjects at specified timepoints 
(pre-Dose 1 (Day 91; Day 151; Day 241 in the Sh_NTHi-Mcat groups and Day 1 in the 
NTHi-Mcat group), and 1 month post-Dose 2 of the NTHi-Mcat investigational vaccine 
(Day 181; Day 241; Day 331 in the Sh_NTHi-Mcat groups and Day 91 in the NTHi-Mcat 
group). 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 8 
Sub-cohorts 
Sub-cohort 
name 
Description 
Estimated 
number of 
subjects 
Sub-cohort for 
CMI 
At specific timepoints 
 
• 
Sh_NTHi-Mcat_1 Day 91 (Visit 3_1); Day 181 (Visit 6_1) 
~15 subjects 
• 
Sh_NTHi-Mcat_3 Day 151 (Visit 3_3); Day 241 (Visit 6_3) 
~15 subjects 
• 
Sh_NTHi-Mcat_6 Day 241 (Visit 3_6); Day 331 (Visit 6_6) 
~15 subjects 
• 
NTHi-Mcat Day 1 (Visit 1) and Day 91 (Visit 4) 
~15 subjects 
CMI = cell-mediated immune response; Sh = Shingrix 
5.4. 
Subject and study completion 
A subject is considered to have completed the study if he/she returns for the concluding 
visit/is available for the concluding contact (Day 661 [Call 4_1, Call 5_3, Visit 7_6, Call 
5]) as described in the protocol. 
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6. 
STUDY POPULATION 
6.1. 
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, return for follow-up 
visits).  
• 
Written informed consent obtained from the subject prior to performance of any 
study specific procedure.  
• 
A male or female between, and including, 50 years and 80 years of age at the time of 
the first vaccination.  
• 
Healthy subjects as established by medical history and clinical examination before 
entering into the study.  
• 
Current or former smoker with a cigarette smoking history ≥10 pack-years.  
Please refer to the glossary of terms for the definitions of pack-years and of current 
and former smoker. 
• 
Female subjects of non-childbearing potential may be enrolled in the study. Non-
childbearing potential is defined as pre-menarche, current bilateral tubal ligation or 
occlusion, hysterectomy, bilateral ovariectomy or post-menopause. Please refer to 
Section 12.6.1 for definitions of menarche and menopause.  
• 
Female subjects of childbearing potential may be enrolled in the study, if the subject 
(refer to Section 12.6.1 for definitions of woman of child bearing potential): has 
practiced adequate contraception for 30 days prior to vaccination (refer to Section 
12.6.2 for definition of adequate contraception), 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.  
6.2. 
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: 
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6.2.1. 
Medical conditions 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).  
• 
History of potential immune-mediated disease (pIMD).  
Note: Please refer to Table 23for a non-exhaustive list of pIMDs. If the subject has 
any condition on this list, they must be excluded unless the aetiology is clearly 
documented to be non-immune mediated. 
The investigator will exercise his/her medical and scientific judgement in deciding 
whether other diseases have an autoimmune origin and thus meet the exclusion 
criteria. 
• 
Diagnosis of COPD regardless of severity.  
• 
History of allergic disease or reactions likely to be exacerbated by any component of 
the vaccines. Additionally, consider allergic reactions to other material or equipment 
related to study participation (such as materials that may possibly contain latex –
gloves, syringes, etc).  
• 
Has significant disease (including significant psychological disorders), in the opinion 
of the investigator, likely to interfere with the study and/or likely to cause death 
within the study duration.  
• 
History of or current condition preventing intramuscular injection as bleeding or 
coagulation disorder.  
• 
Malignancies within previous 5 years (excluding non-melanoma skin cancer) or 
lymphoproliferative disorders.  
6.2.2. 
Prior/concomitant therapy 
• 
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 
vaccine (Day -29 to Day 1), or planned use during the study period. 
• 
Planned administration/administration of a vaccine not foreseen by the study 
protocol in the period starting 30 days before the first dose and ending 30 days after 
the last dose of vaccine administration, with the exception of non-MF59 adjuvanted 
influenza vaccines and pneumococcal vaccines which may be administered ≥15 days 
preceding or following any study vaccine dose.  
Note: For M59 adjuvanted flu vaccine and for any vaccine containing novel adjuvant 
refer to exclusion criteria below.  
• 
Planned administration/administration of a vaccine adjuvanted with the following 
adjuvants AS01, AS02, AS03, AS04 and MF59 in the period starting 6 months 
before the first dose of study vaccine, and ending at the second blood draw (i.e. 
approximately 1 month after the administration of the last dose of NTHi-Mcat 
vaccine). The following non-exhaustive list should be considered as criteria for 
exclusion: Prepandrix, Adjupanrix, Shingrix, Fendrix, Cervarix, FluAd, Chiromas, 
Gripguard.  
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• 
Previous vaccination with any vaccine containing NTHi and/or Mcat antigens.  
• 
Previous vaccination with Shingrix (either registered product or participation in a 
previous vaccine study).  
• 
Previous vaccination with HZ live-attenuated vaccine (ZVL) (either registered 
product or participation in a previous vaccine study) within the 2 months of the first 
study visit (Day 1).  
• 
Administration of long-acting immune-modifying drugs at any time during the study 
period (e.g. infliximab). 
• 
Chronic administration (defined as more than 14 days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 6 
months prior to the first vaccine dose, and ending at the second blood draw (i.e. 
approximately 1 month after the administration of the last dose of NTHi-Mcat 
vaccine). For corticosteroids, this will mean prednisone ≥5 mg/day (for adult 
subjects), or equivalent. Only topical steroids are allowed. 
• 
Administration of immunoglobulins and/or any blood products or plasma derivatives 
during the period starting 3 months before the first dose of study vaccine or planned 
administration starting from Day 1 and ending at the second blood draw (i.e. 
approximately 1 month after the planned administration of the second dose of NTHi-
Mcat vaccine). 
6.2.3. 
Prior/concurrent clinical study experience 
• 
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 (drug or medical device).  
6.2.4. 
Other exclusions 
• 
Pregnant or lactating female.  
• 
Female planning to become pregnant or planning to discontinue contraceptive 
precautions.  
• 
Current alcoholism and/or drug abuse.  
Please refer to the glossary of terms for the definition of alcoholism. 
• 
Any other clinical condition that, in the opinion of the investigator, might pose 
additional risk to the subject due to participation in the study.  
• 
Any study personnel or immediate dependants, family, or household member.  
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6.3. 
Criteria for temporary delay for enrolment and vaccination  
Vaccination may be postponed within the allowed time interval until transient 
circumstances cited below have been resolved: 
• 
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 
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.  
7. 
TREATMENTS 
Study treatment is defined as a set of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a subject. 
7.1. 
Treatments administered 
Table 9 
Treatments administered  
Study Treatment Name: 
Shingrix 
NTHi-Mcat 
Vaccines name 
VZV gE  
AS01B  
NTHi-Mcat 10-10-3  
AS01E  
Presentation 
Lyophilized form 
in monodose 
vials  
Liquid in 
monodose 
vial  
Freeze-dried 
antigens in 
monodose vial  
Liquid in bidose 
vial  
Vaccines formulation: 
gE=50µg  
MPL=50µg; 
QS21=50µg; 
Liposomes  
PD=10µg; PE-
PilA=10µg; 
UspA2=3.3µg  
MPL=25µg; 
QS21=25µg; 
Liposomes  
Route of Administration  
IM 
IM 
Administration site 
 
 
 
 
Location 
Deltoid 
Deltoid 
Directionality 
Upper 
Upper 
Laterality2 
Non-dominant 
Non-dominant 
Number of doses to be 
administered: 
2 
2 
Volume to be administered: 
0.5 ml 
0.5 ml 
Packaging and Labelling 
Refer to SPM for more details 
Refer to SPM for more details 
Manufacturer 
GSK Biologicals SA 
GSK Biologicals SA 
AS = adjuvant system; gE = glycoprotein E; MPL = 3-O-desacyl-4′-monophosphoryl lipid A; IM = intramuscular; PD = 
protein D of NTHi; PE= protein E of NTHi; PiLA = type IV pili subunit of NTHi; QS21 = Quillaja saponaria Molina, 
fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of Agenus Inc., a Delaware, USA 
corporation); Sh = Shingrix; UspA2 = ubiquitous surface protein A from Mcat; VZV = varicella zoster virus 
1 QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation)  
2 The deltoid of the non-dominant arm is the preferred side of injection. All Shingrix and NTHi-Mcat vaccinations should 
be given in the same arm. In rare cases when it is not possible to inject in the non-dominant arm, injection in the 
dominant arm may be performed and clearly documented in the eCRF. Subjects who do not receive all Shingrix 
and NTHi-Mcat vaccinations in the same arm will be excluded from the per protocol analysis. 
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After completing all prerequisite procedures prior to vaccination (refer to Section 8.3) 
regarding the contraindications to subsequent vaccination), 1 dose of study reconstituted 
vaccine will be administered intramuscularly (IM) in the deltoid of the preferably non-
dominant arm. Note that Shingrix and NTHi-Mcat vaccinations should be given in the 
same arm. (Refer to Table 9 for details regarding the treatment administered).  
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be rescheduled 
within the allowed interval for this visit (refer to Table 5). 
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. 
7.2. 
Method of treatment assignment 
7.2.1. 
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 the/each study centre.  
7.2.2. 
Randomization of treatment 
7.2.2.1. 
Randomization of supplies 
The randomization 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 centers/warehouse(s). 
To allow GSK Biologicals to take advantage of greater rates of recruitment in this multi-
centre study and to thus reduce the overall study recruitment period, an over-
randomization of supplies will be prepared.  
7.2.2.2. 
Treatment allocation to the subject 
The treatment numbers will be allocated by dose. 
7.2.2.2.1. Study group and treatment number allocation 
The target will be to enrol approximately 540 eligible subjects who will be randomly 
assigned to 4 study groups in a (1: 1: 1: 1) ratio (approximately 135 subjects in each 
group) (refer to Section 10.1). 
Allocation of the subject to a study group at the investigator site will be performed using 
a randomization system on internet (SBIR). The randomization algorithm will use a 
minimisation procedure accounting for age category (50–59, 60–69, 70–80 years of age), 
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smoking status (current or former smoker), and centre. Minimization factors will have 
equal weight in the minimization algorithm. 
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 randomization 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. 
7.2.2.2.2. Treatment number allocation for subsequent doses  
For each dose subsequent to the first dose, the study staff in charge of the vaccine 
administration will access SBIR, provide the subject identification number, and the 
system will provide a treatment number consistent with the allocated study group. 
The number of each administered treatment must be recorded in the eCRF on the Vaccine 
Administration screen. 
7.3. 
Blinding and unblinding 
Data of Epoch 1 and Epoch 2 will be collected in an open manner. 
This is an open-label study; however, the specific treatment to be taken by a subject will 
be assigned using randomization system on internet (MatEx/SBIR). The site will contact 
the interactive voice/web response system (IVRS/IWRS) or log-on to SBIR prior to the 
start of study treatment administration for each subject. The site will record the treatment 
assignment on the applicable Case Report Form, if required. Potential bias will be 
reduced by central randomization. 
7.4. 
Handling, storage and replacement of study vaccines 
7.4.1. 
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. 
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A temperature excursion is any temperature that is not in range of the label storage 
temperature conditions. Temperatures outside the range of label storage temperature 
conditions must be reported and/or documented. Temperature excursion impacting study 
vaccines must be reported and/or documented. 
In the frame of the reporting, the lack/absence of temperature monitoring documentation 
from a device meeting GSK requirements has to be considered as a temperature 
excursion. 
Study vaccines that are impacted by a temperature excursion may not be used and must 
be quarantined at label storage conditions until usage approval has been obtained 
from/via the local study contact (e.g. Site Monitor). 
Refer to the Module on Clinical Trial Supplies in the SPM for details and instructions on 
the temperature excursion reporting and usage decision process, packaging and 
accountability of the study vaccines. 
7.4.2. 
 Replacement of unusable vaccines 
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 10% additional vaccine/product 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 an open manner, is that the 
replacement vial matches the formulation the subject was assigned to by randomization. 
7.5. 
Concomitant medications/products and concomitant 
vaccinations 
7.5.1. 
Recording of 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. 
The following concomitant medications/products/vaccines must be recorded in the eCRF:  
• 
Relevant medications/products, administered starting from Day 1 and ending at the 
second blood draw (i.e. approximately 1 month after the administration of the second 
dose of of NTHi-Mcat study vaccine).  
• 
All concomitant vaccines/medications/products associated with an AE, except 
vitamins and dietary supplements, administered during the period starting from Day 
1 and ending at the second blood draw (i.e. approximately 1 month after the 
administration of the second dose of of NTHi-Mcat vaccine). 
• 
Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination). 
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Example: 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 axilla. 
• 
Any concomitant medications/products/vaccines leading to the withdrawal or non-
eligibility of the subject from the study. Please refer to Section 7.5.2 for further 
details. 
• 
Any concomitant medications/products/vaccines relevant to a SAE/potential immune 
mediated disease (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 a SAE/pIMD need to be recorded on the expedited Adverse 
Event report. 
7.5.2. 
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses 
(Amended 18 May 2020) 
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 10.2 for populations 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 starting 6 months prior to the first vaccine 
dose (see Section 6.2.2) and ending at the second blood draw (i.e. approximately 1 
month after the administration of the second dose of NTHi-Mcat vaccine). For 
corticosteroids, this will mean prednisone 5 mg/day (for adult subjects), or 
equivalent. Topical steroids are allowed.  
• 
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab). 
• 
Any vaccine not foreseen by the study protocol administered during the period 
starting 30 days before the first dose and ending at the second blood draw (i.e. 
approximately 1 month after the administration of the second dose of NTHi-Mcat 
vaccine),* with the exception of non-MF59 adjuvanted influenza vaccines and 
pneumococcal vaccines which may be administered ≥15 days preceding or following 
any study vaccine dose.  
* In case an emergency mass vaccination for an unforeseen public health threat (e.g.: 
a pandemic) is organized by the public health authorities, outside the routine 
immunization 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. 
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• 
Any vaccine adjuvanted with AS01, AS02, AS03, AS04, or MF59, administered 
until the second blood braw (approximately 30 days after the last dose of NTHi-Mcat 
vaccine administration). 
• 
Immunoglobulins and/or any blood products administered during the period starting 
from Day 1 and ending at the second blood draw (i.e. approximately 1 month after 
the administration of the second dose of NTHi-Mcat study vaccine). 
• 
Drug and/or alcohol abuse. 
7.6. 
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses 
At each study visit starting from Day 1 and ending at the second blood draw (i.e. 
approximately 1 month after the administration of the second dose of NTHi-Mcat 
vaccine), it must be verified if the subject has experienced or is experiencing any 
intercurrent medical condition that may lead to elimination from per protocol analysis. If 
it is the case, the condition(s) must be recorded in the eCRF. 
Subjects may be eliminated from the per-protocol set 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. 
7.7. 
Contraindications to subsequent vaccination 
Prior to receipt of additional study vaccination, subjects must be evaluated to confirm that 
they are eligible for subsequent vaccination.  
If subjects meet any of the original exclusion/inclusion criteria or the criteria listed 
below, they should not receive additional vaccinations. Subjects should be encouraged to 
continue other study procedures at the discretion of the investigator (see Section 8.5.5). 
• 
Subjects who experience any serious adverse event judged to be possibly or probably 
related to study vaccine or non-study vaccines, including hypersensitivity reactions. 
• 
Subjects who develop any new condition which, in the opinion of the investigator, 
may pose additional risk to the subject if he/she continues to participate in the study. 
• 
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 12.5.5.1 for the 
definition of pIMDs. 
7.8. 
Treatment after completion of the study  
Not applicable. 
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7.9. 
Screen and baseline failures 
Screen failures are not applicable to this study. 
Baseline failures may occur where subjects withdraw or are withdrawn following 
informed consent, but before randomization to study treatment, based on the outcome of 
the assessment of eligibility versus inclusion and exclusion criteria and physical 
examination. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
(Amended 18 May 2020) 
Study procedures and their timing are summarized in the SoA (Section 2).  
Protocol waivers or exemptions are not allowed unless necessary for the management of 
immediate safety concerns.  
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject(s) should discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (e.g. blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 
8.1. 
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:  
• 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
• 
Diary cards may be transmitted from and to the site by electronic means and or 
conventional mail. 
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8.2. 
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. 
8.3. 
Pre-vaccination procedures 
8.3.1. 
Informed consent 
The signed/witnessed/thumb printed informed consent of the subject must be obtained 
before study participation. Refer to Section 12.4.3 for the requirements on how to obtain 
informed consent. 
8.3.2. 
Check inclusion and exclusion criteria 
Check all inclusion and exclusion criteria as described in Sections 6.1 and 6.2 before 
enrolment.  
8.3.3. 
Collection of demographic data 
Record demographic data such as year of birth, sex, race and ethnicity in the subject’s 
eCRF. 
Differences in the safety and efficacy of certain medical products, including vaccines 
[Haralambieva, 2013; Pérez-Losada, 2009; Kollmann, 2013], have been observed in 
racially and ethnically distinct subgroups. These differences may be attributable to 
intrinsic factors (e.g. genetics, metabolism, elimination), extrinsic factors (e.g. diet, 
environmental exposure, sociocultural issues), or interactions between these factors. 
Therefore, both race and ethnicity will be collected for all subjects participating in the 
study. 
8.3.4. 
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. 
8.3.5. 
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. 
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8.3.6. 
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 the 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. 
8.3.7. 
Measure/record height and weight 
Measure height and weight of the subject and record the data in the ‘Physical 
examination’ section of the eCRF. 
8.3.8. 
Physical examination 
At Day 1 (Visit 1_1, Visit 1_3, and Visit 1_6 in the Sh_NTHi-Mcat groups and Visit 1 in 
the NTHi-Mcat group) 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_1, Visit 2_3, Visit 2_6 up to and 
including Visit 7_1, Visit 7_3, and Visit 7_6 in the Sh_NTHi-Mcat groups and at Visit 3 
up to and including Visit 5 in the NTHi-Mcat group 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 5). 
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.  
8.3.9. 
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 
pregnancy test is negative.  
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Note: Urine pregnancy test must be performed even if the subject is menstruating at the 
time of the study visit. 
8.3.10. 
Previous vaccination  
At Day 1 (Visit 1_1, Visit 1_3, and Visit 1_6 in the Sh_NTHi-Mcat groups and Visit 1 in 
the NTHi-Mcat group), previous vaccination history must be recorded. 
Please refer to Section 7.5 for details on the management of concomitant vaccination 
during the study. 
8.3.11. 
Check contraindications to vaccination 
Contraindications to vaccination must be checked at the beginning of each vaccination 
visit. Refer to Section 7.7 for more details.  
8.3.12. 
Pre-vaccination body temperature 
The axillary body temperature of each subject 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 (Table 5). 
8.3.13. 
Distribution of Subject Card 
For information regarding the Subject Card, please refer to Section 8.5.7. 
8.3.14. 
Study group and treatment number allocation 
Study group and treatment number allocation will be performed as described in 
Section 7.2.2.2.1. The number of each administered treatment must be recorded in the 
eCRF. 
8.3.15. 
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 7.1 for detailed description of the vaccine administration 
procedure).  
All Shingrix and NTHi-Mcat vaccinations should be given in the same arm for the same 
subject. 
If the investigator or delegate determines that the subject’s health on the day of 
administration temporarily precludes vaccine administration, the visit will be rescheduled 
within the allowed interval for this visit (refer to Table 5). 
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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. 
8.4. 
Immunogenicity assessments 
Please refer to the SPM and to the Central Laboratory manual for details on biospecimen 
management (handling, storage and shipment). 
Samples will not be labelled with information that directly identifies the subject but will 
be coded with the identification number for the subject (subject number). 
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.  
8.4.1. 
Use of specified study materials 
When materials are provided by GSK Biologicals or GSK Biologicals’ designated 
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 10.2 for the definition of populations for analyses). The investigator 
must ensure that his/her personnel and the laboratory(ies) under his/her supervision 
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comply with this requirement. However, when GSK Biologicals or GSK Biologicals’ 
designated 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. 
8.4.2. 
Biological samples 
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. 
8.4.2.1. 
Blood sampling for immunogenicity assessments  
Blood samples will be taken during certain study visits as specified in Section 2 Schedule 
of Activities (SoA). First blood sampling should occur prior to the first NTHi-Mcat 
vaccine administration. 
From all subjects included in the immunogenicity sub-cohort (refer to Section 5.3.1) an 
overall volume of 50 ml of whole blood should be drawn to allow both the analysis of 
humoral immune response and the analysis of CMI response at each pre-defined 
timepoint (see sections below). 
Blood samples for humoral immunogenicity 
(Amended 18 May 2020) 
A volume of approximately 10 ml of whole blood should be drawn from all subjects for 
analysis of humoral immune response at each pre-defined timepoint (Table 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. 
Table 10 
Blood sampling for humoral immunogenicity 
Sample type 
Quantity 
Unit 
Study group 
Timepoint1 
Subjects 
Blood for humoral 
immunogenicity 
~10 
ml 
Sh_NTHi-Mcat_1  
D91 (V3_1) 
D181 (V6_1) 
All subjects in 
study group 
Sh_NTHi-Mcat_3  
D151 (V3_3) 
D241 (V6_3) 
All subjects in 
study group 
Sh_NTHi-Mcat_6  
D241 (V3_6) 
D331 (V6_6) 
All subjects in 
study group 
NTHi-Mcat  
D1 (V1) 
D91 (V4 ) 
All subjects in 
study group 
D = Day; Sh = Shingrix; ml = millilitres; V = Visit 
1. Refer also to Schedule of Activities (Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
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Blood samples for CMI 
(Amended 18 May 2020) 
A volume of approximately 40 ml of whole blood should be drawn from all subjects 
included in the immunogenicity sub-cohort for analysis of CMI response at each pre-
defined timepoint (Table 11). The samples should be kept at room temperature and 
should be shipped as soon as possible 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. 
Table 11 
Blood sampling for CMI 
Sample type 
Quantity 
Unit 
Study group 
Timepoint2 
Subjects 
Blood for CMI  
~40  
ml  
Sh_NTHi-Mcat_1  
D91 (V3_1) 
D181 (V6_1) 
Sub-cohort for 
CMI1 
Sh_NTHi-Mcat_3  
D151 (V3_3) 
D241 (V6_3) 
Sub-cohort for 
CMI1 
Sh_NTHi-Mcat_6  
D241 (V3_6) 
D331 (V6_6) 
Sub-cohort for 
CMI1 
NTHi-Mcat  
D1 (V1) 
D91 (V4 ) 
Sub-cohort for 
CMI1 
CMI = cell-mediated immune response; D = Day; Sh = Shingrix; ml = millilitres; V = Visit 
Notes: 
1 Refer to Section 5.3.1 for details regarding the CMI sub-cohort 
2. Refer also to Schedule of Activities Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
8.4.3. 
Laboratory assays 
Please refer to Appendix 2 for a detailed description of the assays performed in the study. 
Please refer to Appendix 3 for the address of the clinical laboratories used for sample 
analysis. 
8.4.3.1. 
Humoral antibody responses 
Total IgG concentrations will be measured by ELISA at GSK Biologicals’ laboratory (i.e. 
Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Marburg, 
Germany), or a GSK designated laboratory using qualified procedures (refer to Table 10). 
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Table 12 
Humoral immunity (antibody determination) 
System 
Component 
Method 
Kit/Manufacturer 
Unit1 
Assay 
cut-off1 
Laboratory2 
SERUM  
anti-PD antibody  
ELISA  
In-house 
EU/mL  153  
GSK Biologicals3 
or GSK 
designated 
laboratory 
SERUM  
anti-PE antibody  
ELISA  
In-house 
EU/mL  25  
GSK Biologicals3 
or GSK 
designated 
laboratory 
SERUM 
anti-PilA antibody  
ELISA 
In-house 
EU/mL  16  
GSK Biologicals3 
or GSK 
designated 
laboratory 
SERUM  
anti-UspA2 IgG 
antibody  
ELISA  
In-house 
EU/mL  38  
GSK Biologicals3 
or GSK 
designated 
laboratory 
ELISA = Enzyme Linked Immunosorbent Assay; EU/ml = ELISA unit per millilitre; Ig = immunoglobulin; PD = protein D; 
from NTHi; PE = protein E from NTHi; PilA = type IV pili subunit from NTHi; UspA2 = ubiquitous surface protein 
A2 from Mcat 
1 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. 
2 Refer to Appendix 7 for the laboratory addresses. 
3 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 of 
measuring 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. (Amended 18 May 2020) 
8.4.3.2. 
Cell-mediated immune response 
CMI assays will be performed at GSK Biologicals or GSK designated laboratory using 
optimised or qualified procedures (Table 13). 
Table 13 
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 assessing other markers such as 41BB or using other 
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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 testing on the vaccine and/or on the disease under study may be performed 
within the framework of the study if deemed necessary for accurate interpretation of the 
data or should such assay(s) become available at GSK. These assays may not be 
represented in the objectives/endpoints of the study protocol. 
The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures. The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (sponsor-dependent) but laboratory-
independent Quality Department. 
8.4.4. 
Biological samples evaluation 
8.4.4.1. 
Immunological read-outs 
(Amended 18 May 2020) 
Table 14 
Immunological read-outs 
Blood sampling timepoint 
Study group 
No. subjects 
Component 
Type of 
contact and 
timepoint3 
Sampling 
timepoint 
D91 (V3_1) 
Pre NTHi-
Mcat Vacc I 
Sh_NTHi-Mcat_1  All1 (~135) 
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D151 (V3_3) Pre NTHi-
Mcat Vacc I 
Sh_NTHi-Mcat_3  All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D241 (V3_6) Pre NTHi-
Mcat Vacc I 
Sh_NTHi-Mcat_6  All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D1 (V1) 
Pre NTHi-
Mcat Vacc I 
NTHi-Mcat  
All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D181 (V6_1) Post NTHi-
Mcat Vacc II Sh_NTHi-Mcat_1  All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D241 (V6_3) Post NTHi-
Mcat Vacc II Sh_NTHi-Mcat_3  All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D331 (V6_6) Post NTHi-
Mcat Vacc II Sh_NTHi-Mcat_6  All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
D91 (V4) 
Post NTHi-
Mcat Vacc II NTHi-Mcat  
All1 (~135)  
Anti-PD, Anti-PE, Anti-PilA and Anti-UspA2 
CMI sub-cohort (~152) Specific CD4+/CD8+ T-cells 
PD = protein D from NTHi; PE = protein E from NTHi; PilA = type 4 pili subunit from NTHi; Sh = Shingrix; UspA2 – 
ubiquitous surface protein A2 from Mcat; V=Visit ; Vacc= vaccination 
1. All subjects in the study group specified 
2 Subjects in the study group specified in the CMI sub-cohort. Refer to Section 5.3.1 for details regarding the sub-
cohort for CMI response 
3. Refer also to Schedule of Activities (Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
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8.4.5. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen(s) used in the NTHi-Mcat candidate vaccine. 
8.5. 
Safety Assessments 
(Amended 18 May 2020) 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.  
Diagnosis of COVID-19 should be made in accordance with the WHO case definition. 
Cases should be categorised as AEs (unsolicited or AEs leading to withdrawal) or 
SAEs (refer to Section 12.5 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 15 and Table 16. 
The investigator and any designees remain responsible for following up AEs that are 
serious, considered related to the study treatment or the study, or that caused the subject 
to discontinue the NTHI MCAT-009 study.  
8.5.1. 
Safety definitions 
Please refer to Section 12.5 for safety definitions. 
8.5.2. 
Time period and frequency for collecting AE and serious adverse 
event (SAE) information 
An overview of the protocol-required reporting periods for AEs, SAEs, and pregnancies 
is given in Table 15and Table 16. 
Refer to the Section 12.5.8.1 for details on the time period for recording safety 
information. 
All SAEs will be recorded and reported via Expedited AE Reporting Form to the sponsor 
or designee immediately and under no circumstance should this exceed 24 hours after the 
investigator became aware of it, as indicated in Appendix 4. The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 15and Table 16. 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a 
subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study vaccine, the investigator will promptly notify the Study 
Contact for Reporting SAEs. 
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Table 15 
Reporting periods for collecting safety information: Sh_NTHi-Mcat groups (Amended 18 May 2020) 
Event 
Study group 
Contact type (V/C) and timepoint (D) 
Sh_NTHi-Mcat_1 
V1_1 
D1 
V2_1 
D61 
V3_1 
D91 
C1_1 
D98 
V4_1 
D121 
V5_1 
D151 
C2_1 
D158 
V6_1 
D181 
C3_1 
D331 
V7_1 
D511 
N/A 
C4_1 
D661 
Sh_NTHi-Mcat _3 
V1_3 
D1 
V2_3 
D61 
V3_3 
D151 
C1_3 
D158 
V4_3 
D181 
V5_3** 
D211 
C2_3 
D218 
V6_3** 
D241 
C3_3 
D331 
C4_3** 
D391 
V7_3** 
D571 
C5_3 
D661 
Sh_NTHi-Mcat _6 
V1_6 
D1 
V2_6 
D61 
V3_6** 
D241 
C1_6 
D248 
V4_6** 
D271 
V5_6** 
D301 
C2_6 
D308 
V6_6** 
D331 
N/A 
C3_6 
D481 
N/A 
V7_6** 
D661 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Solicited local and general AEs 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to  
withdrawal from the  
study* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or concurrent GSK 
medication/vaccine 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Event 
Study group 
Contact type (V/C) and timepoint (D) 
Sh_NTHi-Mcat_1 
V1_1 
D1 
V2_1 
D61 
V3_1 
D91 
C1_1 
D98 
V4_1 
D121 
V5_1 
D151 
C2_1 
D158 
V6_1 
D181 
C3_1 
D331 
V7_1 
D511 
N/A 
C4_1 
D661 
Sh_NTHi-Mcat _3 
V1_3 
D1 
V2_3 
D61 
V3_3 
D151 
C1_3 
D158 
V4_3 
D181 
V5_3** 
D211 
C2_3 
D218 
V6_3** 
D241 
C3_3 
D331 
C4_3** 
D391 
V7_3** 
D571 
C5_3 
D661 
Sh_NTHi-Mcat _6 
V1_6 
D1 
V2_6 
D61 
V3_6** 
D241 
C1_6 
D248 
V4_6** 
D271 
V5_6** 
D301 
C2_6 
D308 
V6_6** 
D331 
N/A 
C3_6 
D481 
N/A 
V7_6** 
D661 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat_6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs = adverse events; C = Call; D = Day; N/A = not applicable; pIMDs= potential immune mediated diseases; SAEs = serious adverse events; Sh = Shingrix; V = Visit 
* If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (unsolicited AEs, AEs leading to withdrawal) or 
SAEs (refer to Section 12.5 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 
** Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances)  
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Table 16 
Reporting periods for collecting safety information: NTHi-Mcat group (Amended 18 May 2020) 
Event 
Contact type (V/C) and timepoint (D) 
V1 
D1 
C1 
D8 
V2 
D31 
V3 
D61 
C2 
D68 
V4 
D91 
C3 
D241 
C4 
D331 
V5** 
D421 
C5 
D661 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs = adverse events; C = Call; D = Day; N/A = not applicable; pIMDs= potential immune mediated diseases; SAEs = serious adverse events; V = Visit  
* If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (AEs leading to withdrawal) or SAEs (refer to 
Section 12.5 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 
** Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
 
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8.5.3. 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing intensity, causality and outcome of 
AEs and SAEs and the procedures for completing and transmitting SAE reports are 
provided in Section 12.5.8. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence.  
8.5.4. 
Reporting of serious adverse events, pregnancies, and other 
events 
SAEs that occur in the time period defined in Section 8.5.2 will be reported promptly to 
GSK within the timeframes described in Table 17once the investigator determines that 
the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 8.5.2 will be reported 
promptly to GSK within the timeframes described in Table 17, once the investigator 
becomes aware of the pregnancy.  
pIMDs that occur in the time period defined in Section 8.5.2 will be reported promptly to 
GSK within the timeframes described in Table 17, once the investigator determines that 
the event meets the protocol definition of a pIMD. 
Table 17 
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 
pIMD = potential immune-mediated disease; SAEs = serious adverse events 
* Timeframe allowed after receipt or awareness of the information. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD 
‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD  
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8.5.4.1. 
Contact information for reporting of serious adverse events (SAEs), 
pIMDs and pregnancies  
Table 18 
Contact information for reporting of serious adverse events (SAEs), 
pIMD and pregnancies  
Study contact for questions regarding 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: 
 
8.5.4.2. 
Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential for meeting 
legal obligations and ethical responsibilities for the safety of subjects and the safety of a 
study treatment under clinical investigation.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g. summary or listing of SAE) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.5.5. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs and pIMDs (serious or non-serious) will 
be followed until the event is resolved, stabilized, otherwise explained, or the subject is 
lost to follow-up. Further information on follow-up procedures is given in Section 
12.5.11. 
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8.5.6. 
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 7.5). 
8.5.7. 
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. 
8.6. 
Holding rules and safety monitoring 
Not applicable. 
8.7. 
Genetic research (pharmacogenetics) 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and pharmacogenomics 
Not applicable. 
8.9. 
Economic assessment 
Not applicable. 
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9. 
DISCONTINUATION CRITERIA 
9.1. 
Discontinuation from the study 
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who did 
not come back for the concluding visit/was not available for the concluding contact 
foreseen in the protocol.  
All data and samples 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.  
Primary reason for study 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: 
• Adverse events requiring expedited reporting (refer to Section 12.5.9.2) 
• Unsolicited non-serious adverse event 
• Solicited adverse event 
• Protocol deviation  
• Withdrawal by subject, not due to an adverse event* 
• Migrated/Moved from the study area 
• Lost to follow-up 
• Sponsor study termination 
• Other (specify) 
*In case a subject is withdrawn from the study because he/she has withdrawn consent, the 
investigator will document the reason for withdrawal of consent, if specified by the 
subject, in the eCRF. 
Subjects who are withdrawn from the study because of SAEs/AEs must be clearly 
distinguished from subjects who are withdrawn for other reasons. Investigators will 
follow subjects who are withdrawn from the study as result of a SAE/AE until resolution 
of the event (see Section 12.5.11). 
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9.2. 
Discontinuation of study vaccines 
A ‘withdrawal’ from the study vaccine refers to any subject who does not receive the 
complete treatment, i.e. when no further planned dose is administered from the date of 
withdrawal. A subject withdrawn from the study vaccines may continue further study 
procedures (safety or immunogenicity) if planned in the study protocol, as deemed 
appropriate by the investigator.  
Primary reason 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 was made by the 
subject himself/herself, or by the investigator, as well as which of the following possible 
reasons was responsible for withdrawal: 
• Adverse event requiring expedited reporting 
• Non-serious adverse event (specify) 
• Unsolicited non-serious adverse event 
• Solicited adverse event 
• Not willing to be vaccinated 
• Other (specify). 
9.3. 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Sample size determination 
10.1.1. 
Hypotheses related to primary and secondary objectives 
(Amended 18 May 2020) 
The global null hypothesis related to the primary objective of the study is that at least one 
geometric mean concentration (GMC) ratio (Sh_NTHi-Mcat over NTHi-Mcat) among 
anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 in all time-lags under 
investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must be rejected in 
favour of the alternative hypothesis that all 4 GMCs (anti-PD, anti-PE, anti-PilA, anti-
UspA2) are non-inferior in at least one time-lag group. 
As defined in the study criteria of success, non-inferiority (NI) will be claimed for a 
specific time-lag if the lower limit of the 2-sided 95% CI of the GMC ratio (Sh_NTHi-
Mcat_k over NTHi-Mcat, where k= [6, 3, 1]) will be above a limit of 0.667 for all anti-
PD, anti-PE, anti-PilA and anti-UspA2 concentration. Family-wise type I error is fixed at 
2.5% (1-sided). 
If the per-protocol sample size is either not reached in the Sh_NTHi-Mcat_6 group or 
not reached in the Sh_NTHi-Mcat_6 and in Sh_NTHi-Mcat_3 groups due to COVID-
19 containment measures, a modification to the primary objective will be applied as 
follows: 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 due to COVID-
19 containment measures: 
The global null hypothesis related to the primary objective of the study is that at 
least 1 GMC ratio (Sh_NTHi-Mcat_k, where k=3 or 1 over NTHi-Mcat) among 
anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 in all time-
lags under investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must 
be rejected in favour of the alternative hypothesis that all 4 GMCs (anti-PD, anti-
PE, anti-PilA, anti-UspA2) are non-inferior in at least one time-lag group. 
As defined in the study criteria of success, non-inferiority (NI) will be claimed for 
a specific time-lag if the lower limit of the 2-sided 95% CI of the GMC ratio 
(Sh_NTHi-Mcat_k over NTHi-Mcat, where k= [3, 1]) will be above a limit of 0.667 
for all anti-PD, anti-PE, anti-PilA and anti-UspA2 concentration. Family-wise 
type I error is fixed at 2.5% (1-sided). 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 and Sh_NTHI-
Mcat_3 due to COVID-19 containment measures: 
The global null hypothesis related to the primary objective of the study is that the 
GMC ratio (Sh_NTHi-Mcat_1 over NTHi-Mcat) among anti-PD, anti-PE, anti-
PilA, anti-UspA2 is inferior or equal to 0.667 in all time-lags under investigation 
at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must be rejected in favour of 
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the alternative hypothesis that all 4 GMCs (anti-PD, anti-PE, anti-PilA, anti-
UspA2) are non-inferior. 
As defined in the study criteria of success, non-inferiority (NI) will if the lower 
limit of the 2-sided 95% CI of the GMC ratio (Sh_NTHi-Mcat_1 over NTHi-Mcat) 
will be above a limit of 0.667 for all anti-PD, anti-PE, anti-PilA and anti-UspA2 
concentration. Family-wise type I error is fixed at 2.5% (1-sided). 
10.1.2. 
Sample size calculation 
(Amended 18 May 2020) 
The study sample size is defined in order to ensure a global 80% power to conclude NI 
on all anti-PD, anti-PE, anti-PilA and anti-UspA2 for at least one time-lag. The target 
response-wise power is then 94.6%, assuming independence, for the 4 antigens response. 
The sample size calculation is based on a standard deviation of antibody log10-
concentrations of 0.36 (based on NTHI MCAT-001) and a null true difference on the 
log10 scale.  
To control the type I error below 2.5% (one-sided), a sequential procedure will be used 
for the primary objective. Starting from the 6-months lag, the 3-months NI will be tested 
only if the 6-months NI will be demonstrated, while the 1-month NI will be tested only if 
the 6-months and 3-months NI will be both demonstrated. Sequential testing procedure 
ensures also 80% power to conclude NI for each time-lag (i.e. conditionally on 
demonstrating NI at previous steps of the procedure). The power to prove all NI 
hypotheses is 51% (assuming independence). 
The target sample size is 432 subjects evaluable for immunogenicity (108 subjects per 
study group). ‘Evaluable subjects’ means all subjects included in the set for the primary 
statistical analysis defined in Section 10.2. Considering that approximately 20% of the 
randomized subjects might withdraw, not be evaluable for immunogenicity or be 
excluded due to protocol deviations, the target sample size to be randomized is 540 
subjects (135 subjects per study group). 
If the per-protocol sample size is either not reached in the Sh_NTHi-Mcat_6 group or 
not reached in the Sh_NTHi-Mcat_6 and in Sh_NTHi-Mcat_3 groups due to COVID-
19 containment measures, a modification to the primary objective will be applied as 
follows: 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 due to COVID-
19 containment measures:  
To control the type I error below 2.5% (one-sided), a sequential procedure will be 
used for the primary objective. Starting from the 3-months lag, while the 1-month 
NI will be tested only if the 3-months NI will be demonstrated. Sequential testing 
procedure ensures also 80% power to conclude NI for each time-lag (i.e. 
conditionally on demonstrating NI at previous steps of the procedure). The power 
to prove all NI hypotheses is 64% (assuming independence). 
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• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 and Sh_NTHi-
Mcat_3 due to COVID-19 containment measures:  
The power to prove the NI hypothesis is 80%. 
10.2. 
Populations for analyses 
For purposes of analysis, the following analysis sets are defined: 
Analysis Set 
Description 
Enrolled  
All subjects who sign informed consent  
Exposed  
All subjects who received at least 1 dose of the study treatment. The allocation 
in a group is done in function of the administered treatment. 
Full analysis 
All subjects who received at least 1 dose of the study treatment and have 
post-vaccination immunogenicity data 
Modified full analysis 
(mFAS) 
All subjects who received full study treatment course to which they are 
randomized and have post-vaccination immunogenicity data  
Per protocol  
All subjects who received full study treatment course to which they are 
randomized and have post-vaccination data (mFAS) minus subjects with 
protocol deviations that lead to exclusion* 
Unsolicited safety  
All subjects who received at least 1 dose of the study treatment (exposed set) 
that report unsolicited AEs or that report not having unsolicited AEs 
Solicited safety  
All subjects who received at least 1 dose of the study treatment (exposed set) 
who have solicited safety data 
10.3. 
Statistical analyses 
10.3.1. 
Subjects disposition 
Number of enrolled, and number of vaccinated (at least 1 vaccination and full vaccination 
course) subjects, included in each group or in total will be described. These might be 
additionally broken down by country and/or by site.  
10.3.2. 
Demography and baseline characteristics analyses 
Demographic characteristics (including age at first study vaccination in years, gender, 
race, ethnicity and smoking status) will be summarized by study groups and overall, 
using descriptive statistics: 
• 
Frequency tables will be generated for categorical variables such as smoking status. 
• 
Mean, standard deviation, median, minimum and maximum will be provided for 
continuous data such as age, height and weight. 
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Withdrawal status will be summarized 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 the per protocol set (PPS) and mFAS will be tabulated. 
10.3.3. 
Efficacy analyses 
Not applicable. 
10.3.4. 
Immunogenicity analyses 
(Amended 18 May 2020) 
The primary analysis will be based on the PPS. A supplementary analysis may be based 
on the mFAS. 
Endpoint 
Statistical analysis methods 
Primary Endpoint(s) 
Primary  
Between group assessment 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1; _3; _6 group over NTHi-
Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using an analysis 
of covariance (ANCOVA) model on the logarithm10 transformation of the concentrations. 
The ANCOVA model will include study group, smoking status (current or former), age 
category (50–59, 60–69, 70–80 years of age) and centre as factors and the antibody 
concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-sided 95% 
CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-PilA, anti-UspA2. 
The sequential procedure for multiple time-lags will be used: starting from the 6-months 
lag, the 3-months NI will be tested only if the 6-months NI will be demonstrated, while the 
1-month NI will be tested only if the 6-months and 3-months NI will be both 
demonstrated. 
The following 
modification of the 
primary objective 
will be applicable if 
the per-protocol set 
is not reached for 
the Sh_NTHi-Mcat_6 
group:1 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1; _3 group over 
NTHi-Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using 
an analysis of covariance (ANCOVA) model on the logarithm10 transformation of 
the concentrations. The ANCOVA model will include study group, smoking status 
(current or former), age category (50–59, 60–69, 70–80 years of age) and centre as 
factors and the antibody concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-
sided 95% CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-
PilA, anti-UspA2. The sequential procedure for multiple time-lags will be used: 
starting from the 3-months lag, the 1-month NI will be tested only if the 3-months 
NI will be demonstrated.  
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Endpoint 
Statistical analysis methods 
The following 
modification of the 
primary objective 
will be applicable if 
the per-protocol set 
is not reached for 
the Sh_NTHi-Mcat_6 
and the Sh_NTHi-
Mcat_3 groups:2 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1 group over NTHi-
Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using an 
analysis of covariance (ANCOVA) model on the logarithm10 transformation of the 
concentrations. The ANCOVA model will include study group, smoking status 
(current or former), age category (50–59, 60–69, 70–80 years of age) and centre as 
factors and the antibody concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-
sided 95% CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-
PilA, anti-UspA2.  
Secondary Endpoint(s) 
Secondary - humoral 
Within group assessment 
For each study group, for each sampling timepoint and for each antigen, the following 
statistics will be computed: 
• 
Seropositivity rates with exact 95% CI (seropositivity defined using the assay lower 
limits of quantification [LLOQ]) 
• 
Adjusted and unadjusted GMCs with 95% CI (adjustment by ANCOVA model, as 
specified above) 
• 
The range and distribution of antibody concentrations 
The distribution of antibody concentrations for each antigen will be displayed using 
reverse cumulative distribution curves. 
Secondary –cell-
mediated immune 
response 
CMI response induced by the NTHi-Mcat candidate vaccine will be evaluated, presenting 
the frequencies of antigen-specific CD4+ T cells per 106 cells. The specific CD4+ T cells 
being identified as the CD4 + T cells expressing at least 2 different markers among 
CD40 Ligand (CD40L), IL-2, TNF- α, IFN- γ, IL-13 and IL-17 upon in vitro stimulation. 
Descriptive statistics (Min, Q1, Median, Mean, Q3 & Max) will be reported for each group 
at pre-Dose 1 of the NTHi-Mcat investigational vaccine (Day 91; Day 151; Day 241 in the 
Sh-NTHi-Mcat groups and Day 1 in the NTHi-Mcat group), and 1 month after Dose 2 of 
NTHi-Mcat investigational vaccine (Day 181; Day 241; Day 331 in the Sh_NTHi-Mcat 
groups and Day 91 in the NTHi-Mcat group). 
Tertiary –cell-
mediated immune 
response 
 
• 
CMI response induced by the NTHi-Mcat candidate vaccine will be evaluated, 
presenting the frequencies of antigen-specific CD8+T cells per 106 cells. The 
specific CD8+T cells being identified as the CD8+ T cells expressing at least 2 
different markers among CD40L, IL-2, TNF- α, IFN- γ, IL-13 and IL-17 upon in vitro 
stimulation.  
• 
CMI response as the frequencies of specific CD4+/CD8+ T cells per 106 cells 
expressing any combination of cytokines/activation markers will be determined. The 
T-helper profile of the specific T-cell response in T-helper 1, T-helper 2 and T-helper 
17 based on the specific expression of respectively IFN- , IL-13 and IL-17 will be 
characterized. Descriptive statistics (Min, Q1, Median, Mean, Q3 & Max) will be 
reported for each group at pre-Dose 1 of the NTHi-Mcat investigational vaccine 
(Day 91; Day 151; Day 241 in the Sh-NTHi-Mcat groups and Day 1 in the NTHi-
Mcat group), and 1 month after Dose 2 of NTHi-Mcat investigational vaccine (Day 
181; Day 241; Day 331 in the Sh_NTHi-Mcat groups and Day 91 in the NTHi-Mcat 
group). 
1 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 group will be presented 
with all available data. The descriptive analysis may be used to support the interval between Shingrix and 
NTHi-Mcat vaccines administration  
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 
groups will be presented with all available data. The descriptive analysis may be used to support the 
interval between Shingrix and NTHi-Mcat vaccines administration  
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10.3.5. 
Safety analyses 
All safety analyses will be performed on the solicited safety set, unsolicited safety set and 
exposed set.  
Endpoint 
Statistical analysis methods 
Secondary 
Within group assessment 
The percentage of subjects with at least 1 local adverse event (AE) (solicited and unsolicited), 
with at least 1 general AE (solicited and unsolicited) and with any AE during the 7-days 
solicited follow-up period and the 30-days follow-up period will be tabulated by group with 
exact 95% CI after each NTHi-Mcat vaccine dose and overall. The percentage of NTHi-Mcat 
doses followed by at least 1 local AE (solicited and unsolicited), by at least 1 general AE 
(solicited and unsolicited) and by any AE will be tabulated by group with exact 95% CI. The 
same calculations will be performed for AEs rated as Grade 3, for AEs causally related to 
vaccination and Grade 3 AEs causally related to vaccination. 
The percentage of subjects reporting each individual solicited local and general AE during the 
7-days solicited follow-up period after each dose of NTHi-Mcat vaccine will be tabulated by 
group with exact 95% CI. The percentage of NTHi-Mcat doses followed by each individual 
solicited local and general AE will be tabulated by group with exact 95% CI. 
Fever will be reported per 0.5°C cumulative increments. 
For all solicited symptoms, the same tabulation will be performed for Grade 3 AEs. 
The verbatim reports of unsolicited symptoms will be reviewed by a physician and the signs 
and symptoms will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) Dictionary for Adverse Event Terminology. The percentage of subjects with at least 
1 report of unsolicited adverse event classified by the MedDRA, and reported up to 30 days 
after NTHi-Mcat vaccinations will be tabulated by group with exact 95% CI. The same 
tabulation will be performed for Grade 3 unsolicited adverse events, for unsolicited adverse 
events with a causal relationship to vaccination and for Grade 3 AEs causally related to 
vaccination. 
The number of subjects who experienced any serious adverse event (SAE) or any potential 
immune-mediated disease (pIMD) from Day 1 to Day 331 and from Day 331 to Day 661 will 
be reported.   
The number of subjects who experienced any AE leading to study withdrawal, from first 
vaccination up to study conclusion, or any SAE related to study participation or concurrent 
GSK medication/vaccination, during the entire study period, will be reported. 
A summary of subjects reporting concomitant medication/product will be provided. 
10.3.6. 
Other analyses  
Not applicable. 
10.3.7. 
Interim analyses 
No interim analysis is planned for this study. Data up to and including Day 331 are 
considered ‘final’ and completed data, while the remaining safety data are considered 
long-term safety follow-up. 
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10.4. 
Sequence of analyses 
The integrated clinical study report will contain at least the final analyses of all primary 
and secondary endpoints. If the data for tertiary endpoints become available at a later 
stage, (an) additional analysis/ analyses will be performed. These analyses will be 
documented in annex(es) to the study report. 
The analyses will be performed stepwise: 
• 
A final analysis of immunogenicity, safety and reactogenicity for all subjects up to 
and including Day 331 (‘Epoch 001’) will be performed in a first step.  
A complete study report containing all data of ‘Epoch 001’ will be written and made 
available to the investigators at this stage. 
• 
Analysis conducted on the data collected for all subjects from Day 331 up to and 
including Day 661 (‘Epoch 002’) will be performed in a second step. 
An integrated study report containing all data from Epoch 001 and Epoch 002 will be 
written and made available to the investigators. 
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11. 
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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations, glossary of terms and 
trademarks 
12.1.1. 
List of abbreviations 
(Amended 18 May 2020) 
AE: 
adverse event 
AECOPD: 
acute exacerbation of chronic obstructive pulmonary 
disease 
AS01: 
adjuvant system 01 
C: 
Call 
CDC: 
Centers for Disease Control 
CI: 
confidence interval 
CLS: 
Clinical Laboratory Sciences 
CMI: 
cell-mediated immune 
CoP: 
Correlate of Protection 
COPD: 
chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease 2019 
CP: 
concept protocol 
eCRF: 
electronic Case Report Form 
eTDF: 
Electronic Temperature excursion Decision Form 
D: 
Day 
ELISA: 
enzyme-linked immunosorbent assay 
EoS: 
End of Study 
EU/mL: 
ELISA unit per millilitre 
FDA: 
Food and Drug Administration, United States of America 
FEV1: 
forced expiratory volume in 1 second 
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FVC: 
forced vital capacity 
GCP: 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
gE: 
glycoprotein E 
GMC: 
geometric mean concentration  
GOLD: 
Global Initiative for Chronic Obstructive Lung Disease 
GSK: 
GlaxoSmithKline 
HZ: 
herpes zoster 
HZ/su: 
herpes zoster subunit 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
ICH: 
International Council on Harmonisation 
IEC: 
Independent Ethics Committee 
Ig: 
immunoglobulin 
IM: 
intramuscular 
IMP: 
Investigational Medicinal Product 
IDMC: 
Independent Data Monitoring Committee 
IND: 
Investigational New Drug 
IRB: 
Institutional Review Board 
iSRC: 
Internal Safety Review Committee 
LLOQ: 
lower limit of quantification 
LSLV: 
Last Subject Last Visit 
MACDP: 
Metropolitan Atlanta Congenital Defects Program 
Mcat: 
Moraxella catarrhalis 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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MPL: 
3-O-desacyl-4’-Monophosphoryl Lipid A 
NI: 
non-inferiority 
NTHi: 
non-typeable Haemophilus influenzae 
PBMC: 
peripheral blood mononuclear cells 
PCD: 
Primary Completion Date 
PD: 
protein D  
PE: 
protein E  
PilA: 
type IV pili subunit  
pIMD: 
potential immune-mediated disease 
PP: 
per protocol 
PRO: 
patient related outcomes 
QS21: 
Quillaja saponaria Molina, fraction 21 (Antigenics, New 
York, NY, US) 
SAE: 
Serious Adverse Event 
SBIR: 
System Built for Randomization 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 
UspA2: 
ubiquitous surface protein A2  
V: 
Visit 
vacc: 
vaccination 
VZV: 
varicella zoster virus 
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12.1.2. 
Glossary of terms 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.  
An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), 
abuse or misuse. 
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 1 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 
open-label study, no blind is used. Both the investigator 
and the subject know the identity of the treatment 
assigned.  
Certified copy: 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e. by a dated 
signature or by generation through a validated process) to 
have the same information, including data that describe 
the context, content, and structure, as the original. 
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Child in care: 
A child who has been placed under the control or 
protection of an agency, organisation, institution or entity 
by the courts, the government or a government body, 
acting in accordance with powers conferred on them by 
law or regulation. The definition of a child in care can 
include a child cared for by foster parents or living in a 
care home or institution, provided that the arrangement 
falls within the definition above. The definition of a child 
in care does not include a child who is adopted or has an 
appointed legal guardian. 
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 (EoS)  
(Synonym of End of 
Trial) 
For studies with collection of human biological samples 
and/or imaging data, the End of Study is defined as 
follows: last subject last visit (Day 661). 
Epoch: 
Interval of time in the planned conduct of a study. An 
epoch is associated with a purpose (e.g. screening, 
randomization, treatment, follow-up), which applies 
across all arms of a study. NOTE: Epoch is intended as a 
standardized term to replace: period, cycle, phase, stage.  
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of the 
data produced 
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 Section 10.2 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. 
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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 authorization 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.  
Investigator 
A person responsible for the conduct of the clinical trial 
at a trial site. If a trial is conducted by a team of 
individuals at a trial site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate trial-related duties and 
functions conducted at the trial site to qualified individual 
or party to perform those trial-related duties and functions 
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. 
Pharmacogenomics 
The International Council on Harmonisation (ICH) E15 
Guidance for Industry defines pharmacogenomics as 
Study of variation of DNA and RNA characteristics as 
related to drug or treatment response. Pharmacogenetics, 
which is a subset of pharmacogenomics, is “the study of 
variations in DNA sequence as related to drug response.” 
Pharmacogenomic biomarkers include germline (host) 
DNA and RNA as well as somatic changes (e.g. 
mutations) that occur in cells or tissues. 
Pharmacogenomic biomarkers are not limited to human 
samples but include samples from viruses and infectious 
agents as well as animal samples. The term 
pharmacogenomic experiment includes both the 
generation of new genetic or genomic (DNA and/or 
RNA) data with subsequent analysis as well as the 
analysis of existing genetic or genomic data to understand 
drug or treatment response (pharmacokinetics, safety, 
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efficacy or effectiveness, mode of action). Proteomic and 
metabolomic biomarker research are not 
pharmacogenomics. 
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. 
Randomization: 
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 1 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. 
Source data: 
All information in original records and certified copies of 
original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or 
certified copies). 
Source documents: 
Original documents, data, and records (e.g. hospital 
records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified 
after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-
rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments 
involved in the clinical trial). 
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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. 
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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12.1.3. 
Trademarks 
Trademark Information 
Trademarks of the GSK group of 
companies 
 
Generic description 
Shingrix  
 
GlaxoSmithKline Biologicals’ herpes zoster 
vaccine (recombinant, adjuvanted) 
Adjupanrix 
 
GlaxoSmithKline Biologicals’ pandemic 
influenza vaccine (H5N1) (split virion, 
inactivated, adjuvanted) 
Prepandrix 
 
GlaxoSmithKline Biologicals’ prepandemic 
influenza vaccine (H5N1) (split virion, 
inactivated, adjuvanted) 
Fendrix 
 
GlaxoSmithKline Biologicals’ hepatitis B 
(rDNA) vaccine (adjuvanted, adsorbed) 
Cervarix 
 
GlaxoSmithKline Biologicals’ Human 
Papillomavirus vaccine (Types 16, 18) 
(Recombinant, adjuvanted, adsorbed) 
 
Trademarks not owned by the GSK 
group of companies 
 
Generic description 
FluAd (Seqirus UK Ltd) 
 
Influenza vaccine, adjuvanted 
Chiromas (Seqirus, Inc) (Spain) 
 
Influenza vaccine, adjuvanted 
Gripguard (Seqirus, Inc) (France) 
 
Influenza vaccine, adjuvanted 
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12.2. 
Appendix 2: Clinical laboratory tests 
12.2.1. 
Laboratory assays: immune response 
12.2.1.1. 
Humoral immunity 
Serological assays will be performed at GSK Biologicals’ laboratory or in a GSK 
designated laboratory using assays as described below and in Section 8.4.3. 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). 
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 25 EU/ml. 
Anti-PilA antibodies 
Anti-PilA antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-PilA antibodies will be determined, using an 
in-house made reference serum. The technical cut-off of the assay is 16 EU/ml. 
Anti-UspA2 antibodies 
Anti-UspA2 antibodies will be determined using an ELISA assay developed by GSK 
Biologicals. Concentration of specific anti-UspA2 antibodies will be determined, using 
an in-house made reference serum. The technical cut-off of the assay is 38 EU/ml. 
12.2.1.2. 
Cell-mediated immunity 
The intracellular cell staining (ICS) 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 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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12.3. 
Appendix 3: Clinical laboratories 
Table 19 
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 
Clinical Laboratory Sciences, 
Marburg, Germany 
Emil-von-Behring-Str. 76 
35041 Marburg 
Germany 
Table 20 
Outsourced laboratories 
Laboratory 
Address 
CEVAC-University of Gent 
De Pintelaan, 185 Gent, Belgium 
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12.4. 
Appendix 4: Study governance considerations 
12.4.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, Informed Consent Form (ICF) or Informed 
Assent Form (IAF), Investigator Brochure, and other relevant documents (e.g. 
advertisements) must be submitted, to an IRB/IEC by the investigator for review and 
approval. These documents will be signed and dated by the investigator before the 
study is initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects.  
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
− 
Notifying the IRB/IEC of SAE(s) or other significant safety findings as required 
by IRB/IEC procedures. 
− 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
12.4.2. 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interest prior 
initiation of the centre and at the end of the study. Investigators are responsible for 
providing an update of Financial Disclosure if their financial interest changes at any point 
during their participation in a study and for 1 year after completion of the study.  
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12.4.3. 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the 
subject or his/her legally authorized representative and answer all questions regarding the 
study.  
Subjects must be informed that their participation is voluntary.  
Freely given and written or witnessed/thumb printed informed consent must be obtained 
from each subject prior to participation in the study. 
The content of informed consent form must meet the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) or an ICF 
addendum during their participation in the study.  
A copy of the ICF(s) must be provided to the subject.  
Subjects who are rescreened are required to sign a new ICF. 
12.4.4. 
Data protection 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
12.4.5. 
Committees structure 
No additional information. 
12.4.6. 
Publication policy 
GSK aims to publish the results of this study in searchable, peer reviewed scientific 
literature. GSK will target to submit within 18 months from LSLV for interventional 
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studies and from the completion of the analysis for non-interventional studies and follows 
the guidance from the International Committee of Medical Journal Editors. 
12.4.7. 
Dissemination of clinical study data 
The key design elements of this protocol will be posted on the GSK Clinical Study 
Register and on publicly accessible registers including ClinicalTrials.gov. Where 
required, protocol summaries will also be posted on national or regional clinical trial 
registers or databases (e.g. EudraCT database) in compliance with the applicable 
regulations. 
GSK also assures that results will be submitted to ClinicalTrials.gov within the required 
time-frame, in compliance with the current regulations mentioned in the table below.  
At the time of study results posting, the full study protocol and statistical analysis plan 
will also be posted on ClinicalTrials.gov.  
In addition, for studies that are in scope of the EU Clinical Trial Regulation, summaries 
of the results of GSK interventional studies (phase I-IV) in adult population will be 
posted within defined timelines on the publicly EU Clinical Trial Register.  
If it is not possible to submit a summary of the results within the required timelines 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.  
 
Clinicaltrial.gov 
EU 
Protocol summary 
Before enrolment of subjects 
As per CTA submission/Before 
enrolment of subjects 
Results summary 
Within 12 months of PCD (Primary 
and safety endpoint results)/Within 
12 months of LSLV* (for secondary 
endpoint results) 
Within 6 months (for paediatric 
population studies)/Within 12 months 
(for adult population studies) of EoS*. 
* As defined in the study protocol. 
Under the framework of the SHARE initiative, anonymized patient-level data from GSK 
sponsored interventional studies that evaluate products will be made available within 6 
months of this publication to independent researchers whose research proposals have 
been approved by an independent panel. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, provided reasonable access to statistical 
tables, figures, and relevant reports. GSK Biologicals will also provide the investigator 
with the full summary of the study results. The investigator is encouraged to share the 
summary results with the study subjects, as appropriate. 
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12.4.8. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents including source documents. The storage system used during the trial and for 
archiving (irrespective of the type of media used) should provide for document 
identification, version history, search, and retrieval.  
Essential documents for the trial may be added or reduced where justified (in advance of 
trial initiation) based on the importance and relevance to the trial. When a copy is used to 
replace an original document (e.g. source documents, CRF), the copy should fulfil the 
requirements for certified copies.  
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
The investigator must maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial subjects that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data.  
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data should be traceable, should not 
obscure the original entry, and should be explained if necessary (e.g. via an audit trail). 
Safety and rights of subjects must be protected and study be conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
Trial records and source documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
12.4.9. 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Investigator should maintain a record of the location(s) of 
their source documents.  
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Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Definition of what constitutes source data and source documents can be found in the 
Glossary of terms. 
12.4.10. 
Study and site closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK, provided there is sufficient notice given 
to account for patient’s safe exit from study participation. Study sites regular closure will 
be upon study completion. A study site is considered closed when all required 
data/documents and study supplies have been collected and a study-site closure visit has 
been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of subjects by the investigator 
• 
Discontinuation of further study treatment development 
The investigator will: 
• 
Review data collected to ensure accuracy and completeness. 
• 
Complete the Study Conclusion screen in the eCRF. 
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12.5. 
Appendix 5: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting 
12.5.1. 
Definition of AE 
12.5.1.1. 
AE Definition 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment. 
NOTE: 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 study treatment. 
12.5.1.2. 
Events Meeting the AE Definition  
Significant or unexpected worsening or exacerbation of the condition/indication under 
study. 
• 
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, or the clinical sequelae of a suspected overdose of either study 
vaccine or a concurrent medication (overdose per se should not be reported as an 
AE/SAE). 
• 
Signs, symptoms temporally associated with study vaccine administration. 
• 
Significant failure of expected pharmacological or biological action.  
• 
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). 
• 
Medically attended visits related to adverse events (e.g. Hospital stays, physician 
visits and emergency room visits). 
AEs to be recorded as endpoints (solicited AEs) are described in Section 12.5.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE.  
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12.5.1.3. 
Events NOT Meeting the AE Definition  
• 
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 vaccination. These events will be recorded in the medical history section of the 
eCRF. 
12.5.2. 
Definition of SAE 
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 hospitalization, 
Note: In general, hospitalization signifies that the subject has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or in an out-patient setting. Complications 
that occur during hospitalization are also considered AEs. If a complication prolongs 
hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred, or was necessary, 
the AE should be considered serious. 
Hospitalization 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 hospitalization but may jeopardize 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. 
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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 hospitalization. 
12.5.3. 
Solicited adverse events 
Solicited local and general AEs occurring during a 7-day follow-up period after each 
NTHi-Mcat 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 NTHi-Mcat 
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. 
a. Solicited local (injection-site) adverse events 
The following local (injection-site) AEs will be solicited: 
 
Table 21 
Solicited local adverse events 
Pain at injection site 
Redness at injection site 
Swelling at injection site 
b. Solicited general adverse events 
The following general AEs will be solicited: 
Table 22 
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 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. 
12.5.4. 
Unsolicited adverse events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject who has signed the 
informed consent. 
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalisation, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subject. In case of such events, subjects will be instructed to 
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contact the site as soon as possible to report the event(s). The detailed information about 
the reported unsolicited AEs will be collected by the qualified site personnel during the 
interview and will be documented in the subject’s records. 
Unsolicited AEs that are not medically attended nor perceived as a concern by subjects 
will be collected during interview with the subject and by review of available medical 
records at the next visit. 
12.5.5. 
Adverse events of special interest (AESIs) 
12.5.5.1. 
Potential immune-mediated diseases 
Potential immune-mediated diseases (pIMDs) are a subset of AESIs 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 the Table 23(refer to Section 12.5.9.2).  
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin and should also be recorded 
as a pIMD. 
 
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Table 23 
List of potential immune-mediated diseases (pIMDs) 
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. 
• 
Localized 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),  
− 
Necrotising vasculitis (cutaneous or systemic),  
− 
anti-neutrophil cytoplasmic antibody (ANCA) 
positive vasculitis (type unspecified), 
− 
Henoch-Schonlein purpura (IgA vasculitis),  
− 
Behcet's syndrome, 
− 
Leukocytoclastic vasculitis. 
• 
Autoimmune haemolytic 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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12.5.5.2. 
Other adverse events of special interest  
When there is enough evidence to make any of the above diagnoses, the AE must be 
reported as AESI. Symptoms, signs or conditions which might (or might not) represent 
the above diagnoses, should be recorded and reported as AEs but not as AESI until the 
final or definitive diagnosis has been determined, and alternative diagnoses have been 
eliminated or shown to be less likely.  
12.5.6. 
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 (e.g. in consultation with a 
physician) 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 12.5.1 and 
12.5.2). Clinically significant abnormal laboratory findings or other abnormal 
assessments that are present at baseline and significantly worsen following the start of the 
study will also be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease 
being studied, unless judged by the investigator as more severe than expected for the 
subject’s condition, or that are present or detected at the start of the study and do not 
worsen, will not be reported as AEs or SAEs. 
The investigator will exercise his or her medical and scientific judgement in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
12.5.7. 
Events or outcomes not qualifying as adverse events or serious 
adverse events 
12.5.7.1. 
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 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 should always be recorded on an electronic pregnancy report.  
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The following should always be considered as SAE and will be reported as described in 
Sections 12.5.9.1 and 12.5.9.4: 
• Spontaneous pregnancy loss, including: 
− 
spontaneous abortion, (spontaneous pregnancy loss before/at 22 weeks of 
gestation) 
− 
ectopic and molar pregnancy 
− 
stillbirth (intrauterine death of foetus after 22 weeks of gestation). 
Note: the 22 weeks’ cut-off in gestational age is based on WHO-ICD 10 noted in the 
EMA Guideline on pregnancy exposure [EMA, 2006]. It is recognised that national 
regulations might be different. 
• Any early neonatal death (i.e. death of a live born infant occurring within the first 7 
days of life).  
• Any congenital anomaly or birth defect 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 12.5.9. While the investigator is not obligated to 
actively seek this information from former subjects, he/she may learn of a pregnancy 
through spontaneous reporting. 
12.5.8. 
Detecting and recording adverse events, serious adverse events 
and pregnancies 
A pDiary, hereafter referred to as Subject Diary will be used in this study to capture 
solicited and unsolicited adverse events. The subject should be trained on how and when 
to complete each field of the Subject Diary. 
The subjects will be instructed to contact the investigator immediately should the subjects 
manifest any signs or symptoms they perceive as serious.  
Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject, but if a person other than the subject enters 
information into the Subject Diary, this person’s identity must be documented in the 
Subject Diary. Any individual that makes entries into the Subject Diary must receive 
training on completion of the Subject Diary at the time of the visit when Subject Diary is 
dispensed. This training must be documented in the subject’s source record. 
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At each NTHi-Mcat vaccination visit, diary cards will be provided to the subject. The 
subject will be instructed to measure and record the axillary body temperature, and any 
solicited local/general AEs (i.e. on the day of vaccination and during the next 6 days) or 
any unsolicited AEs (i.e. on the day of vaccination and during the next 29 days occurring 
after 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 Day 
121; Day 181; Day 271 (Visit 4_1, Visit 4_3, Visit 4_6), and Day 181; Day 241; Day 
331 (Visit 6_1, Visit 6_3, Visit 6_6) in the Sh_NTHi-Mcat groups and on Day 31 
(Visit 2) and Day 91 (Visit 4) in the NTHi-Mcat group. 
• 
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. 
12.5.8.1. 
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies 
All AEs during 30 days following administration of each dose of NTHi-Mcat study 
vaccine (Day 1 to Day 30) must be recorded onto/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 or phone contact for each subject. See Section 
12.5.9 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. 
SAEs that are related to the study vaccine will be collected and recorded from the time of 
the first receipt of study vaccine until the subject is discharged from the study. 
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/phone contact. See section 12.5.9 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/phone contact. See section 12.5.9.5 for 
instructions on reporting of pIMDs. 
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12.5.8.2. 
Evaluation of adverse events and serious adverse events 
12.5.8.2.1. 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. 
12.5.8.2.2. Assessment of adverse events 
1. Assessment of intensity 
The intensity of the following solicited AEs will be assessed as described: 
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Table 24 
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 
Temperature* 
 
Record temperature in °C (with 1 decimal) 
Headache 
0 
Normal 
 
1 
Mild: Headache that is easily tolerated 
 
2 
Moderate: Headache that interferes with normal activity 
 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
 
1 
Mild: Fatigue that is easily tolerated 
 
2 
Moderate: Fatigue that interferes with normal activity 
 
3 
Severe: Fatigue that prevents normal activity 
Gastrointestinal symptoms 
0 
Normal 
(nausea, vomiting, diarrhoea and/or 
abdominal pain) 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
 
2 
Moderate: Gastrointestinal symptoms that interfere with 
normal activity 
 
3 
Severe: Gastrointestinal symptoms that prevent normal 
activity 
Myalgia 
 
 
0 
Normal 
1 
Mild: Myalgia that is easily tolerated 
2 
Moderate: Myalgia that interferes with normal activity  
3 
Severe: Myalgia that prevents normal activity 
Chills 
 
 
 
0 
Normal 
1 
Mild: Chills that are easily  tolerated 
2 
Moderate: Chills that interfere with normal activity  
3 
Severe: 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 
axilla 
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 
Temperature 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 
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The investigator will assess the maximum intensity that occurred over the duration of the 
event for all unsolicited AEs (including SAEs) recorded during the study. The assessment 
will be based on the investigator’s clinical judgement. 
The intensity should be assigned to 1 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 1 of the pre-defined 
outcomes as described in Section 12.5.2. 
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 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 1 of the criteria 
used when determining regulatory reporting requirements. 
All solicited local (injection site) and general reactions will be considered causally related 
to vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question: 
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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. 
*Assessment of causality for non-serious AEs is requested for NTHi-Mcat study vaccine 
only while assessment of causality for SAEs is required for both Shingrix and NTHi Mcat 
study vaccines. 
If an event meets the criteria to be determined as ‘serious’ (see Section 12.5.2), 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. 
• 
Erroneous administration. 
• 
Other cause (specify). 
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). 
12.5.8.2.3. 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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12.5.9. 
Reporting of serious adverse events, pregnancies, and other 
events 
12.5.9.1. 
Prompt reporting of serious adverse events, pregnancies, and other 
events to GSK Biologicals 
SAEs that occur in the time period defined in Section 12.5.8 will be reported promptly to 
GSK within the timeframes described in Table 15, once the investigator determines that 
the event meets the protocol definition of a SAE. 
Pregnancies that occur in the time period defined in Section 12.5.8 will be reported 
promptly to GSK within the timeframes described in Table 17, once the investigator 
becomes aware of the pregnancy.  
pIMDs that occur in the time period defined in Section 12.5.8 will be reported promptly 
to GSK within the timeframes described in Table 17, once the investigator determines 
that the event meets the protocol definition of a pIMD. 
12.5.9.2. 
SAEs requiring expedited reporting 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. 
12.5.9.3. 
Back-up system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designate) must 
complete, then date and sign a paper Expedited Adverse Events Report and fax it to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information) or to GSK 
Biologicals Clinical Safety and Pharmacovigilance department within 24 hours.  
This back-up system should only be used if the electronic reporting system is not working 
and NOT if the system is slow. As soon as the electronic reporting system is working 
again, the investigator (or designate) must complete the electronic Expedited Adverse 
Events Report within 24 hours. The final valid information for regulatory reporting will 
be the information reported through the electronic SAE reporting system.  
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12.5.9.4. 
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. 
12.5.9.5. 
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 specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
event, in accordance with the pIMD standard questionnaire provided. Even if the 
investigator does not have all information regarding a pIMD, the report should still be 
completed within 24 hours. Once additional relevant information is received, the report 
should be updated WITHIN 24 HOURS. 
The investigator will always provide an assessment of causality at the time of the initial 
report. The investigator will be required to confirm the review of the pIMD causality by 
ticking the ‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 
hours of submission of the pIMD. 
Refer to Section 12.5.9.3 for back-up system in case the electronic reporting system does 
not work. 
12.5.10. 
Updating of SAE, pregnancy, and AESI 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 17. 
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12.5.11. 
Follow-up of adverse events, serious adverse events, and 
pregnancies 
12.5.11.1. Follow-up of adverse events and serious adverse events  
12.5.11.1.1. 
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 17). 
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 study visit/phone contact 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. 
12.5.11.1.2. 
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, stabilized, disappeared, or 
until the event is otherwise explained, or the subject is lost to follow-up.  
• 
with other non-serious AEs, until resolution of the event or if 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 recognized follow-up period, 
GSK Biologicals will be provided with any available post-mortem findings, including 
histopathology. 
12.5.11.2. 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 6 to 8 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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12.6. 
Appendix 6: Contraceptive guidance and collection of 
pregnancy information 
12.6.1. 
Definitions 
12.6.1.1. 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
12.6.1.1.1. Women in the following categories are not considered WOCBP 
• 
Premenarchal 
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). 
• 
Premenopausal female with ONE of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of subject’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use 1 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
12.6.2. 
Contraception guidance 
• 
Female subjects of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as 
described in Table 25.  
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Table 25 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
oral 
• 
intravaginal  
• 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
injectable 
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.)  
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; 
medical examination and/or semen analysis, or medical history interview provided by her or her partner). 
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject.)  
NOTES:  
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects in clinical studies.  
b. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the 
treatment period and for at least 1 month after the last dose of study treatment  
12.6.3. 
Collection of pregnancy information 
12.6.3.1. 
Male subjects with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male subject’s 
female partner of a male study subject who becomes pregnant while participating in 
this study. This applies only to subjects who receive study treatment. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 2 weeks of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
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• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
• 
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. 
12.6.3.2. 
Female subjects who become pregnant 
• 
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.  
• 
Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on subject and neonate, which will be 
forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in 12.5.9. While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting.  
Any female subject who becomes pregnant while participating will be discontinued from 
study treatment and followed-up until the final outcome.  
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12.7. 
Appendix 7: Country-specific requirements 
12.7.1. 
Requirements for Estonia 
No country-specific requirements. 
12.7.2. 
Requirements for Finland 
No country-specific requirements. 
12.7.3. 
Requirements for France 
This appendix includes all applicable requirements of French Public Health Code / 
specific local GSK requirements and identifies, item per item, the mandatory 
modifications or additional information to the study protocol. 
1. Concerning the « SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA»  
• 
Subjects will be compensated for the inconvenience of participating in the study. The 
amount of compensation is stated in the Informed Consent Form. Subjects not 
completing the study for whatever reason could be compensated generally on a pro 
rata basis. 
• 
According to French Public Health Code law (L.1121-16 and R.1121-16), the 
following people must be registered in National File (“Fichier National”): 
− 
Healthy volunteer; 
− 
Subjects if the aim of the study is not linked to their disease; 
− 
Subjects on request of the ethics committee regarding study risks and 
constraints. 
The following details will be described: 
− 
Reference of the study 
− 
Surname and first name 
− 
Date and place of birth 
− 
Gender 
− 
Dates of beginning and termination of the study 
− 
Exclusion period during which the subject cannot participate to another study 
(French Public Health Code law L.1121-12) 
− 
The total amount of compensation. 
The subjects’ registration in national file (“Fichier National”) should be documented 
in the source document - subject notes and monitored by the CRA. 
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• 
The following vulnerable subject populations will be excluded: minors, protected 
subjects, adult subjects not in condition to express their consent, subjects deprived of 
liberty, subjects receiving psychiatric cares, subjects hospitalized in a Health and 
Social Establishment for other purpose than the participation to the study. 
• 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category (French Public Health Code law L.1121-8-
1). (exception for a participant to a non-interventional study if authorised by the 
Ethics Committee). 
It is the investigator’s responsibility to ensure and to document (in the source 
document - subject notes) that the subject: 
− 
is either affiliated to or beneficiary of a social security category;  
− 
has got an authorisation by the Ethics Committee. 
2. Concerning the “STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES” and specially in the “SAMPLE SIZE ASSUMPTIONS” 
The expected number of subjects to be recruited in France is declared to the French 
regulatory authority. 
3. Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
• 
In section “Regulatory and Ethical Considerations, including the Informed Consent 
Process” 
− 
Concerning the process for informing the subject, the following text is added: 
French Patient Informed Consent Form is a document which summarizes the main 
features of the study and allows collection of the subject written consent in triplicate. 
It also contains a reference to the authorisation of ANSM and the approval from the 
French Ethics Committee and the maintenance of confidentiality of the returned 
consent form by GlaxoSmithKline France.  
− 
Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
The first copy of the Patient Informed Consent Form is kept by the investigator. The 
second copy is kept by the Medical Direction of GlaxoSmithKline France and the 
last copy is given to the subject.  
The second copy of all the consent forms will be collected by the Clinical Research 
Assistant (CRA) under the Investigator’s control, and placed in a sealed envelope 
bearing only:  
− 
the study number,  
− 
the identification of the Centre: name of the principal investigator and centre 
number, 
− 
the number of informed consents, 
− 
the date,  
− 
and the principal investigator’s signature. 
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Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director.  
• 
NOTIFICATION TO THE HOSPITAL DIRECTOR 
In accordance with Article L1123-13 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The Hospital 
Director is supplied with the protocol and any information needed for the financial 
disposition, the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial (R.1123-69). 
• 
INFORMATION TO THE HOSPITAL PHARMACIST 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning the 
product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), the 
number of sites involved in her/his establishment and the estimated time schedule of the 
trial. 
4. Concerning the “DATA MANAGEMENT” the following text is added: 
• 
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacists if applicable, involved in 
this clinical trial, and data regarding the subjects recruited in this clinical trial 
(subject number, treatment number, subjects status with respect to the clinical trial, 
dates of visit, medical data) will be collected and computerized in GlaxoSmithKline 
data bases by GlaxoSmithKline Laboratory or on its behalf, for reasons of follow up, 
clinical trial management and using the results of said clinical trial. According to the 
Data Protection French Law n° 78-17 of 6th January 1978, each of these people 
aforesaid has a right of access, correction and opposition on their own data through 
GlaxoSmithKline Laboratory (Clinical Operations Department). 
• 
DEMOGRAPHIC DATA 
In accordance with the Data Protection French Law n° 78-17 of 6th January 1978 – 
article 8, the ethnic origin can only be collected if the collection of this data is strictly 
necessary and relevant for the purpose of the study. 
• 
TESTING OF BIOLOGICAL SAMPLES 
In accordance with the French Public Health Code law – article L1211-2, a 
biological sample without identified purpose at the time of the sample and subject’s 
preliminary information is not authorized. 
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5. SAE  
• 
“TRANSMISSION OF THE SAE REPORTS”: 
(Amended 18 May 2020) 
The notification of all serious adverse events and all serious adverse reactions is 
done promptly (and at the latest within 24 hours) by the investigator to 
GlaxoSmithKline as explained in Section 8.5.4 and Table 17 of 209538 (NTHI 
MCAT-009) study protocol. GlaxoSmithKline has a legal responsibility to promptly 
notify both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation and this is applicable for all the study 
sites where 209538 study is planned to be conducted. As sponsor of 209538 study, 
GlaxoSmithKline has in place processes meant to communicate any issue 
(including: suspicions of unexpected serious adverse reactions (SUSAR) occurring 
in France and outside the national territory, expected serious adverse reactions 
and serious adverse events occurring in France, new facts and urgent security 
measures) as soon as possible to the ANSM in order to safeguard the subjects 
enrolled in the clinical trials in accordance with the national reporting requirements 
in France (Article R1123-54 and Article R1123-46 of the French Public Health 
Code). This communication applies as soon as the sponsor has the following 
information:  
− 
Suspected investigational product 
− 
Patient/subject who presents with the effect/event 
− 
Reporter 
− 
Single identification number for the research/number of the protocol 
− 
Causality assessment if applicable. 
In case of paper notification, the SAE Reports have to be transmitted to the 
GlaxoSmithKline France Drug Safety Department, which name, address and phone 
number are:  
Département de Pharmacovigilance 
Laboratoire GlaxoSmithKline 
23, rue François Jacob  
92 500 Rueil-Malmaison 
Tel: 
 
Fax: 
 
 
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6. Monitoring visits 
The Health Institution and the Investigator agree to receive on a regular basis a Clinical 
Research Assistant (CRA) of GLAXOSMITHKLINE or of a service provider designated 
by GLAXOSMITHKLINE. The Health Institution and the Investigator agree to be 
available for any phone call and to systematically answer to all correspondence regarding 
the Study from GLAXOSMITHKLINE or from a service provider designated by 
GLAXOSMITHKLINE. In addition, the Health Institution and the Investigator agree that 
the CRA or the service provider designated by GLAXOSMITHKLINE have direct access 
to all the data concerning the Study (test results, medical record, etc …). This 
consultation of the information by GLAXOSMITHKLINE is required to validate the data 
registered in the electronic Case Report Form (eCRF), in particular by comparing them 
directly to the source data. In accordance with the legal and regulatory requirements, the 
strictest confidentiality will be respected. 
7. Data entry into the eCRF 
The Health Institution and the Investigator agree to meet deadlines, terms and conditions 
of the Study’s electronic Case Report Form (eCRF) use here below: 
The Health Institution and the Investigator undertake: 
1. That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 
electronic Case Report Form (eCRF) of the Study provided by 
GLAXOSMITHKLINE or by a company designated by GLAXOSMITHKLINE. 
2. That the Investigator and the staff of the investigator center use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended and 
for which they have been entrusted to them, namely for the Study achievement, to 
the exclusion of any other use. 
3. That the Investigator and the staff of the investigator center use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations which 
will have been provided by GLAXOSMITHKLINE. 
4. To keep the IT Equipment and/or access codes in a safe and secure place and to 
authorize only the use of this IT Equipment by investigator center staff designated by 
the principal investigator to enter the data of the Study. 
5. To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes. 
6. To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by GLAXOSMITHKLINE 
and any training material and documentation. The IT Equipment cannot under any 
circumstances be kept by the Health Institution or the Investigator for any reason 
whatsoever.  
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8. CTR publication 
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can make 
available to the public the results of the Study by the posting of the said results on a 
website of the GLAXOSMITHKLINE Group named Clinical Trial Register (CTR) 
including the registration of all the clinical trials conducted by the 
GLAXOSMITHKLINE Group and this before or after the publication of such results by 
any other process. 
9. Data Protection French Law of 6th January 1978 (CNIL) 
In accordance with the Data Protection French Law of 6 January 1978, computer files 
used by GLAXOSMITHKLINE to monitor and to follow the implementation and the 
progress of the Study are declared with CNIL by GLAXOSMITHKLINE. The 
Investigator has regarding the processing data related to her/him a right of access, of 
rectification and of opposition with GLAXOSMITHKLINE in accordance with the legal 
provisions. This information can be transferred or be accessed to other entities of 
GLAXOSMITHKLINE Group, what the Investigator agrees by the signature of the 
present protocol. 
12.7.4. 
Requirements for Italy 
No country-specific requirements. 
12.7.5. 
Requirements for Spain 
No country-specific requirements. 
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12.8. 
Appendix 8: Protocol Amendment/Administrative change 
history 
The Protocol Amendment Summary of Changes Table for the current amendment 
is located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Amendment 1 
18-MAY-2020 
Administrative change 1 
14-DEC-2018 
Original Protocol 
03-DEC-2018 
Overall Rationale for the Administrative Change 1 14 December 2018  
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page, 
Contributing 
authors 
Inclusion of Study Delivery Lead in list 
of contributing authors 
Inclusion of details for study delivery lead which 
were missing in the previous protocol  
Section 12.7.3 
Requirements for 
France 
In this administrative change, the 
phrase “legally appointed 
representative (LAR)” was removed 
from Appendix 7 “Country-specific 
Requirements: France” and a 
typographical error was corrected (see 
below).  
In this administrative change, the phrase “legally 
appointed representative (LAR)” was removed 
from Appendix 7 “Country-specific Requirements: 
France” in order that that the protocol was 
aligned with study documentation at a local level, 
and a typographical error was corrected for clarity 
Detailed description of Protocol Administrative Change 1 14 December 2018 
changes: 
Table of contents, list of tables, list of figures and in-text cross references were updated 
following the protocol administrative changes. 
In the list of contributing authors on the title page the study delivery lead was added to 
the list of contributors indicated using bold italic below: 
• 
 (Study Delivery Lead) 
In Section 12.7.3 “Requirements for France” text was removed indicated using 
strikethrough formatting, below: 
3. 
Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
• 
In section “Regulatory and Ethical Considerations, including the Informed Consent 
Process” 
− 
Concerning the process for informing the subject and/or his/her legally 
authorized representative, the following text is added:  
French Patient Informed Consent Form is a document which summarizes the main 
features of the study and allows collection of the subject and/or his/her legally 
authorized representative written consent in triplicate. It also contains a reference to 
the authorisation of ANSM and the approval from the French Ethics Committee and 
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the maintenance of confidentiality of the returned consent form by GlaxoSmithKline 
France. 
− 
Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
The first copy of the Patient Informed Consent Form is kept by the investigator. The 
second copy is kept by the Medical Direction of GlaxoSmithKline France and the 
last copy(ies) is (are) given to the subject and/or his/her legally authorized 
representative. 
The second copy of all the consent forms will be collected by the Clinical Research 
Assistant (CRA) under the’s the Investigator’s control, and placed in a sealed 
envelope bearing only: 
− 
the study number,  
− 
the identification of the Centre: name of the principal investigator and centre 
number, 
− 
the number of informed consents, 
− 
the date,  
− 
and the principal investigator’s signature. 
Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director. 
Overall Rationale for the Amendment 1 18 May 2020 
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. 
The current analysis of the primary objective is planned on the per-protocol population. 
The use of the per protocol defined windows for vaccination and blood draws minimizes 
potential variability within the data for statistical comparisons. The planned analysis 
would test at least 1 geometric mean concentration (GMC) ratio (Sh_NTHi-Mcat over 
NTHi-Mcat) among anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 
in all time-lags under investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. To 
control the type I error below 2.5% (one-sided), a sequential procedure -is planned in the 
protocol. Starting from the 6-months lag, the 3-months NI will be tested only if the 6-
months NI will be demonstrated, while the 1-month NI will be tested only if the 6-months 
and 3-months NI will be both demonstrated. The expected sample size would allow to 
reach 80% of power. 
The study started on 23 Apr 2019. At the time of writing, group Sh_NTHi-Mcat_1 and 
control group NTHi-Mcat have completed the vaccination schedule and the blood draw 
as dictated by the study protocol, whereas the less advanced groups (Sh_NTHi-Mcat_3 
and Sh_NTHi-Mcat_6) are either due to receive the study vaccine or to undergo a blood 
draw. In accordance with the safety measures applied for COVID-19 containment in the 
Countries where the study is conducted, a number of study visits are unlikely to occur as 
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planned. This is expected to impact 2 of the study groups (Sh_NTHi-Mcat_3 and 
Sh_NTHi-Mcat_6), for which the visits to collect data for primary endpoint are likely to 
occur while COVID-19 containment measures are in place.  
This protocol amendment 1 includes a modified primary objective, should the Sh-NTHI-
Mcat_6 or the Sh-NTHI-Mcat_3 and Sh_NTHi-Mcat_3 groups not meet the per-protocol 
defined sample size.  To complement this modified primary analysis, a descriptive 
analysis where the 95% confidence intervals around the geometric mean concentration 
(GMC) ratio will be presented for any group not meeting the per protocol sample size 
using all available data. The descriptive analysis may be used to support the interval 
between Shingrix and NTHi-Mcat vaccines administration for the planned NTHi-Mcat 
Phase III studies. 
This protocol amendment 1 also outlines measures (e.g. for safety monitoring) that may 
be applicable during special circumstances, like COVID-19 pandemic, in order 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. 
In addition, provisions relating to specific reporting of serious adverse events and serious 
adverse reactions, in accordance with Article R1123-54 and Article R1123-46 of the 
French Public Health Code, are incorporated into the "Requirements for France” Section 
of this Protocol Amendment, in order to fulfill the commitment taken with French Health 
Authority. 
Amended text is indicated in bold italics in the body of the protocol. 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
To swap the identifiers “short title” 
and “Detailed Title”. 
Identifiers need to be corrected 
 
Contributing authors 
Addition of new team members  
To reflect changes in the Team and 
contributions to the protocol 
amendment 
Sponsor signature page 
To change the identifier “short title” 
to “Detailed Title”.  
The detailed title is presented on 
this page and the identifier needs to 
be corrected. 
Investigator signature page 
To change the identifier “short title” 
to “Detailed Title”.  
The detailed title is presented on 
this page and the identifier needs to 
be corrected. 
Section 1 Synopsis; Objectives and 
endpoints 
Modification of the primary objective 
in case the per-protocol sample 
size for 1 (or more) of the 4 study 
groups is not reached, including 
addition of footnote and update of 
subsequent footnote referencing. 
To add a modified primary objective 
to be applied in case the per-
protocol sample size for 1 (or more) 
of the 4 study groups is not 
reached. This is necessary because 
the current analysis of the primary 
objective is planned on the per-
protocol population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
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Section # and Name 
Description of Change 
Brief Rationale 
study visits are unlikely to occur as 
planned.  
Section 2 Schedule of Activities 
(SoA) – Table 3 and Table 4 
Addition of footnotes:  
• 11 to add information related to 
the diagnosis of COVID-19 per 
the WHO case definition and to 
clarify that routine study 
procedures and timeframes for 
reporting of AEs / SAEs should 
be followed; and,  
• 12 to add information 
regarding alternatives to study 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic) 
To provide a reference to the WHO 
case definition for COVID-19, and 
to clarify that recording of AEs 
(unsolicited AEs or AEs leading to 
withdrawal) or SAEs should be 
aligned with routine procedures for 
the detection, reporting and 
recording of AEs or SAEs and 
timeframes set out in the protocol. 
And, to add information regarding 
alternatives to study contacts due to 
special circumstances (e.g. COVID-
19 pandemic) 
Section 4 Objective(s) and 
endpoint(s); Table 6 Objectives and 
endpoints 
Modification of the primary objective 
in case the per-protocol sample 
size for 1 (or more) of the 4 study 
groups is not reached, including 
addition of footnote and update of 
subsequent footnote referencing. 
To add a modified primary objective 
to be applied in case the per-
protocol sample size for 1 (or more) 
of the 4 study groups is not 
reached. This is necessary because 
the current analysis of the primary 
objective is planned on the per-
protocol population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned.  
Section 7.5.2 Concomitant 
medications/products/vaccines that 
may lead to the elimination of a 
subject from per-protocol analyses 
Correction of typographical error  
To correct a minor typographical 
error to improve readability 
Section 8 Study assessments and 
procedures  
Addition of a subsection (Section 
8.1) outlining study procedures 
during special circumstances (e.g. 
COVID-19 pandemic). (Subsequent 
Level 2 and Level 3 heading 
numbering updated.) 
To propose alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
can be sent back by conventional 
mail, etc.. 
Section 8.4.2.1 Blood sampling for 
immunogenicity assessment / Table 
10 and Table 11 
Addition of a footnote to clarify 
study procedures in special 
circumstances 
To highlight alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
can be sent back by conventional 
mail, etc.. 
Section 8.4.3.1 Humoral antibody 
responses 
Correction of typographical error  
To correct a minor typographical 
error to improve readability 
Section 8.4.4.1 Immunological 
read-outs Table 14 
Addition of a footnote to clarify 
study procedures in special 
circumstances 
To highlight alternatives to reduce 
contacts due to special 
circumstances (e.g. COVID-19 
pandemic): e.g. for safety follow up 
visits can be replaced by phone 
calls or virtual contacts, diary cards 
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Section # and Name 
Description of Change 
Brief Rationale 
can be sent back by conventional 
mail, etc.. 
Section 8.5 Safety assessments 
Addition of a sentence to clarify 
reference for case definition and 
recording of COVID-19 cases 
To note that diagnosis of COVID-19 
should be aligned with WHO case 
definition, and routine procedures 
as outlined in the study protocol for 
detection, recording and follow-up 
of AEs/SAEs should be followed 
Section 8.5.2 Time period and 
frequency for collecting AE and 
serious adverse event (SAE) 
information (and Table 15 and 
Table 16) 
Addition of footnotes to clarify 
reference for case definition and 
recording of COVID-19 cases 
To note that diagnosis of COVID-19 
should be aligned with WHO case 
definition, and routine procedures 
as outlined in the study protocol for 
detection, recording and follow-up 
of AEs/SAEs should be followed 
Section 10.1.1 Hypotheses related 
to primary and secondary 
objectives 
Modification of the hypotheses 
related to the primary objective in 
case the per-protocol sample size 
for 1 (or more) of the 4 study 
groups is not reached. 
To include the hypothesis related to 
the modified primary objective to be 
applied in case the per-protocol 
sample size for 1 (or more) of the 4 
study groups is not reached. This is 
necessary because the current 
analysis of the primary objective is 
planned on the per-protocol 
population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned. This is expected to impact 
1 or 2 study groups depending on 
the ongoing viability of visits.  
Section 10.1.2 Sample size 
calculation 
Modification of the sample size 
calculation related to the primary 
objective in case the per-protocol 
sample size for 1 (or more) of the 4 
study groups is not reached. Figure 
2 removed as linked only to the 
primary objective without 
modifications. 
To include the sample size 
calculation related to the modified 
primary objective to be applied in 
case the per-protocol sample size 
for 1 (or more) of the 4 study 
groups is not reached. This is 
necessary because the current 
analysis of the primary objective is 
planned on the per-protocol 
population but, due to the 
containment measures for COVID-
19 applied in the countries where 
the study is conducted, a number of 
study visits are unlikely to occur as 
planned. This is expected to impact 
1 or 2 study groups depending on 
the ongoing viability of visits.  
Section 10.3.4 Immunogenicity 
analyses 
Modification of the primary objective 
and detail related to the statistical 
analyses to be applied in case the 
per-protocol sample size for 1 (or 
more) of the 4 study groups is not 
reached. 
To include the planned 
immunogenicity analyses in case 
the per-protocol sample size for 1 
(or more) of the 4 study groups is 
not reached. This is necessary 
because the current analysis of the 
primary objective is planned on the 
per-protocol population but, due to 
the containment measures for 
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Section # and Name 
Description of Change 
Brief Rationale 
COVID-19 applied in the countries 
where the study is conducted, a 
number of study visits are unlikely 
to occur as planned. This is 
expected to impact 1 or 2 study 
groups depending on the ongoing 
viability of visits. 
Section 12.1.1 List of abbreviations 
Addition of COVID-19 and definition 
To include a new abbreviation and 
corresponding definition used in the 
protocol 
Section 12.4.5 Committees 
Structure 
Addition of “No additional 
information” 
To complete an empty section 
Section 12.7.3 Requirements for 
France 
Addition of specific provisions 
relating to specific reporting of 
serious adverse events and serious 
adverse reactions in accordance 
with Article R1123-54 and Article 
R1123-46 of the French Public 
Health Code. 
To fulfil a commitment with the 
French Health Authority (ANSM), 
whereby GSK agreed that the term 
“issue” included: 
• suspicions of unexpected serious 
adverse reactions (SUSAR) 
occurring in France and outside the 
national territory; 
• expected serious adverse 
reactions and serious adverse 
events occurring in France; 
• new facts and urgent security 
measures. 
Detailed description of Protocol Amendment 1 changes: 
In the following sections, deleted text is indicated in strikethrough and changed text in 
bold italics: 
Cover page (short title and title) 
Short Title Detailed Title 
 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine.  
Contributing authors 
• 
 (Study Statisticians) 
• 
 (Oversight Data Managers) 
• 
 (Clinical Trials Supply Managers) 
Protocol Amendment 1 Sponsor Signatory Approval 
Short Title Detailed Title 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
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administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine. 
Protocol Amendment 1 Investigator Agreement 
Short Title Detailed Title 
 
A Phase IIA, open-label study to evaluate the 
immunogenicity and safety of sequential use of 
GSK’s investigational vaccine GSK3277511A when 
administered to healthy smokers and ex-smokers aged 
50 to 80 years following receipt of Shingrix vaccine. 
Section 1. 
Synopsis / Objectives and endpoints 
Objectives and Endpoints:  
Objectives 
Endpoints 
Primary 
Confirmatory 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine versus the humoral immune 
response 1 month after Dose 2 of GSK 
Biologicals' NTHi-Mcat investigational vaccine 
alone.  
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above 
a limit of 0.667 for all anti-PD, anti-PE, anti-PilA, 
anti-UspA2.  
• 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 of 
NTHi-Mcat vaccine in the Sh_NTHi-Mcat groups 
(Day 181; Day 241; Day 331) compared to 
antibody concentrations 1 month after Dose 2 in 
the NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 group:2 
Confirmatory 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 of 
GSK Biologicals' NTHi-Mcat investigational vaccine 
when administered 1 or 3 months after Shingrix 
vaccine versus the humoral immune response 1 
month after Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean 
concentration (GMC) ratio (Sh_NTHi-
Mcat/NTHi-Mcat) is above a limit of 0.667 for all 
anti-PD, anti-PE, anti-PilA, anti-UspA2 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 
of NTHi-Mcat vaccine in the Sh_NTHi-Mcat_3 
group (Day 241) and Sh_NTHi-Mcat_1 group 
(Day 181) compared to antibody 
concentrations 1 month after Dose 2 in the 
NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups:3 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 
Humoral immune response  
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Objectives 
Endpoints 
2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine when administered 1 
month after Shingrix vaccine versus the 
humoral immune response 1 month after Dose 
2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above a 
limit of 0.667 for all anti-PD, anti-PE, anti-PilA, anti-
UspA2.  
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations 1 month after Dose 2 of NTHi-Mcat 
vaccine in the Sh_NTHi-Mcat_1 group (Day 181) 
compared to antibody concentrations 1 month after 
Dose 2 in the NTHi-Mcat group (Day 91).1 
Secondary 
Descriptive 
• 
To describe the humoral immune response of 
GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered alone. 
• 
Humoral response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations and seropositivity in all 
subjects before Dose 1 (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in the 
NTHi-Mcat group), and 1 month after Dose 2 of 
NTHi-Mcat vaccine (Day 181; Day 241; Day 331 
in the Sh_NTHi-Mcat groups and Day 91 in the 
NTHi-Mcat group).1,24 
1 Given the different intervals between vaccines, the label for study visits or contacts varies between treatment groups. 
Please refer to the study design diagram. 
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 group will be presented 
with all available data. The descriptive analysis may be used to support the interval between Shingrix and 
NTHi-Mcat vaccines administration  
3 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the GMC ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups will be presented with all 
available data. The descriptive analysis may be used to support the interval between Shingrix and NTHi-
Mcat vaccines administration  
24 Cut-off for seropositivity will be the lower limit of quantification (LLOQ) of the assay. 
 
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Section 2 Schedule of Activities (SoA) 
Table 3 
Schedule of Activities: Sh_NTHi-Mcat groups  
 
Epoch 001 
Epoch 002 
Contact type and contact 
timepoint by study group 
Sh_NTHi-Mcat_1  
V1_1 
D1  
V2_1 
D61  
V3_1 
D91  
C1_1 
D98  
V4_1 
D121  
V5_1 
D151  
C2_1 
D158  
V6_1 
D181  
C3_1 
D331  
N/A 
V7_1 
D511  
C4_1 
D661  
Sh_NTHi-Mcat_3  
V1_3 
D1  
V2_3 
D61  
V3_3  
D151  
C1_3 
D158  
V4_3 
D181  
V5_312 
D211  
C2_3 
D218  
V6_312 
D241  
C3_3 
D331  
C4_3 
D391  
V7_312 
D571  
C5_3 
D661  
Sh_NTHi-Mcat_6  
V1_6  
D1  
V2_6 
D61  
V3_612 
D241  
C1_6 
D248  
V4_612 
D271  
V5_612 
D301  
C2_6 
D308  
V6_612 
D331  
N/A 
C3_6 
D481  
V7_612 
D661  
N/A 
Sampling timepoint (vaccinations) 
Sh1 
Sh2 
NM1 
 
 
NM2 
 
 
 
 
 
 
Recording of unsolicited AEs11 
 
 
● 
● 
● 
● 
● 
● 
 
 
 
 
Recording of AEs leading to withdrawal11 
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
Recording of SAEs11 and pregnancies  
● 
● 
● 
● 
● 
● 
● 
● 
●7 
●8 
● 
●7 
11. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (unsolicited AEs or AEs leading to withdrawal) 
or SAEs (refer to Section 12.5 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 15 
12. Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
Table 4 
Schedule of Activities: NTHi-Mcat group 
Epoch 
Epoch 001  
Epoch 002 
Type of contact 
V1  
C1  
V2  
V3  
C2  
V4  
C3  
C4  
V5  
C5  
Time points 
D1  
D8  
D31  
D61  
D68  
D91  
D241  
D331  
D4219  
D661  
Sampling time points 
NM 1 
 
 
NM 2 
 
 
 
 
 
 
Recording of AEs leading to withdrawal8 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Recording of SAEs8 and pregnancies  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
8. If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (AEs leading to withdrawal) or SAEs (refer to 
Section 12.5 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 
9. Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
 
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Section 4 Objectives and Endpoints 
Table 6 
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
Confirmatory 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 
of GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine versus the humoral immune 
response 1 month after Dose 2 of GSK Biologicals' 
NTHi-Mcat investigational vaccine alone.  
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above 
a limit of 0.667 for all anti-PD, anti-PE, anti-PilA, 
anti-UspA2.  
• 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 of 
NTHi-Mcat vaccine in the Sh_NTHi-Mcat groups 
(Day 181; Day 241; Day 331) compared to 
antibody concentrations 1 month after Dose 2 in 
the NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 group:2 
Confirmatory 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 2 of 
GSK Biologicals' NTHi-Mcat investigational vaccine 
when administered 1 or 3 months after Shingrix 
vaccine versus the humoral immune response 1 
month after Dose 2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
• 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean 
concentration (GMC) ratio (Sh_NTHi-
Mcat/NTHi-Mcat) is above a limit of 0.667 for all 
anti-PD, anti-PE, anti-PilA, anti-UspA2 
Humoral immune response  
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations 1 month after Dose 2 
of NTHi-Mcat vaccine in the Sh_NTHi-Mcat_3 
group (Day 241) and Sh_NTHi-Mcat_1 group 
(Day 181) compared to antibody 
concentrations 1 month after Dose 2 in the 
NTHi-Mcat group (Day 91).1 
The following modification of the primary objective will be applicable if the per-protocol set is not reached for 
the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups:2 
• 
To demonstrate the non-inferiority (NI) of the 
humoral immune response 1 month after Dose 
2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine when administered 1 
month after Shingrix vaccine versus the 
humoral immune response 1 month after Dose 
2 of GSK Biologicals' NTHi-Mcat 
investigational vaccine alone. 
Criterion: 
Lower limit (LL) of the 2-sided 95% confidence 
interval (CI) of the geometric mean concentration 
(GMC) ratio (Sh_NTHi-Mcat/NTHi-Mcat) is above a 
limit of 0.667 for all anti-PD, anti-PE, anti-PilA, anti-
UspA2.  
Humoral immune response  
Anti-PD, anti-PE, anti-PilA and anti-UspA2 antibody 
concentrations 1 month after Dose 2 of NTHi-Mcat 
vaccine in the Sh_NTHi-Mcat_1 group (Day 181) 
compared to antibody concentrations 1 month after 
Dose 2 in the NTHi-Mcat group (Day 91).1 
Secondary 
Descriptive 
• 
Humoral response  
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Objectives 
Endpoints 
• 
To describe the humoral immune response of 
GSK Biologicals' NTHi-Mcat investigational 
vaccine when administered 1 or 3 or 6 months 
after Shingrix vaccine or when administered alone. 
− 
Anti-PD, anti-PE, anti-PilA and anti-UspA2 
antibody concentrations and seropositivity in all 
subjects before Dose 1 (Day 91; Day 151; Day 
241 in the Sh_NTHi-Mcat groups and Day 1 in the 
NTHi-Mcat group), and 1 month after Dose 2 of 
NTHi-Mcat vaccine (Day 181; Day 241; Day 331 
in the Sh_NTHi-Mcat groups and Day 91 in the 
NTHi-Mcat group).1, 24 
Descriptive 
• 
To describe the cell mediated immune (CMI) 
response (CD4+ T-cells) of GSK Biologicals’ 
NTHi-Mcat investigational vaccine when 
administered 1 or 3 or 6 months after Shingrix 
vaccine or when NTHi-Mcat is administered alone, 
in the CMI response sub-cohort. 
• 
CMI response 
− 
NTHi-specific and Mcat-specific CMI responses as 
measured by flow cytometry ICS (frequency of 
specific CD4+ T-cells expressing at least 2 
different markers among CD40 ligand (CD40L), 
interleukin (IL)-2, IL-13, IL-17, interferon gamma 
(IFN-γ), tumour necrosis factor alpha (TNF-α) 
upon in vitro stimulation) before Dose 1 (Day 91; 
Day 151; Day 241 in the Sh_NTHi-Mcat groups 
and Day 1 in the NTHi-Mcat group), and 1 month 
after Dose 2 of NTHi-Mcat vaccine (Day 181; Day 
241; Day 331 in the Sh_NTHi-Mcat groups and 
Day 91 in the NTHi-Mcat group) in the CMI 
response sub-cohort.1,35 
1 Given the different intervals between vaccines, the label for study visits or contacts varies between treatment groups. 
Please refer to the study design diagram. 
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the GMC ratio of the Sh_NTHi-Mcat_6 group will be presented with all available data. The 
descriptive analysis may be used to support the interval between Shingrix and NTHi-Mcat vaccines 
administration  
3 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the GMC ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 groups will be presented with all 
available data. The descriptive analysis may be used to support the interval between Shingrix and NTHi-
Mcat vaccines administration 
24 Cut-off for seropositivity will be the lower limit of quantification (LLOQ) of the assay. 
35 Refer to Section 5.3.1 for details regarding the CMI response sub-cohort. 
Section 7.5.2 Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses 
• 
Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e. more than 14 days in total) during the starting 6 months prior to the first vaccine 
dose (see Section 6.2.2.) and ending at the second blood draw (i.e. approximately 1 
month after the administration of the second dose of of NTHi-Mcat vaccine). For 
corticosteroids, this will mean prednisone 5 mg/day (for adult subjects), or 
equivalent. Topical steroids are allowed.  
• 
Any vaccine not foreseen by the study protocol administered during the period 
starting 30 days before the first dose and ending at the second blood draw (i.e. 
approximately 1 month after the administration of the second dose of ofNTHi-Mcat 
vaccine),* with the exception of non-MF59 adjuvanted influenza vaccines and 
pneumococcal vaccines which may be administered ≥15 days preceding or following 
any study vaccine dose.  
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Section 8 Study assessments and procedures 
8.1 Study procedures during special circumstances  
Under special circumstances, modification of specific study procedures may be 
implemented:  
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:  
• 
Safety follow-up may be made by a telephone call, other means of virtual contact 
or home visit, if appropriate. 
• 
Diary cards may be transmitted from and to the site by electronic means and or 
conventional mail. 
Section 8.4.2.1 Blood sampling for immunogenicity assessments 
Table 10 
Blood sampling for humoral immunogenicity 
Sample type 
Quantity 
Unit 
Study group 
Timepoint1 
Subjects 
1. Refer also to Schedule of Activities (Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
Table 11 
Blood sampling for CMI 
Sample type 
Quantity 
Unit 
Study group 
Timepoint2 
Subjects 
2. Refer also to Schedule of Activities (Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
Section 8.4.3.1 Humoral antibody responses 
Other assays may be developed and/or validated on blood samples with the aim of 
measuring 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. 
Section 8.4.4.1 Immunological read-outs 
Table 14 
Immunological read-outs 
Blood sampling timepoint 
Study group 
No. subjects 
Component 
Type of 
contact and 
timepoint3 
Sampling 
timepoint 
3. Refer also to Schedule of Activities (Table 3 and Table 4), and Section 8.1 for information on study 
procedures during special circumstances 
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Section 8.5 Safety assessment 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.  
Diagnosis of COVID-19 should be made in accordance with the WHO case definition. 
Cases should be categorised as AEs (unsolicited or AEs leading to withdrawal) or 
SAEs (refer to Section 12.5 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 15 and Table 16. 
Section 8.5.2 Time period and frequency for collecting AE and serious adverse event 
(SAE) information (Table 15 and Table 16) 
 
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Table 15 
Reporting periods for collecting safety information: Sh_NTHi-Mcat groups 
Event 
Study group 
Contact type (V/C) and timepoint (D) 
Sh_NTHi-Mcat_1 
V1_1 
D1 
V2_1 
D61 
V3_1 
D91 
C1_1 
D98 
V4_1 
D121 
V5_1 
D151 
C2_1 
D158 
V6_1 
D181 
C3_1 
D331 
V7_1 
D511 
N/A 
C4_1 
D661 
Sh_NTHi-Mcat _3 
V1_3 
D1 
V2_3 
D61 
V3_3 
D151 
C1_3 
D158 
V4_3 
D181 
V5_3** 
D211 
C2_3 
D218 
V6_3** 
D241 
C3_3 
D331 
C4_3 
D391 
V7_3** 
D571 
C5_3 
D661 
Sh_NTHi-Mcat _6 
V1_6 
D1 
V2_6 
D61 
V3_6** 
D241 
C1_6 
D248 
V4_6** 
D271 
V5_6** 
D301 
C2_6 
D308 
V6_6** 
D331 
N/A 
C3_6 
D481 
N/A 
V7_6** 
D661 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to  
withdrawal from the  
study* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs* 
Sh_NTHi-Mcat_1 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _3 
 
 
 
 
 
 
 
 
 
 
 
 
Sh_NTHi-Mcat _6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs = adverse events; C = Call; D = Day; N/A = not applicable; pIMDs= potential immune mediated diseases; SAEs = serious adverse events; Sh = Shingrix; V = Visit 
* If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (unsolicited AEs, AEs leading to withdrawal) or 
SAEs (refer to Section 12.5 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 
** Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
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Table 16 
Reporting periods for collecting safety information: NTHi-Mcat group 
Event 
Contact type (V/C) and timepoint (D) 
V1 
D1 
C1 
D8 
V2 
D31 
V3 
D61 
C2 
D68 
V4 
D91 
C3 
D241 
C4 
D331 
V5** 
D421 
C5 
D661 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to withdrawal from the study* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study participation or concurrent 
GSK medication/vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs = adverse events; C = Call; D = Day; N/A = not applicable; pIMDs= potential immune mediated diseases; SAEs = serious adverse events; V = Visit  
* If a diagnosis of COVID-19 is made in accordance with the current WHO case definition, cases should be reported as AEs (AEs leading to withdrawal) or SAEs (refer to 
Section 12.5 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 
** Visit may be a telephone contact, or other means of virtual contact or home visit during special circumstances (refer to Section 8.1 for information on study procedures 
during special circumstances) 
 
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Section 10.1.1 Hypotheses related to primary and secondary objectives 
The global null hypothesis related to the primary objective of the study is that at least one 
geometric mean concentration (GMC) ratio (Sh_NTHi-Mcat over NTHi-Mcat) among 
anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 in all time-lags under 
investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must be rejected in 
favour of the alternative hypothesis that all 4 GMCs (anti-PD, anti-PE, anti-PilA, anti-
UspA2) are non-inferior in at least one time-lag group. 
As defined in the study criteria of success, non-inferiority (NI) will be claimed for a 
specific time-lag if the lower limit of the 2-sided 95% CI of the GMC ratio (Sh_NTHi-
Mcat_k over NTHi-Mcat, where k= [6, 3, 1]) will be above a limit of 0.667 for all anti-
PD, anti-PE, anti-PilA and anti-UspA2 concentration. Family-wise type I error is fixed at 
2.5% (1-sided). 
If the per-protocol sample size is either not reached in the Sh_NTHi-Mcat_6 group or 
not reached in the Sh_NTHi-Mcat_6 and in Sh_NTHi-Mcat_3 groups due to COVID-
19 containment measures, a modification to the primary objective will be applied as 
follows: 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 due to COVID-
19 containment measures: 
The global null hypothesis related to the primary objective of the study is that at 
least 1 GMC ratio (Sh_NTHi-Mcat_k, where k=3 or 1 over NTHi-Mcat) among 
anti-PD, anti-PE, anti-PilA, anti-UspA2 is inferior or equal to 0.667 in all time-
lags under investigation at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must 
be rejected in favour of the alternative hypothesis that all 4 GMCs (anti-PD, anti-
PE, anti-PilA, anti-UspA2) are non-inferior in at least one time-lag group. 
As defined in the study criteria of success, non-inferiority (NI) will be claimed for 
a specific time-lag if the lower limit of the 2-sided 95% CI of the GMC ratio 
(Sh_NTHi-Mcat_k over NTHi-Mcat, where k= [3, 1]) will be above a limit of 0.667 
for all anti-PD, anti-PE, anti-PilA and anti-UspA2 concentration. Family-wise 
type I error is fixed at 2.5% (1-sided). 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 and Sh_NTHI-
Mcat_3 due to COVID-19 containment measures: 
The global null hypothesis related to the primary objective of the study is that the 
GMC ratio (Sh_NTHi-Mcat_1 over NTHi-Mcat) among anti-PD, anti-PE, anti-
PilA, anti-UspA2 is inferior or equal to 0.667 in all time-lags under investigation 
at 1 month post-Dose 2 of NTHi-Mcat vaccine. This must be rejected in favour of 
the alternative hypothesis that all 4 GMCs (anti-PD, anti-PE, anti-PilA, anti-
UspA2) are non-inferior. 
As defined in the study criteria of success, non-inferiority (NI) will if the lower 
limit of the 2-sided 95% CI of the GMC ratio (Sh_NTHi-Mcat_1 over NTHi-Mcat) 
will be above a limit of 0.667 for all anti-PD, anti-PE, anti-PilA and anti-UspA2 
concentration. Family-wise type I error is fixed at 2.5% (1-sided). 
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Section 10.1.2 Sample size calculation 
The study sample size is defined in order to ensure a global 80% power to conclude NI 
on all anti-PD, anti-PE, anti-PilA and anti-UspA2 for at least one time-lag. The target 
response-wise power is then 94.6%, assuming independence, for the 4 antigens response. 
The sample size calculation is based on a standard deviation of antibody log10-
concentrations of 0.36 (based on NTHI MCAT-001) and a null true difference on the 
log10 scale.  
To control the type I error below 2.5% (one-sided), a sequential procedure will be used 
for the primary objective. Starting from the 6-months lag, the 3-months NI will be tested 
only if the 6-months NI will be demonstrated, while the 1-month NI will be tested only if 
the 6-months and 3-months NI will be both demonstrated. Sequential testing procedure 
ensures also 80% power to conclude NI for each time-lag (i.e. conditionally on 
demonstrating NI at previous steps of the procedure). The power to prove all NI 
hypotheses is 51% (assuming independence). 
The target sample size is 432 subjects evaluable for immunogenicity (108 subjects per 
study group). ‘Evaluable subjects’ means all subjects included in the set for the primary 
statistical analysis defined in Section 10.2. Considering that approximately 20% of the 
randomized subjects might withdraw, not be evaluable for immunogenicity or be 
excluded due to protocol deviations, the target sample size to be randomized is 540 
subjects (135 subjects per study group). 
Figure 2 Sequence for evaluating the primary objective in order to control the overall 
type I error below 2.5% (one-sided) 
If the per-protocol sample size is either not reached in the Sh_NTHi-Mcat_6 group or 
not reached in the Sh_NTHi-Mcat_6 and in Sh_NTHi-Mcat_3 groups due to COVID-
19 containment measures, a modification to the primary objective will be applied as 
follows: 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 due to COVID-
19 containment measures:  
To control the type I error below 2.5% (one-sided), a sequential procedure will be 
used for the primary objective. Starting from the 3-months lag, while the 1-month 
NI will be tested only if the 3-months NI will be demonstrated. Sequential testing 
procedure ensures also 80% power to conclude NI for each time-lag (i.e. 
conditionally on demonstrating NI at previous steps of the procedure). The power 
to prove all NI hypotheses is 64% (assuming independence). 
• 
Per protocol sample size is not reached in group Sh_NTHi-Mcat_6 and Sh_NTHi-
Mcat_3 due to COVID-19 containment measures:  
The power to prove the NI hypothesis is 80%. 
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Section 10.3.4 Immunogenicity analyses 
Endpoint 
Statistical analysis methods 
Primary Endpoint(s) 
Primary  
Between group assessment 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1; _3; _6 group over NTHi-
Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using an analysis 
of covariance (ANCOVA) model on the logarithm10 transformation of the concentrations. 
The ANCOVA model will include study group, smoking status (current or former), age 
category (50–59, 60–69, 70–80 years of age) and centre as factors and the antibody 
concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-sided 95% 
CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-PilA, anti-UspA2. 
The sequential procedure for multiple time-lags will be used: starting from the 6-months 
lag, the 3-months NI will be tested only if the 6-months NI will be demonstrated, while the 
1-month NI will be tested only if the 6-months and 3-months NI will be both 
demonstrated. 
The following 
modification of the 
primary objective 
will be applicable if 
the per-protocol set 
is not reached for 
the Sh_NTHi-Mcat_6 
group:1 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1; _3 group over 
NTHi-Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using 
an analysis of covariance (ANCOVA) model on the logarithm10 transformation of 
the concentrations. The ANCOVA model will include study group, smoking status 
(current or former), age category (50–59, 60–69, 70–80 years of age) and centre as 
factors and the antibody concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-
sided 95% CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-
PilA, anti-UspA2. The sequential procedure for multiple time-lags will be used: 
starting from the 3-months lag, the 1-month NI will be tested only if the 3-months 
NI will be demonstrated.  
The following 
modification of the 
primary objective 
will be applicable if 
the per-protocol set 
is not reached for 
the Sh_NTHi-Mcat_6 
and the Sh_NTHi-
Mcat_3 groups:2 
Considering the sampling timepoint at 1 month after Dose 2 of NTHi-Mcat vaccine, 
the 2-sided 95% CIs for the group GMC ratio (Sh_NTHi-Mcat_1 group over NTHi-
Mcat group) of anti-PD, anti-PE, anti-PilA, anti-UspA2 will be computed using an 
analysis of covariance (ANCOVA) model on the logarithm10 transformation of the 
concentrations. The ANCOVA model will include study group, smoking status 
(current or former), age category (50–59, 60–69, 70–80 years of age) and centre as 
factors and the antibody concentration before Dose 1 as covariate. 
Non-inferiority for a specific time-lag will be claimed if the lower limit of the 2-
sided 95% CI for the GMC ratio will be above 0.667 for all anti-PD, anti-PE, anti-
PilA, anti-UspA2.  
Secondary Endpoint(s) 
1 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 group will be presented 
with all available data. The descriptive analysis may be used to support the interval between Shingrix and 
NTHi-Mcat vaccines administration  
2 To complement this modified primary analysis, a descriptive analysis where the 95% confidence intervals 
around the geometric mean concentration (GMC) ratio of the Sh_NTHi-Mcat_6 and Sh_NTHi-Mcat_3 
groups will be presented with all available data. The descriptive analysis may be used to support the 
interval between Shingrix and NTHi-Mcat vaccines administration 
Section 12.1.1 List of abbreviations 
COVID-19 
Coronavirus Disease 2019 
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Section 12.4.5 Committees Structure 
No additional information 
Section 12.7.3 Requirements for France 
5. SAE  
• 
“TRANSMISSION OF THE SAE REPORTS”: 
The notification of the all serious adverse events and all serious adverse reactions is 
done promptly (and at the latest within 24 hours) by the investigator to GlaxoSmithKline 
as explained in Section 8.4.4 and Table 17 of 209538 (NTHI MCAT-009) study protocol. 
GlaxoSmithKline has a legal responsibility to promptly notify both the local regulatory 
authority and other regulatory agencies about the safety of a product under clinical 
investigation and this is applicable for all the study sites where 209538 study is planned 
to be conducted. As sponsor of 209538 study, GlaxoSmithKline has in place processes 
meant to communicate any issue (including: suspicions of unexpected serious adverse 
reactions (SUSAR) occurring in France and outside the national territory, expected 
serious adverse reactions and serious adverse events occurring in France, new facts 
and urgent security measures) as soon as possible to the ANSM in order to safeguard the 
subjects enrolled in the clinical trials in accordance with the national reporting 
requirements in France (Article R1123-54 and Article R1123-46 of the French Public 
Health Code). This communication applies as soon as the sponsor has the following 
information: 
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