Clinical trial NCT04090658
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline
Start date: 2019-09-25; Completion date: 2020-12-11
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, reactogenicity and immunogenicity of 2 doses of GSK Biologicals' RSV candidate vaccine adjuvanted with AS01B for the prevention of lower respiratory tract diseases caused by RSV in ethnic Japanese adults 60-80 years of age.

Detailed description:

Arms: arm 1: Subjects aged 60 to 80 years received 2 doses of the investigational adjuvanted RSV\_PreF3 vaccine (GSK3844766A), at Day 1 and Day 61, by intramuscular (IM) injection into the deltoid region of the non-dominant arm preferably. arm 2: Subjects aged 60 to 80 years received 2 doses of placebo as control, at Day 1 and Day 61, by IM injection into the deltoid region of the non-dominant arm preferably.
Interventions: intervention 1: RSV_PreF3 Vaccine (GSK3844766A) adjuvanted with AS01B intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects aged 60 to 80 years received 2 doses of the investigational adjuvanted RSV\_PreF3 vaccine (GSK3844766A), at Day 1 and Day 61, by intramuscular (IM) injection into the deltoid region of the non-dominant arm preferably. intervention 2: Subjects aged 60 to 80 years received 2 doses of placebo as control, at Day 1 and Day 61, by IM injection into the deltoid region of the non-dominant arm preferably.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals SA
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary study vaccine and 
number
GlaxoSmithKline Biologicals SA (GSK)’s
investigational respiratory syncytial virus (RSV) 
vaccine BIO RSV OA=ADJ (GSK3844766A):

RSVPreF3 recombinant antigen, 120 g 
adjuvanted with AS01B
Other study 
vaccine/product
Control: Saline solution
eTrack study number and 
abbreviated title
209699 (RSV OA=ADJ-003)
Date of protocol
Final Version 1: 30 April 2019
Title
Phase I, observer-blind, safety, reactogenicity and 
immunogenicity study of GSK’s respiratory syncytial 
virus (RSV) vaccine GSK3844766A in Japanese 
subjects aged 60-80 years.
Short title
A phase I, randomized, placebo-controlled, observer-
blind study to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational respiratory 
syncytial virus (RSV) vaccine (adjuvanted with 
AS01B) when administered intramuscularly according 
to a 0, 2-month schedule in Japanese adults 60-80 
years of age.
Co-ordinating author
, Scientific Writer (XPE Pharma and 
Science, for GSK)
Contributing authors

, Clinical Research and 
Development Lead

, Project Statistician

, Lead Statistician

, Study Delivery Lead

and 
, Clinical 
Trial Supply Managers

 and 
, Clinical 
Laboratory Sciences Study Manager (Business & 
Decision, for GSK)
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eTrack study number and 
abbreviated title
209699 (RSV OA=ADJ-003)
Short title
A phase I, randomized, placebo-controlled, observer-
blind study to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational respiratory 
syncytial virus (RSV) vaccine (adjuvanted with 
AS01B) when administered intramuscularly according 
to a 0, 2-month schedule in Japanese adults 60-80 
years of age.
Contributing authors

, Clinical Read-out Team 
Leader

, Safety Scientist 

, Safety Physician

, Oversight Data Manager

, Study Data Manager

, Global Regulatory Affairs

, Global Patent Representative

and 
, Local 
Delivery Leads

, Clinical and Epidemiology 
R&D Project Lead
GSK Protocol WS v 16.0.1
©2019 GSK group of companies or its licensor.
PPD
PPD
PPD
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PPD
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Protocol Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
209699 (RSV OA=ADJ-003)
Date of Protocol
Final Version 1: 30 April 2019
Short Title 
A phase I, randomized, placebo-controlled, observer-
blind study to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational respiratory 
syncytial virus (RSV) vaccine (adjuvanted with 
AS01B) when administered intramuscularly according 
to a 0, 2-month schedule in Japanese adults 60-80 
years of age.
Sponsor signatory
Narcisa Mesaros, Clinical and Epidemiology R&D 
Project Lead
Signature
Date


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Protocol 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 SA.

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 study vaccine 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 and the express written informed consent of 
the subject.

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 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, and more generally about his/her financial 
ties with the sponsor. GSK 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 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 may disclose any information about such ownership interests and 
financial ties to regulatory authorities.

Agree to provide GSK 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
209699 (RSV OA=ADJ-003)
Date of Protocol
Final Version 1: 30 April 2019
Short Title
A phase I, randomized, placebo-controlled, observer-
blind study to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational respiratory 
syncytial virus (RSV) vaccine (adjuvanted with 
AS01B) when administered intramuscularly according 
to a 0, 2-month schedule in Japanese adults 60-80 
years of age.
Investigator name
Signature
Date
GSK Japan study 
representative name, 
function and title
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
GSK Central Back-up Study Contact for Reporting SAEs: refer to protocol Section 
12.5.8.3.
Study Contact for Reporting SAEs: refer to the local study contact information 
document.
5.
GSK Central Safety Physician On-Call Contact information for Emergency 
Unblinding
GSK Central Safety Physician and Back-up Phone contact: refer to protocol Section
8.5.4.1.


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TABLE OF CONTENTS
PAGE
SPONSOR INFORMATION ............................................................................................7
1.
SYNOPSIS.............................................................................................................16
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................19
3.
INTRODUCTION....................................................................................................24
3.1.
Study rationale............................................................................................24
3.2.
Background ................................................................................................24
3.3.
Benefit/Risk assessment.............................................................................25
3.3.1.
Risk assessment..........................................................................26
3.3.2.
Benefit assessment .....................................................................28
3.3.3.
Overall Benefit: Risk conclusion...................................................28
4.
OBJECTIVES AND ENDPOINTS...........................................................................29
5.
STUDY DESIGN ....................................................................................................31
5.1.
Scientific rationale for study design.............................................................31
5.1.1.
Vaccine antigen and adjuvant selection.......................................31
5.1.2.
Dose regimen ..............................................................................32
5.1.3.
Safety monitoring.........................................................................32
5.1.4.
Study blinding ..............................................................................32
5.1.5.
Rationale for the use of placebo ..................................................33
5.2.
Overall design.............................................................................................33
5.3.
Number of subjects.....................................................................................36
5.4.
Subject and study completion .....................................................................36
6.
STUDY POPULATION...........................................................................................37
6.1.
Inclusion criteria for enrolment....................................................................37
6.2.
Exclusion criteria for enrolment...................................................................37
6.2.1.
Medical conditions .......................................................................37
6.2.2.
Prior/Concomitant therapy ...........................................................38
6.2.3.
Prior/Concurrent clinical study experience ...................................39
6.2.4.
Other exclusions..........................................................................39
6.3.
Criteria for temporary delay for screening and vaccination..........................39
6.4.
Screen and baseline failures.......................................................................40
7.
TREATMENTS.......................................................................................................41
7.1.
Treatments administered ............................................................................41
7.2.
Method of treatment assignment.................................................................42
7.2.1.
Subject identification....................................................................42
7.2.2.
Randomization of treatment.........................................................42
7.2.2.1.
Randomization of supplies..........................................42
7.2.2.2.
Treatment allocation to the subject.............................42
7.2.2.2.1.
Study group and treatment 
number allocation ...................................42
7.2.2.2.2.
Treatment number allocation for 
subsequent doses ..................................43
7.3.
Blinding and unblinding...............................................................................43


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7.3.1.
Emergency unblinding .................................................................44
7.4.
Handling, storage and replacement of study vaccine ..................................45
7.4.1.
Storage and handling of study vaccine ........................................45
7.4.2.
Replacement of unusable vaccine doses.....................................45
7.5.
Concomitant medications/products and concomitant vaccinations..............46
7.5.1.
Recording of concomitant medications/products and 
concomitant vaccinations.............................................................46
7.5.2.
Concomitant medications/products/vaccines that may lead 
to the elimination of a subject from per-protocol analyses............46
7.6.
Intercurrent medical conditions that may lead to elimination of a 
subject from per-protocol analyses .............................................................47
7.7.
Contraindications to subsequent vaccine administration.............................47
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
8.1.
General study aspects ................................................................................49
8.1.1.
Informed consent.........................................................................49
8.2.
Screening procedures to check subject eligibility ........................................50
8.2.1.
Check inclusion and exclusion criteria .........................................50
8.2.2.
Collect demographic data, medical history, vaccination 
history and perform physical examination ....................................50
8.2.3.
Blood sampling for eligibility assessment.....................................50
8.2.4.
Screening conclusion...................................................................50
8.3.
Pre-vaccination procedures ........................................................................51
8.3.1.
Check inclusion and exclusion criteria .........................................51
8.3.2.
Collection of demographic data....................................................51
8.3.3.
Medical history.............................................................................51
8.3.4.
Vaccination history.......................................................................51
8.3.5.
Physical examination ...................................................................51
8.3.6.
Check contraindications to vaccination ........................................52
8.3.7.
Pre-vaccination body temperature ...............................................52
8.3.8.
Study group and treatment number allocation..............................52
8.3.9.
Study vaccine administration .......................................................52
8.3.10.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions ....................................................52
8.3.11.
Distribution of eDiary devices.......................................................53
8.3.12.
Distribution of paper diary cards ..................................................53
8.3.13.
Recording of AEs and SAEs ........................................................53
8.3.14.
Recording of potential immune-mediated diseases 
(pIMDs)........................................................................................53
8.3.15.
Study conclusion..........................................................................53
8.4.
Efficacy assessments .................................................................................54
8.4.1.
Use of specified study materials ..................................................54
8.4.2.
Biological samples.......................................................................55
8.4.2.1.
Blood sampling for safety or immunogenicity 
response assessments...............................................55
8.4.2.2.
Other biological samples ............................................55
8.4.3.
Laboratory assays .......................................................................56
8.4.4.
Biological samples evaluation......................................................58
8.4.4.1.
Immunological read-outs ............................................59
8.4.4.2.
Hematology/blood chemistry ......................................59
8.4.4.3.
Molecular biology .......................................................60
8.4.5.
Immunological correlates of protection.........................................60


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8.5.
Safety Assessments ...................................................................................60
8.5.1.
Safety definitions .........................................................................60
8.5.2.
Time period and frequency for collecting AE, serious 
adverse event (SAE), and pIMD information................................60
8.5.3.
Method of detecting AEs and SAEs .............................................61
8.5.4.
Reporting of serious adverse events and other events.................62
8.5.4.1.
Contact information for reporting of serious 
adverse events (SAEs), pIMDs and study 
holding rules...............................................................62
8.5.4.2.
Regulatory reporting requirements for SAEs ..............63
8.5.5.
Follow-up of AEs and SAEs.........................................................63
8.5.6.
Treatment of adverse events .......................................................63
8.5.7.
Clinical safety laboratory assessments ........................................63
8.5.8.
Subject card.................................................................................64
8.5.9.
Safety follow-up calls ...................................................................64
8.6.
RTI Surveillance .........................................................................................65
8.6.1.
Active surveillance .......................................................................65
8.6.2.
Passive surveillance ....................................................................65
8.6.3.
Assessment Visit for potential RSV-RTI.......................................66
8.7.
Holding rules and safety monitoring............................................................67
8.7.1.
Outcome of safety evaluation.......................................................68
8.7.1.1.
Process of stopping the vaccination ...........................69
8.7.2.
Study holding rules ......................................................................69
8.7.3.
Risk assessment..........................................................................71
8.8.
Genetic Research (Pharmacogenetics) ......................................................72
9.
DISCONTINUATION CRITERIA.............................................................................73
9.1.
Discontinuation from the study....................................................................73
9.2.
Discontinuation of study vaccine.................................................................74
9.3.
Lost to follow-up..........................................................................................74
10. STATISTICAL CONSIDERATIONS........................................................................75
10.1.
Sample size determination..........................................................................75
10.1.1.
Sample size calculation ...............................................................75
10.2.
Populations for analyses.............................................................................76
10.3.
Statistical analyses .....................................................................................76
10.3.1.
Demography and baseline characteristics analyses.....................76
10.3.2.
Safety analyses ...........................................................................77
10.3.3.
Immunogenicity analyses.............................................................78
10.3.4.
Other analyses ............................................................................79
10.3.4.1.
Analysis of RTI ...........................................................79
10.3.5.
Interim analyses...........................................................................79
10.4.
Sequence of analyses.................................................................................79
11. REFERENCES.......................................................................................................80
12. APPENDICES........................................................................................................83
12.1.
Appendix 1: Abbreviations, glossary of terms and trademarks....................83
12.1.1.
List of abbreviations.....................................................................83
12.1.2.
Glossary of terms.........................................................................86
12.1.3.
Trademarks .................................................................................91
12.2.
Appendix 2: Clinical and safety laboratory tests..........................................92


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12.2.1.
Laboratory assays .......................................................................92
12.3.
Appendix 3: Clinical laboratories.................................................................94
12.4.
Appendix 4: Study governance considerations ...........................................94
12.4.1.
Regulatory and ethical considerations .........................................94
12.4.2.
Financial disclosure .....................................................................95
12.4.3.
Informed consent process............................................................95
12.4.4.
Data protection ............................................................................96
12.4.5.
Publication policy.........................................................................96
12.4.6.
Dissemination of clinical study data .............................................96
12.4.7.
Data quality assurance ................................................................97
12.4.8.
Source documents.......................................................................98
12.4.9.
Study and site closure..................................................................98
12.5.
Appendix 5: Adverse events: definitions and procedures for 
recording, evaluating, follow-up, and reporting..........................................100
12.5.1.
Definition of AE..........................................................................100
12.5.1.1.
AE definition .............................................................100
12.5.1.2.
Events meeting the AE definition..............................100
12.5.1.3.
Events NOT meeting the AE definition......................101
12.5.2.
Definition of SAE........................................................................101
12.5.3.
Solicited adverse events............................................................102
12.5.4.
Unsolicited adverse events ........................................................103
12.5.5.
Adverse events of special interest (AESIs) ................................103
12.5.5.1.
Potential immune-mediated diseases .......................103
12.5.6.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ..........................................................................107
12.5.7.
Detecting and recording adverse events and serious 
adverse events ..........................................................................108
12.5.7.1.
Time period for detecting and recording 
adverse events and serious adverse events.............109
12.5.7.2.
Evaluation of adverse events and serious 
adverse events.........................................................110
12.5.7.2.1.
Active questioning to detect 
adverse events and serious 
adverse events .....................................110
12.5.7.2.2.
Assessment of adverse events .............111
12.5.7.2.3.
Medically attended visits.......................113
12.5.8.
Reporting of serious adverse events, and other events..............114
12.5.8.1.
Prompt reporting of serious adverse events, 
and other events to GSK ..........................................114
12.5.8.2.
SAEs requiring expedited reporting to GSK..............114
12.5.8.3.
Back-up system in case the electronic 
reporting system does not work................................114
12.5.8.4.
Reporting of pIMDs to GSK ......................................115
12.5.9.
Updating of SAE and pIMD information after removal of 
write access to the subject’s eCRF ............................................115
12.5.10. Follow-up of adverse events and serious adverse events..........115
12.5.10.1. Follow-up of adverse events and serious 
adverse events.........................................................115
12.5.10.1.1. Follow-up during the study....................115
12.5.10.1.2. Follow-up after the subject is 
discharged from the study ....................116


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12.6.
Appendix 6: Country-specific requirements...............................................117
12.6.1.
Regulatory and ethical considerations .......................................117
12.6.2.
Informed consent.......................................................................117
12.6.3.
Study administrative structure....................................................117
12.6.4.
Unapproved medical device.......................................................117
12.7.
Appendix 7: FDA guidance for industry: toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in preventive 
vaccine clinical trials (September 2007) - Tables for laboratory 
abnormalities ............................................................................................118


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LIST OF TABLES
PAGE
Table 1
Schedule of activities .............................................................................19
Table 2
Intervals between study visits.................................................................23
Table 3
Study objectives and endpoints..............................................................29
Table 4
Study groups, treatment and epochs foreseen in the study....................34
Table 5
Treatments administered........................................................................41
Table 6
Contact information for emergency unblinding .......................................44
Table 7
Biological samples .................................................................................55
Table 8
Humoral immunity (antibody determination) ...........................................56
Table 9
Hematology/biochemistry.......................................................................57
Table 10
Molecular biology (qRT-PCR tests) ........................................................57
Table 11
Immunological read-outs........................................................................59
Table 12
Hematology and biochemistry read-outs ................................................59
Table 13
Molecular biology tests on combined nasal and throat swab 
specimen................................................................................................60
Table 14
Reporting periods for collecting safety information .................................61
Table 15
Timeframes for submitting serious adverse event, and other 
events reports to GSK............................................................................62
Table 16
Contact information for reporting of serious adverse events 
(SAEs), pIMDs and study holding rules..................................................62
Table 17
Study holding rules identifiable by the investigator .................................69
Table 18
Study holding rules identifiable by the iSRC...........................................70
Table 19
Two-sided 95% exact confidence intervals based on the 
percentage of subjects with adverse events following vaccination 
of 20 subjects per group.........................................................................75
Table 20
Protocol-required safety laboratory assessments...................................92
Table 21
GSK laboratories....................................................................................94
Table 22
Outsourced laboratories.........................................................................94


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Table 23
Solicited local adverse events ..............................................................102
Table 24
Solicited general adverse events..........................................................102
Table 25
List of potential immune-mediated diseases (pIMDs) ...........................104
Table 26
Intensity scales for solicited symptoms in adults...................................111
Table 27
FDA toxicity grading scales for hematology/ biochemistry 
parameters evaluated in the current study RSV OA=ADJ-003 .............118


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LIST OF FIGURES
PAGE
Figure 1
Study design overview ...........................................................................33
Figure 2
Evaluations based on 20 subjects per group - risk assessment 
curve for 1 group based on the proposed safety holding rules................71


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1.
SYNOPSIS
Indication:
Active immunization in the prevention of moderate-to-severe lower respiratory tract 
disease (LRTD) caused by respiratory syncytial virus (RSV) in adults aged 60 years or 
above.
Rationale:
RSV is a ribonucleic acid (RNA) virus of which 2 antigenically distinct subgroups exist, 
referred to as RSV-A and RSV-B. RSV is a highly contagious human pathogen that 
causes respiratory tract infections (RTI) in people of all ages. According to the ‘Centers 
for Disease Control and Prevention’ (CDC) website, RSV leads to 177 000 
hospitalizations and 14 000 deaths on average each year among adults older than 65 years 
in the United States (US). The current studies available in Japan are on a smaller scale 
when compared to the current abundance of data obtainable for RSV disease burden 
globally and in the US. Although a limited amount of information is currently available, 
recent studies suggest that the burden of disease for RSV infections is high, and can 
conclude that RSV is an important and underreported disease in the older adult 
population in Japan.
Despite the significant medical need, there is currently no prophylactic vaccine approved 
for the prevention of LRTD caused by RSV. GlaxoSmithKline Biologicals SA (GSK) is 
developing a new investigational RSV vaccine against moderate to severe RSV-
associated (subtypes A and B) disease in adults aged 60 years or above.
This study in Japan will evaluate an investigational RSV vaccine formulation, with 
120 µg of pre-fusion conformation antigen RSVPreF3 adjuvanted with AS01B when 
administered intramuscularly according to a 2-dose schedule at 0, 2 months in older 
adults (60-80 years). The main purpose will be to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational RSV vaccine in ethnic Japanese adults 60-80 
years of age, for further development of the RSV vaccine based on those results. 


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Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the safety and reactogenicity of 2 doses of 
the investigational RSV vaccine administered IM 
according to a 0, 2-month schedule, up to one month 
after the last dose (Day 91, Visit 6).

Occurrence of AEs from first vaccination up to 30 days 
after the second vaccination (Day 91):

Occurrence of each solicited local and general AE 
during a 7-day follow-up period (i.e., on the day of 
vaccination and 6 subsequent days) after each 
vaccination.

Occurrence of any unsolicited AE during a 30-day 
follow up period (i.e., on the day of vaccination and 
29 subsequent days) after each vaccination.

Occurrence of any hematological (erythrocytes, 
WBC and differential count, platelets count and 
hemoglobin level) and biochemical (ALT, AST, 
creatinine, BUN and uric acid) laboratory 
abnormalities at Days 1, 8, 61 and 68.

Occurrence of all Grade 3 non-serious AEs (solicited 
and unsolicited) during the 30-day follow-up period 
after each vaccination.

Occurrence of SAEs from Dose 1 up to 30 days after 
the second vaccine dose (Day 91).

Occurrence of pIMDs from Dose 1 up to 30 days 
after the second vaccine dose (Day 91).
Secondary
To evaluate the humoral immune responses of the 
investigational RSV vaccine administered IM according 
to a 0, 2-month schedule, up to one month after the last 
dose (Day 91, Visit 6).

Humoral immune response with respect to components of 
the investigational vaccine at pre-vaccination (Day 1), 30 
days post-Dose 1 (Day 31), on the day of second 
vaccination (Day 61) and 30 days post-Dose 2 (Day 91):

Neutralizing antibody titers against RSV-A.

RSVPreF3-specific IgG antibody concentrations.
To evaluate the safety of 2 doses of the investigational 
RSV vaccine administered IM according to a 0, 2 -
month schedule, up to the end of follow-up (Month 14, 
Phone call 2).

Occurrence of SAEs from Dose 1 up to the end of follow-
up.

Occurrence of pIMDs from Dose 1 up to the end of follow-
up.
To evaluate the occurrence of RSV-associated
respiratory tract infections (RTI) during the RSV 
seasons in combined nasal and throat swab samples 
collected during the assessment visit for potential RSV-
RTI.

Occurrence of qRT-PCR confirmed RSV-associated RTI 
in the combined nasal and throat swabs collected during 
the assessment visit for potential RSV-RTI during the 
RSV seasons, up to the end of follow-up.
Tertiary
To further characterize immune responses to 
investigational RSV vaccine formulation.

Humoral immune response with respect to components of 
the investigational vaccine at pre-vaccination (Day 1) and 
30 days post-Dose 2 (Day 91):

Neutralizing antibody titers against RSV serotype B.

Any further exploratory immunology to detect RSV-related 
immune responses, such as but not limited to:

Antibodies against specific protein F epitopes.

Potential new immunological markers for protection.

Cross-reactive neutralizing antibody titers against 
hMPV.
To evaluate the occurrence of RSV-associated RTI
during the RSV seasons using self-collected nasal 
swabs.

Occurrence of qRT-PCR confirmed RSV-associated RTI 
in self-collected nasal swab samples during the RSV 
seasons, up to the end of follow-up.


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Overall Design:
BS S: Blood sample for safety evaluation (hematology/biochemistry)
BS H: Blood sample for humoral immune responses
qRT-PCR: quantitative reverse transcription polymerase chain reaction
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only 
laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria.
** An internal Safety Review Committee (iSRC) evaluation of safety data up to Day 8 from all subjects will be 
performed before proceeding with administration of Dose 2. Additional iSRC evaluations will happen during the 
conduct of the study.
† In case of RTI symptoms during the RSV seasons (from August until end of February), the subject will be asked to 
collect a nasal swab at home and contact the investigator/study staff to schedule an assessment visit for collection of 
an additional nasal swab and a throat swab at the site. The assessment visit should take place as soon as possible 
after the start of symptoms (ideally within 48 hours, but no later than 7 days).
£ A first analysis will be performed on all data collected up to Day 91 for at least primary and secondary endpoints
(except for the occurrence of RSV RTI). The analysis will be based on data as clean as possible.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of activities
Epoch
Screening
(Epoch 
001)
Vaccination phase
(Epoch 002)
Follow-up
(Epoch 003)
RTI surveillance
Notes
Type of contact
Screening 
Visit 1
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Phone 
call 1
Phone
call 2
Regular 
contact for 
RTI 
surveillance
Assessment 
visit for 
potential 
RSV-RTI
Time points
Day 1
Day 8 Day 31 Day 61 Day 68 Day 91 Month 
8
Month 
14
Sampling time points
Pre-Day 1
Pre-
Vacc
PI D8
PI D31 PI D61 PII D68 PII D91
Informed consent
●
[See Section 12.4.3 for details]
Check inclusion/exclusion criteria
●
O
[See Section 6.1 and 6.2 for 
Inclusion and Exclusion criteria]
[See Section 8.2.1 for more 
information]
Collect demographic data
O
●
[See Section 8.2.2 for more 
information]
Medical history
O
●
[See Section 8.3.3 for more 
information]
Vaccination history 2
O
●
[See Section 8.3.4 for more 
information]
Physical examination /Vital signs
O
●
O 3
O 3
O 3
O 3
O 3
●
[See Section 8.3.5 for more 
information]
Check contraindications to 
vaccination
O
O
[See Section 7.7 for more 
information]
Pre-vaccination body 
temperature
●
●
[See Section 8.3.7 for more 
information]
Vaccine
Study group and treatment 
number allocation
O
[See Section 7.2.2.2.1 for more 
information]
Treatment number allocation for 
subsequent doses
O
[See Section 7.2.2.2.2 for more 
information]
Vaccine administration
●
●
[See Section 8.3.9 for more 
information]


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Epoch
Screening
(Epoch 
001)
Vaccination phase
(Epoch 002)
Follow-up
(Epoch 003)
RTI surveillance
Notes
Type of contact
Screening 
Visit 1
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Phone 
call 1
Phone
call 2
Regular 
contact for 
RTI 
surveillance
Assessment 
visit for 
potential 
RSV-RTI
Time points
Day 1
Day 8 Day 31 Day 61 Day 68 Day 91 Month 
8
Month 
14
Sampling time points
Pre-Day 1
Pre-
Vacc
PI D8
PI D31 PI D61 PII D68 PII D91
Recording of administered 
treatment number
●
●
[See Section 7.2.2 for more 
information]
Laboratory assay
Blood sampling for antibody 
determination (~10 mL)
●4
●
●4
●
[See Section 8.4.2.1 for more 
information]
Blood sampling for hematology 
and biochemistry analysis (~5.5 
mL)
●1
●4
●
●4
●
[See Section 8.4.2.1 for more 
information]
RTI surveillance
Instruct/remind subjects of RTI 
surveillance during RSV seasons
●
[See Section 8.6 for more 
information]
Distribution of material for nasal 
swab collection at home 
(including instructions)
O
O
Recording of nasal swab 
collection at home
●
[See Section 8.6.3 for more 
information]
Nasal and throat swab samplings
●
[See Section 8.4.2.2 and 8.6.3 for 
more information]
Documentation of symptoms and 
signs of RTI
●
See Section 8.6.3 for more 
information
Safety assessments
Recording of any concomitant 
medications/vaccinations
●
●
●
●
●
●
●
●
●
[See Section 7.5.1 for more 
information]
Recording of any intercurrent 
medical conditions
●
●
●
●
●
●
●6
[See Section 7.6 for more 
information]
Distribute and instruct subject on 
the use of eDiary devices for 
solicited AEs
O
O 5
[See Sections 8.3.11 and 12.5.7 for 
more information]


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Epoch
Screening
(Epoch 
001)
Vaccination phase
(Epoch 002)
Follow-up
(Epoch 003)
RTI surveillance
Notes
Type of contact
Screening 
Visit 1
Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Phone 
call 1
Phone
call 2
Regular 
contact for 
RTI 
surveillance
Assessment 
visit for 
potential 
RSV-RTI
Time points
Day 1
Day 8 Day 31 Day 61 Day 68 Day 91 Month 
8
Month 
14
Sampling time points
Pre-Day 1
Pre-
Vacc
PI D8
PI D31 PI D61 PII D68 PII D91
Return of eDiary devices
O
Distribution of paper diary cards 
for unsolicited AEs
O
O
[See Section 8.3.12 for more 
information]
Return of paper diary cards
O
O
O
O
Recording of unsolicited AEs 
within 30 days post-vaccination 
(Days 1-30)
●
●
●
●
●
●
[See Section 8.3.13 for more 
information]
Recording of SAEs and pIMDs
●
●
●
●
●
●
●
●
●
[See Sections 12.5.7, 12.5.8 and 
12.5.5.1 for more information]
Recording of SAEs related to 
study participation, or to a 
concurrent GSK 
medication/vaccine
●
●
●
●
●
●
●
●
●
●
Recording of AEs/SAEs leading 
to withdrawal from the study
●
●
●
●
●
●
●
●
●
Recording of causality 
assessment for solicited general 
AEs on eDiary web-portal
●
●
Screening conclusion
●
Study Conclusion
●
[See Section 5.4 for more 
information]
Note: The double-line borders following Day 91 indicate the analysis which will be performed. See Section 10.4 for all details. 
Pre-Vacc: pre-vaccination; PI: Post-Dose 1; PII: Post-Dose 2; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X; D: Day.
● is used to indicate a study procedure that requires documentation in the individual eCRF or on web-portal.
○ is used to indicate a study procedure that does not require documentation in the individual eCRF or on web-portal.
1In case Visit 1 occurs more than 30 days after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection for safety laboratory 
assessment must be repeated (maximum one re-screening per subject is allowed). Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a 


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re-screening visit occurs. Only data from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. The subject can only be randomized once the 
investigator receives the results and confirms the eligibility criteria.
2Any vaccination administered up to 5 years before administration of the first dose of study vaccine should be recorded in the eCRF.
3If deemed necessary by the investigator.
4 Blood sampling to be performed before vaccination.
5 Only re-instruction on the use of eDiary device at Visit 4.
6 Intercurrent medical conditions will only be collected up to Visit 6 (Day 91); thus, not during Assessment visits for potential RSV-RTI occurring after Visit 6.


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Whenever possible, the investigator should arrange study visits within the intervals
described in Table 2.
Table 2
Intervals between study visits
Interval
Length of interval
Allowed interval
Screening Visit Visit 1
3 – 30 days*
Visit 1Visit 2
7 days
7 - 10 days
Visit 1Visit 3
30 days
30 - 37 days
Visit 1Visit 4
60 days
55 - 65 days
Visit 4Visit 5
7 days
7 - 10 days
Visit 4Visit 6
30 days
30 - 37 days
Visit 4Phone call 1
180 days
180 - 200 days
Visit 4Phone call 2
365 days
365 - 395 days
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only 
laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria.


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3.
INTRODUCTION
3.1.
Study rationale
Despite the significant medical need, there is currently no prophylactic vaccine approved 
for the prevention of lower respiratory tract disease (LRTD) caused by respiratory 
syncytial virus (RSV). Several attempts have been made to develop an RSV vaccine but 
to date all have been unsuccessful. In the 1960’s, a formalin-inactivated RSV vaccine not 
only failed to show protection, but it promoted more frequent and more severe clinical 
symptoms of LRTD after RSV natural infection in vaccinated children. In 2015, Novavax 
announced results of their Phase II Proof of Concept clinical trial showing the first ever 
demonstration of efficacy following the administration of an active RSV vaccine in older 
adults over 60 years of age. However, in September 2016, Novavax announced the 
vaccine candidate had failed the primary and secondary efficacy endpoints in its pivotal 
Phase III study.
GlaxoSmithKline Biologicals SA (GSK) is developing a new investigational RSV 
vaccine against moderate to severe RSV-associated (subtypes A and B) disease in adults 
aged 60 years or above.
The purpose of this study in Japan is to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational RSV vaccine in ethnic Japanese adults 60-80 
years of age, for further development of the RSV vaccine based on those results.
The rationale for the study design is presented in Section 5.1.
3.2.
Background
RSV is a ribonucleic acid (RNA) virus of which 2 antigenically distinct subgroups exist, 
referred to as RSV-A and RSV-B [Borchers, 2013]. RSV is a highly contagious human 
pathogen that causes respiratory tract infections (RTI) in people of all ages. In temperate 
climates throughout the world, RSV predictably causes fall-winter epidemics whereas 
viral activity is more endemic in (sub) tropical regions and outbreaks are less temporally 
focused.
According to the ‘Centers for Disease Control and Prevention’ (CDC) website [CDC, 
2017], RSV leads to 177 000 hospitalizations and 14 000 deaths on average each year 
among adults older than 65 years in the United States (US). As the global population 
ages, the morbidity and mortality of respiratory infections appear to be steadily 
increasing. In the US, the burden of the disease has been shown to be significant and data 
indicate that RSV is comparable to influenza (in an influenza vaccinated population) in 
terms of number of infections, hospitalization and deaths. Based on epidemiological data 
collected prospectively in 2008-2010 in 14 countries worldwide (including North 
America, Europe and East Asia), the average percentage of documented RSV infection in 
older adults (65 years) with influenza-like illness is 7.4%, with values between 0% and 
17.1% across countries [Falsey, 2014].


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Previous infection with RSV does not prevent subsequent infections. Therefore, re-
infection with RSV occurs throughout an individual’s lifetime and is common in all age 
groups [Simoes, 1999; Krilov, 2011]. Generally, these re-infections go undiagnosed 
because they usually manifest as common acute upper RTIs. However, in more 
vulnerable individuals (e.g. immunocompromised subjects or older adults), re-infections 
can also lead to severe disease [Graham, 2011].
The current studies available in Japan are on a smaller scale when compared to the 
current abundance of data obtainable for RSV disease burden globally and in the US. 
Although a limited amount of information is currently available, recent studies [Ikematsu, 
2012; Morimoto, 2015; Doi, 2014; Kanou, 2018; Takahashi, 2016; Kurai, 2016] suggest 
that the burden of disease for RSV infections is high, and can conclude that RSV is an 
important and under-reported disease in the older adult population in Japan.
Data on hospitalization rates, co-morbidity and mortality rate for RSV in older adults in 
Japan are limited. One study assessing the burden of community-onset pneumonia (COP)
in Japan found RSV to be the third leading viral pathogen found in COP cases. Out of 
1201 cases who underwent Multiplex-PCR in sputum specimens, 51 (4%) tested positive 
for RSV and 64 (5%) with Influenza; 23% of all pneumonia cases were found to be 
associated with respiratory viruses. The majority (75%) of the patients with COP were 
65 years of age [Morimoto, 2015]. In another study [Takahashi, 2016], 5.3% (43/817) of 
the adult cases with pneumonia during two consecutive winter seasons were diagnosed as 
having RSV-related illness, while 3.1% (25/817) had influenza-related illness. For the 43 
patients with RSV-related pneumonia, the mean age was 81.0 years (range: 24–95). In
terms of co-morbidity in patients with RSV-related pneumonia, the same study found 
respiratory disorders in 30.2% (13 patients), house oxygen therapy in 7% (3 patients), and 
other systemic disorders in 72.1% (31 patients). Finally, the 30-day mortality rate for 
RSV-related pneumonia was found to be 7.0% compared to 8.0% for influenza-related 
pneumonia. The overall hospital mortality rates for RSV-related pneumonia were found 
to be 11.6%, compared to 8.0% for influenza-related pneumonia [Takahashi, 2016].
Please refer to the current Investigator Brochure for information regarding the pre-
clinical studies of the investigational RSV older adult vaccine.
3.3.
Benefit/Risk assessment
In total, approximately 20 subjects in this study will be exposed to the investigational 
RSV vaccine, whereas approximately 20 subjects will receive placebo.
The following section outlines the risk assessment and mitigation strategy for this study 
protocol.
Please refer to the current Investigator Brochure for the summary of potential risks and 
benefits of the investigational RSV older adult vaccine.


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3.3.1.
Risk assessment
Important/Potential/Identified/Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational vaccine
Hypersensitivity including allergic reaction such as 
anaphylaxis
Acute allergic reactions such as a rare case of 
anaphylactic event may occur with any vaccine 
administration. These are serious, but rare occurrences 
estimated in the range of 1 to 10 cases per million of 
vaccinations, depending on the vaccine studied 
[Ruggerberg, 2007].
Anaphylaxis following vaccine administration is a 
contraindication to vaccination. The onset of vaccine-
related allergic symptoms is typically quite prompt. In 
order to treat subjects with a serious allergic reaction to 
vaccination, all subjects will need to remain under 
observation (i.e. visibly followed; no specific procedure) at 
the vaccination center for at least 60 minutes after 
vaccination.
Syncope
Syncope (fainting) can occur following or even before any 
vaccination as a psychogenic response to the needle 
injection. 
All subjects will remain under observation at the 
vaccination center for at least 60 minutes after 
vaccination.
Intramuscular (IM) injection
Intramuscular vaccination commonly precipitates a 
transient and self-limiting local inflammatory reaction. This 
may typically include pain at injection site, redness, and 
swelling.
All subjects will remain under observation at the 
vaccination center for at least 60 minutes after 
vaccination.
Solicited local adverse events (AE) will be collected and 
reviewed up to Day 8.
RSVPreF3
Due to the limited experience in human subjects to date, 
there is currently not enough information available to 
identify the risks of AEs related to the administration of 
the RSVPreF3 investigational vaccine.
Any untoward symptoms experienced by the subject after 
receiving the vaccine should be reported to the 
investigator.
Safety evaluations will be performed by an iSRC. Holding 
rules that have been established will be applied (refer to 
Section 8.7).
Adjuvant Systems
Potential immune-mediated diseases (pIMDs) are a 
theoretical concern with adjuvanted vaccines. 
There are no safety findings suggesting a causal link 
between pIMDs and AS01-containing vaccines [Stassijns, 
2016].
During the informed consent process, the subjects will be 
informed of this potential risk and the need to attend the 
clinic if they are unwell. pIMD is an AE of specific interest 
and will be collected up to 12 months after administration 
of the last dose of study vaccine (see Section 12.5.5.1). 
The occurrence of pIMD cases will be described.


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Important/Potential/Identified/Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures – Blood sampling
Pain and bruising
Pain or bruising at the site where blood is drawn. 
A topical analgesic may be applied to the site where 
blood will be taken.
Syncope
Syncope (fainting) can occur following or even before any 
blood draw as a psychogenic response to the needle 
insertion.
Subject Monitoring 
All subjects will remain under observation at the clinical 
center for at least 60 minutes after vaccination.
Nerve Injury
There is a possibility that in the process of collecting 
blood a nerve may be injured.
Procedure to be performed by qualified personnel.


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3.3.2.
Benefit assessment
The subjects receiving investigational RSV vaccine may not directly benefit from this 
vaccination because vaccine efficacy has not been assessed yet and it is hence not known 
whether the investigational RSV vaccine is effective in protecting against RSV infection.
An indirect benefit is that the information obtained in this study will aid the development 
of an RSV vaccine, which is intended to prevent LRTD associated with RSV infection in 
older adults.
Another benefit for all study participants may include gaining of information about their 
general health status through the medical evaluations/assessments associated with this 
study (i.e., physical examination, blood testing [hematology and biochemistry data]).
3.3.3.
Overall Benefit: Risk conclusion
The investigational RSV vaccine is currently in an early stage of clinical development. 
Taking into account the measures to minimize the risk to subjects participating in this 
study, the potential risks are justified by the potential benefits linked to the development 
of this RSV vaccine.


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4.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives and endpoints
Objectives
Endpoints
Primary

To evaluate the safety and reactogenicity of 2 
doses of the investigational RSV vaccine 
administered IM according to a 0, 2-month 
schedule, up to one month after the last dose (Day 
91, Visit 6).

Occurrence of AEs from first vaccination up to 30 
days after the second vaccination (Day 91):

Occurrence of each solicited local and general 
AE during a 7-day follow-up period (i.e., on the 
day of vaccination and 6 subsequent days) after 
each vaccination.

Occurrence of any unsolicited AE during a 30-day 
follow up period (i.e., on the day of vaccination 
and 29 subsequent days) after each vaccination.

Occurrence of any hematological (erythrocytes, 
WBC and differential count, platelets count and 
hemoglobin level) and biochemical (ALT, AST, 
creatinine, BUN and uric acid) laboratory 
abnormalities at Days 1, 8, 61 and 68.

Occurrence of all Grade 3 non-serious AEs 
(solicited and unsolicited) during the 30-day 
follow-up period after each vaccination.

Occurrence of SAEs from Dose 1 up to 30 days 
after the second vaccine dose (Day 91).

Occurrence of pIMDs from Dose 1 up to 30 days 
after the second vaccine dose (Day 91).
Secondary

To evaluate the humoral immune responses of the 
investigational RSV vaccine administered IM 
according to a 0, 2-month schedule, up to one 
month after the last dose (Day 91, Visit 6).

Humoral immune response with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1), 30 days post-Dose 1 (Day 31), 
on the day of second vaccination (Day 61) and 30 
days post-Dose 2 (Day 91):

Neutralizing antibody titers against RSV-A.

RSVPreF3-specific IgG antibody concentrations.

To evaluate the safety of 2 doses of the 
investigational RSV vaccine administered IM 
according to a 0, 2 -month schedule, up to the end 
of follow-up (Month 14, Phone call 2).

Occurrence of SAEs from Dose 1 up to the end of 
follow-up.

Occurrence of pIMDs from Dose 1 up to the end of 
follow-up.

To evaluate the occurrence of RSV-associated 
respiratory tract infections (RTI) during the RSV 
seasons in combined nasal and throat swab 
samples collected during the assessment visit for 
potential RSV-RTI.

Occurrence of qRT-PCR confirmed RSV-associated 
RTI in the combined nasal and throat swabs
collected during the assessment visit for potential 
RSV-RTI) during the RSV seasons, up to the end of 
follow-up.
Tertiary

To further characterize immune responses to 
investigational RSV vaccine formulation.

Humoral immune response with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1) and 30 days post-Dose 2 (Day 
91):

Neutralizing antibody titers against RSV serotype 
B.

Any further exploratory immunology to detect RSV-
related immune responses, such as but not limited 
to:


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Objectives
Endpoints

Antibodies against specific protein F epitopes.

Potential new immunological markers for 
protection.

Cross-reactive neutralizing antibody titers against 
hMPV.

To evaluate the occurrence of RSV-associated RTI 
during the RSV seasons using self-collected nasal 
swabs.

Occurrence of qRT-PCR confirmed RSV-associated 
RTI in self-collected nasal swab samples during the 
RSV seasons, up to the end of follow-up.
IM: intramuscular; RSV: respiratory syncytial virus; AE: adverse event; WBC: white blood cells; ALT: alanine 
aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; SAE: serious adverse event; pIMD: 
potential immune-mediated disease; RTI: respiratory tract infection; qRT-PCR: quantitative reverse transcription 
polymerase chain reaction.


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5.
STUDY DESIGN
5.1.
Scientific rationale for study design
This study will evaluate an investigational RSV vaccine formulation, 120 g of pre-
fusion conformation antigen RSVPreF3 adjuvanted with AS01B, when administered 
intramuscularly (IM) according to a 2-dose schedule at 0, 2 months in older adults (60-
80 years). The main purpose will be to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational RSV vaccine in ethnic Japanese adults 60-80 
years of age, for further development of the RSV vaccine based on those results. 
5.1.1.
Vaccine antigen and adjuvant selection
The antigen which will be used in the investigational RSV vaccine is an engineered 
version of the RSV fusion (F) surface glycoprotein, stabilized in the pre-fusion 
conformation, resulting in the “RSVPreF3” pre-fusion molecule. The F protein has been 
selected because it is a major surface antigen of the RSV virus that is well conserved 
among RSV-A and RSV-B subtypes. It was shown that most of the RSV neutralizing 
activity present in serum from previously infected individuals is directed to the pre-fusion 
conformation of RSV F protein [Ngwuta, 2015]. In addition, antibodies specific for the 
RSV F pre-fusion conformation are typically more potent than those common to the post-
and pre-fusion forms [Kwakkenbos, 2010]. Finally, an RSV F antigen in the pre-fusion 
conformation elicited higher levels of neutralizing antibodies than those observed with an 
RSV F protein in the post-fusion conformation [McLellan, 2013; Steff, 2017].
In addition to boosting pre-existing neutralizing antibodies, another important element for 
the RSV candidate vaccine in older adults might be to boost or elicit RSV-specific T-cell 
responses. The use of an adjuvant may enable induction of CD4+ T-cells in addition to 
antibodies, leading to a stronger and persistent protection. Amongst the current GSK 
portfolio of adjuvants, AS01 has the potential to induce the targeted immune profile as it 
has been shown to improve antibody and T-cell response in older adults [Chlibek, 2013; 
Chlibek, 2014; Chlibek, 2016; Schwarz, 2018]. Based on the available evidence, AS01 
would be expected to boost the CD4+ T-cell as well as B-cell memory responses.
The AS01B adjuvant has been evaluated in several GSK candidate vaccines. As of 30 
June 2017, over 35 000 participants have been vaccinated with at least one dose of an 
AS01-containing vaccine in completed clinical trials. The population vaccinated with an 
AS01-adjuvanted vaccine consists in over 12 700 infants and toddlers participating in 
Malaria trials and over 22 500 adults and older adults mainly coming from Zoster trials. 
Clinical data from the efficacy trials of the Herpes Zoster subunit vaccine (HZ/su) in 
adults aged 50 years or above and adults aged 70 years or above have demonstrated the 
added value of AS01-based adjuvants for older adults. HZ/su (glycoprotein E 
[gE]/AS01B) can induce strong and persistent gE-specific antibody and CD4+ T-cell 
responses up to 9 years in a population known for diminished immune response 
(immune-senescence) [Chlibek, 2016; Schwarz, 2018]. The HZ/su (gE/AS01B) vaccine is
currently licensed in several countries, including the US, Canada, the European Union,
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5.1.2.
Dose regimen
It is proposed to evaluate a 2-dose vaccination regimen with an interval of 2 months 
between doses. This is supported by available data from several clinical studies in GSK’s 
Herpes Zoster and chronic obstructive pulmonary disease (COPD) vaccine development 
programs conducted with an AS01-adjuvanted protein in older adults.
In the Phase II study ZOSTER-003 (Herpes Zoster vaccine program), conducted in older 
adults aged 60 years and above, a statistically significant higher cellular immune 
response (based on frequency of gE-specific CD4+ T-cells) and humoral immune 
response was observed in all groups who received 2 doses of the adjuvanted gE 
(gE/AS01B) vaccine (at 3 different gE dosage levels tested) compared to a single dose of 
the highest concentration of gE/AS01B tested [Chlibek, 2014]. Descriptive data for
persistence over 3 years further support this observation, as the median gE-specific CD4+ 
T-cell frequencies and anti-gE antibody concentrations remained higher in the 2-dose 
group as compared to the 1-dose group [Chlibek, 2014].
Similarly, in the Phase I study NTHI-003 (COPD vaccine development program) in older 
adults aged 50 to 70 years, a second dose of any of the adjuvanted non-typeable 
Haemophilus influenzae protein vaccine formulations administered 2 months following 
the first dose, induced higher antibody concentrations and cellular immune response 
(based on the frequency of antigen-specific CD4+ T-cells) as compared to one dose 
[Leroux-Roels, 2016].
5.1.3.
Safety monitoring
Safety evaluations post-Dose 1 will be performed by an internal Safety Review 
Committee (iSRC) based on data collected up to 7 days post-vaccination from all 
subjects. Only upon favorable outcome of the iSRC evaluation, administration of Dose 2
will be initiated. For more detailed information on the study holding rules and safety 
monitoring, refer to Section 8.7.
5.1.4.
Study blinding
Given the difference in reconstitution and visual appearance of the vaccines, double 
blinding is not possible and the study will be conducted in an observer- blind manner for 
the vaccination phase (up to one month post-Dose 2).
A statistical analysis will be performed on data up to one month post-Dose 2. Given that 
summary results may unblind some specific subjects, the follow-up phase (Epoch 003) 
will be considered as single-blind, with subjects remaining blinded up to study end. The 
investigators will not be provided with the individual data listings or with the 
randomization listings until the end of study analysis.
Please refer to the Section 12.1.2 (Glossary of Terms) for the definition of observer-blind 
and single-blind.


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5.1.5.
Rationale for the use of placebo
As there is currently no licensed RSV vaccine available, a placebo group (receiving 
saline solution) will be used as control for the safety, reactogenicity and immunogenicity 
assessments.
5.2.
Overall design
Figure 1
Study design overview
BS S: Blood sample for safety evaluation (hematology/biochemistry)
BS H: Blood sample for humoral immune responses
qRT-PCR: quantitative reverse transcription polymerase chain reaction
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only 
laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria.
** An internal Safety Review Committee (iSRC) evaluation of safety data up to Day 8 from all subjects will be 
performed before proceeding with administration of Dose 2. Additional iSRC evaluations will happen during the 
conduct of the study.
† In case of RTI symptoms during the RSV seasons (from August until end of February), the subject will be asked to 
collect a nasal swab at home and contact the investigator/study staff to schedule an assessment visit for collection of 
an additional nasal swab and a throat swab at the site. The assessment visit should take place as soon as possible 
after the start of symptoms (ideally within 48 hours, but no later than 7 days).
£ A first analysis will be performed on all data collected up to Day 91 for at least primary and secondary endpoints
(except for the occurrence of RSV RTI). The analysis will be based on data as clean as possible.


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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 SoA (Section 2), are essential and required for study 
conduct. 

Type of study: self-contained.

Experimental design: a phase I, observer-blind, randomized, placebo-controlled,
single-country study with 2 parallel groups (see Figure 1):

Duration of the study: Approximately 14 months per subject.

Epoch 001: Screening Visit (Day -30 to -3)

Epoch 002: Primary (vaccination phase) starting at Visit 1 (Day 1) and ending at 
Visit 6 (Day 91) 

Epoch 003: Follow-up starting after Visit 6 (Day 91) and ending at Phone call 2 
(Month 14)

Primary completion Date (PCD): last visit of the vaccination phase (Visit 6
[Day 91]). 
Refer to Section 12.1.2 (Glossary of Terms) for the definition of PCD.

End of Study (EoS): Last testing results released of samples collected up to Phone 
call 2 (Month 14) (for assays related to secondary endpoints only), or Last subject 
last Phone Call, whichever comes last.
While no samples will be collected at Phone calls 1 and 2, nasal and throat swabs 
may be collected in case of RTI symptoms up to the Phone call 2 (Month 14) 
timepoint, if this timepoint falls within the RSV season.
Refer to Section 12.1.2 (Glossary of Terms) for the definition of EoS.

Study groups:

RSV Group: subjects receiving 2 doses of the investigational RSV vaccine 
containing 120 g RSVPreF3 adjuvanted with AS01B. 

Placebo: subjects receiving 2 doses of placebo as control.
Table 4
Study groups, treatment and epochs foreseen in the study
Study 
Groups
Number 
of 
subjects
Age
(Min-Max)
Treatment name
Epochs
(Blinding)
Epoch 001
(N/A)
Epoch 002
(observer-blind)
Epoch 003
(single-blind)
RSV 
Group
~20
60 - 80
years
120 µg 
RSVPreF3/AS01B
x
x
x
Placebo
~20
60 - 80
years
Placebo
x
x
x
N/A: Not applicable


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
Control: placebo control.

Vaccination schedule: Two vaccine doses administered IM at Day 1 and Day 61.

Treatment allocation: Subjects will be randomized using a centralized
randomization system on internet (SBIR) on Day 1. 
A total of approximately 40 participants are planned to be enrolled in this study in a 
1:1 ratio. The target is to enroll approximately 28 eligible participants aged 60-69 
years (approximately 14 per group) and approximately 12 (and minimum 10) eligible 
participants aged 70-80 years (approximately 6 per group). The randomization 
algorithm will use a minimization procedure accounting for age, center and gender.
For a detailed description of the randomization method, refer to Section 7.2.2.

Blinding: observer-blind.
The vaccination phase (Epoch 002) will be observer-blind. A first statistical analysis 
will be performed on data available up to one month post-Dose 2 (Visit 6, Day 91) 
(see Section 10.4 for details on the sequence of analyses). Given that summary safety
results may unblind some specific subjects, the follow-up phase (Epoch 003) will be 
considered as single-blind with subjects remaining blinded up to study end (Phone 
Call 2 [Month 14]). The investigators will not be provided with the individual data 
listings or with the randomization listings until the end of study analysis.
Refer to Section 7.3 for details on blinding and unblinding procedures.

RTI surveillance: Active and passive surveillance will only be carried out during 
RSV seasons (from August until end of February) throughout the entire study:

Active surveillance: study participants will be contacted by the 
investigator/study staff every 2 weeks to identify if they experienced an RTI.

Passive surveillance: study participants are instructed to contact the 
investigator/study staff as soon as they experience an RTI.
At the beginning of RSV seasons, study participants will be reminded of the start of 
the RTI surveillance.

Sampling schedule: 

At Screening (Pre-Day 1), a blood sample for eligibility assessment will be 
drawn from all subjects (Section 8.2.3). In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 
during which blood sample collection must be repeated (maximum one re-
screening per subject is allowed). 

Blood samples for safety assessment (hematology/biochemistry) will be drawn 
from all subjects on Days 1, 8, 61 and 68 (Visits 1, 2, 4 and 5). 

Blood samples for humoral immunogenicity testing will be drawn from all 
subjects at Days 1, 31, 61 and 91 (Visits 1, 3, 4 and 6).

Nasal and throat swabs: In case of RTI symptoms during the RSV season (from 
August until end of February), the study participants will be asked to collect a 
nasal swab at home and contact the investigator/study staff to schedule an 


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assessment visit for collection of an additional nasal swab and a throat swab by 
qualified staff from the study team. The assessment visit should take place as 
soon as possible after the start of symptoms (ideally within 48 hours, but no later 
than 7 days; refer to Section 8.6 for further details).

Data collection: standardized electronic Case Report Form (eCRF). Solicited 
symptoms will be collected using an electronic Diary (eDiary). Unsolicited 
symptoms will be collected using a paper Diary.

Safety monitoring: The study will be conducted with oversight by an iSRC. An 
iSRC evaluation of safety data up to Day 8 from all subjects will be performed 
before proceeding with administration of Dose 2. Additional iSRC evaluations will 
happen during the conduct of the study (see Section 8.7). If any safety concern is 
identified by the investigator or the sponsor, ad-hoc safety evaluations by the iSRC 
may be performed.
The investigator is not permitted to start the administration of the next dose until receipt 
of the favorable outcome of the safety evaluation, documented and provided in writing 
(scanned and emailed), authorizing the investigator to proceed. Moreover, if the 
investigator becomes aware of a holding rule being met, he/she will suspend vaccination 
and will inform GSK immediately (refer to Table 17 and Table 18 for holding rules, and 
Section 8.7.2 for flow of communication related to holding rules).
Refer to Section 8.7 for detailed description of holding rules and safety monitoring.
5.3.
Number of subjects
Approximately 40 subjects will be randomized such that about 36 evaluable subjects 
complete the study, considering a 10% rate of non-evaluable subjects.
Withdrawals will not be replaced.
Refer to Section 10.1 for further information on sample size determination.
Overview of the recruitment plan 
The study is planned to be conducted in Japan. The recruitment rate will be monitored 
and transfer of supplies will be tracked using SBIR. Monitoring visits frequency will be 
adapted to the pace of enrolment. Vaccine doses will be distributed respecting the 
randomization block size. 
Prior to Visit 1 (Day 1), a Screening Visit will be scheduled to screen potential study 
participants for eligibility. The purpose of the screening is to collect informed consent, 
check eligibility for study participation and collect a blood sample for eligibility 
evaluation.
5.4.
Subject and study completion
A subject is considered to have completed the study if he/she is available for the 
concluding contact (Phone call 2) 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 eDiaries, 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, 60 and 80 years of age at the time of the 
first vaccination.

Subjects with residence status allowing free mixing with general community or in an 
assisted-living facility that provides minimal assistance, such that the subject is 
primarily responsible for self-care and activities of daily living, may be enrolled.

Japanese ethnic origin (defined as having been born in Japan with four ethnic 
Japanese grandparents and able to speak Japanese).

Subject satisfying screening requirements.
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.
6.2.1.
Medical conditions

Any medical condition that in the judgment of the investigator would make IM 
injection unsafe.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
based on medical history and physical examination (no laboratory testing required).

History of any reaction or hypersensitivity likely to be exacerbated by any 
component of the vaccine.

Hypersensitivity to latex.


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
Serious or unstable chronic illness. Patients with chronic stable conditions with or 
without specific treatment, such as diabetes, hypertension or cardiac disease, are 
allowed to participate in this study.

Any other condition (e.g. chronic obstructive pulmonary disease or severe 
respiratory condition) that, in the opinion of the investigator, might interfere with the 
evaluations required by the study.

History of any neurological disorders or seizures.

Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal 
functional abnormality, as determined by the investigator based on medical history, 
physical examination or laboratory screening tests.

Hepatomegaly, right upper quadrant abdominal pain or tenderness.

Significant underlying illness that in the opinion of the investigator would be 
expected to prevent completion of the study (e.g., life-threatening disease likely to 
limit survival to less than 2 years).

Lymphoproliferative disorder and malignancy within 5 years.

At Screening: Hematology parameters (complete blood cell count [red blood cells, 
white blood cells], white blood cells differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or hemoglobin level) and/or biochemistry parameters 
(creatinine, blood urea nitrogen or liver enzymes [alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST]) outside the normal laboratory ranges, unless the 
laboratory abnormalities are considered not clinically significant by the investigator.
6.2.2.
Prior/Concomitant therapy

Use of any investigational or non-registered product (drug or vaccine) other than the 
study vaccine during the period starting 30 days before the first dose of study 
vaccine (Day -29 to Day 1), or planned use during the study period.

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 study vaccine administration, with the exception of inactivated and 
subunit influenza vaccines which can be administered up to 14 days before or from 
30 days after each study vaccination.

Previous vaccination with an RSV vaccine.

Known previous administration of a vaccine containing MPL, QS-21 and/or MF59 
(e.g. GSK’s vaccine against human papillomavirus infection marketed as Cervarix, 
GSK’s Herpes Zoster vaccine marketed as Shingrix, an adjuvanted recombinant 
varicella zoster virus envelope gE subunit vaccine [HZ/su], or MF59 adjuvanted 
influenza vaccines [e.g. Fluad]).

Planned administration of GSK’s Herpes Zoster vaccine marketed as Shingrix or an 
adjuvanted recombinant varicella zoster virus envelope gE subunit vaccine [HZ/su] 
within 180 days after the second dose of the study vaccine.


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
Chronic administration (defined as more than 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 
6 months prior to the first vaccine dose. For corticosteroids, this will mean 
prednisone (20 mg/day, or equivalent). Inhaled and topical steroids are allowed.

Administration of long-acting immune-modifying drugs or planned administration at 
any time during the study period (e.g. infliximab).

Administration of immunoglobulins and/or any blood products during the period 
starting 3 months before the first dose of study vaccine or planned administration 
during the study period.
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 (pharmaceutical product or device).
6.2.4.
Other exclusions

History of chronic alcohol consumption and/or drug abuse as deemed by the 
investigator to render the potential subject unable/unlikely to provide accurate safety 
reports.

Body mass index > 40 kg/m².

Planned move to a location that will prohibit participating in the trial until study end.

Bedridden subjects.
6.3.
Criteria for temporary delay for screening 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 screening and vaccination.

Fever is defined as temperature 38.0°C. The preferred location for measuring 
temperature in this study will be the oral cavity.

Subjects with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be screened at the discretion of the investigator, and 
can be administered all vaccines. 
For subjects with acute disease and/or fever at the time of screening/vaccination, the 
visit may be re-scheduled within the allowed time-window.


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6.4.
Screen and baseline failures
Screening failures are defined as subjects who are withdrawn from the study after giving 
informed consent, but who do not meet the inclusion and exclusion criteria.
The following information will be collected for screening failures:

Informed consent.

Inclusion/exclusion criteria.

Demographic data.

Blood samples for hematology and biochemistry.

SAEs related to study participation, or to a concurrent GSK medication/vaccine.

Screening conclusion.


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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 5
Treatments administered
Study Treatment Name:
120 µg RSVPreF3/AS01B
Placebo
Study group
RSV Group
Placebo
Vaccine name
RSVPreF3 high dose *
NaCl
AS01B
Presentation
Freeze-dried antigen (174 µg/vial)
Liquid in monodose vial
Liquid in monodose vial
Vaccine formulation:
RSVPreF3=120µg
NaCl=150mM
MPL=50µg; QS21=50µg; Liposomes
Route of Administration 
IM injection
IM injection

Location
Deltoid
Deltoid

Laterality**
Non-dominant
Non-dominant
Number of doses to be administered:
2
2
Type of contact and timepoint
Visit 1 (Day 1)
Visit 4 (Day 61)
Visit 1 (Day 1)
Visit 4 (Day 61)
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
Hollister-Stier Laboratories
AS01B = Adjuvant System AS01B; MPL = 3-O-desacyl-4’-monophosphoryl lipid A; SPM: Study Procedures Manual,
QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation)
* Corresponding to the highest dose of antigen evaluated in the RSV OA=ADJ 002 dose selection study.
** The non-dominant arm is the preferred arm of injection. In case it is not possible to administer the vaccine in the 
non-dominant arm, an injection in the dominant arm may be performed.
Refer to the Study Procedures Manual (SPM) for detailed instructions on study vaccine
reconstitution.
After completing all prerequisite procedures prior to vaccination, 1 dose of study vaccine 
will be administered IM in the deltoid of the non-dominant arm (refer to Table 5 for 
details regarding the treatment administered). If the investigator or delegator 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 2; Section 6.2). Please refer to Section 12.1.2 (Glossary of Terms) for the 
definition of delegator.
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 and syncope.


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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 each study center.
7.2.2.
Randomization of treatment
7.2.2.1.
Randomization of supplies
The randomization of supplies within blocks will be performed at GSK, using MATerial 
EXcellence (MATEX), a program developed for use in Statistical Analysis System 
(SAS®) (Cary, NC, USA) by GSK. Entire blocks will be shipped to the study centers 
/warehouse(s).
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 enroll approximately 40 eligible subjects who will be randomly 
assigned to 2 study groups in a 1:1 ratio. The aim is to enroll approximately 28 eligible 
participants aged 60-69 years (approximately 14 per group) and approximately 12 (and 
minimum 10) eligible participants aged 70-80 years (approximately 6 per group).
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 
minimization procedure accounting for age, center and gender. Minimization factors will 
have equal weight in the minimization algorithm.
After obtaining the signed and dated Informed Consent Form (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 
age category (60-69 or 70-80 years) and the gender, 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 SPM for specific 
instructions.


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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
During the vaccination phase, data will be collected in an observer-blind manner. By 
observer-blind, it is meant that during the course of the study, the vaccine recipient and 
those responsible for the evaluation of any study endpoint (e.g. safety and reactogenicity) 
will all be unaware of which vaccine was administered. To do so, vaccine preparation and 
administration will be done by authorized medical personnel who will not participate in 
any of the study clinical evaluation assays.
A first statistical analysis will be performed on data available up to one-month post-Dose 
2 (Visit 6, Day 91) (See Section 10.4 for details on the sequence of analyses). Given that 
summary safety results may unblind some specific subjects (e.g. an AE occurring only in 
a single group), anyone having access to this first analysis could become unblinded 
regarding that specific case. Therefore, the follow-up phase (Epoch 003) will be 
considered as single-blind with subjects remaining blinded up to study end (Phone call 2 
[Month 14]). The investigators will not be provided with the individual data listings or 
with the randomization listings until the end of study analysis.
The laboratory in charge of the laboratory testing will be blinded to the treatment, and 
codes will be used to link the subject and study (without any link to the treatment 
attributed to the subject) to each sample.
GSK’s policy (which incorporates ICH E2A guidance, EU Clinical Trial Directive and 
US Federal Regulations) is to unblind the report of any SAE which is unexpected and 
attributable/suspected to be attributable to the study vaccine, prior to regulatory reporting. 
The GSK Central Safety Physician is responsible for unblinding the treatment assignment 
in accordance with the specified timeframes for expedited reporting of SAEs (refer to 
Section 12.5.8.1).


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7.3.1.
Emergency unblinding
Unblinding of a subject’s individual treatment code should occur only in the case of a 
medical emergency when knowledge of the treatment is essential for the clinical 
management or welfare of the subject.
The emergency unblinding process consists of the automated Internet-based system 
(SBIR) that allows the investigator to have unrestricted, immediate and direct access to 
the subject’s individual study treatment.
As back up process, the investigator has the option of contacting a GSK Helpdesk (refer 
to Table 6) if he/she needs support to perform the unblinding (i.e. he/she cannot access 
the automated Internet-based system).
Non-investigator physician (e.g. physician from emergency room) or subject/care 
giver/family member can also request emergency unblinding either via the investigator 
(preferred option) or via the GSK Helpdesk (back up process). Contact details of 
investigator and GSK Helpdesk are reported in the patient/subject card.
Table 6
Contact information for emergency unblinding
GSK Helpdesk
24/24 hour and 7/7 day availability
The Helpdesk is available by phone, fax and email
Phone:
Fax:
email:
A subject may continue in the study if that subject’s treatment assignment is unblinded. 
GSK Vaccines Clinical Safety and Pharmacovigilance (VCSP) staff may unblind the 
treatment assignment for any subject in case of Suspected Unexpected Serious Adverse 
Reaction (SUSAR) as well as in case of fatal or life-threatening cases. If the SAE 
requires that an expedited regulatory report be sent to 1 or more regulatory agencies, a 
copy of the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
PPD
PPD
PPD


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7.4.
Handling, storage and replacement of study vaccine
The candidate vaccine to be used has been developed and manufactured by GSK. 
The Quality Control Standards and Requirements for the candidate vaccine are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained. 
The vaccines are labelled and packed according to applicable regulatory requirements.
For information on dosage and administration of the study vaccine, refer to Table 5.
Administration will occur on Visit 1 (Day 1) and Visit 4 (Day 61).
7.4.1.
Storage and handling of study vaccine
The study vaccine 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. 
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 
vaccine(s)/product(s) 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 vaccine(s)/product(s) 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, storage and 
accountability of the study vaccine.
7.4.2.
Replacement of unusable vaccine doses
In addition to the vaccine doses provided for the planned number of subjects (including 
over-randomization when applicable), at least 10% additional vaccine doses will be 
supplied to replace those that are unusable. 
The investigator will use SBIR to obtain the replacement vial number. The replacement 
numbers will be allocated by dose. The system will ensure, in a blinded manner, that the 
replacement vial matches the formulation the subject was assigned to by randomization.


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7.5.
Concomitant medications/products and concomitant 
vaccinations
7.5.1.
Recording of concomitant medications/products and 
concomitant vaccinations
At each study contact, the investigator or delegator should question the subject about any 
medications/products taken and vaccinations received by the subject.
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF:

All concomitant medications/products, except vitamins and dietary supplements, 
administered during the period of 30 days post-vaccination (Day 1 to Day 30 and 
Day 61 to Day 90).

Any concomitant vaccination administered in the period starting from the first dose 
of study vaccine and ending at the last study visit (Day 1 to Month 14).

Prophylactic medication (i.e. medication administered in the absence of ANY 
symptom and in anticipation of a reaction to the vaccination).
E.g. an anti-pyretic is considered to be prophylactic when it is given in the absence 
of fever and any other symptom, to prevent fever from occurring (fever is defined as 
temperature 38.0°C regardless the location of measurement). The preferred 
location for measuring temperature in this study will be the oral cavity. 

Any concomitant medications/products/vaccines listed in Section 7.5.2

Any concomitant medications/products/vaccines relevant to an SAE/pIMD to be 
reported as per protocol or administered at any time during the study period for the 
treatment of an SAE/pIMD. In addition, concomitant medications relevant to SAEs
and pIMDs need to be recorded on the expedited Adverse Event report.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.5.2.
Concomitant medications/products/vaccines that may lead to the 
elimination of a subject from per-protocol analyses
The use of the following concomitant medications/products/vaccines will not require 
withdrawal of the subject from the study but may determine a subject’s evaluability in the 
per-protocol analysis. See Section 10.2 for populations to be analyzed.

Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period (up to Month 14).

Immunosuppressants or other immune-modifying drugs administered chronically 
(i.e., more than 14 consecutive days in total) during the study period (up to Month 
14). For corticosteroids, this will mean prednisone 20 mg/day, or equivalent. 
Inhaled and topical steroids are allowed.


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
Long-acting immune-modifying drugs administered at any time during the study 
period (e.g. infliximab).

A vaccine not foreseen by the study protocol administered during the period starting 
30 days before the first dose and ending 30 days after the last vaccine dose*, except 
for inactivated and subunit influenza vaccines which can be administered up to 14 
days before or from 30 days after each vaccination.
*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.

Immunoglobulins and/or any blood products administered during the study period 
(up to Month 14).
7.6.
Intercurrent medical conditions that may lead to elimination 
of a subject from per-protocol analyses
At each study visit subsequent to the first vaccination, it must be verified if the subject 
has experienced or is experiencing any intercurrent medical condition that may lead to 
elimination from per protocol analysis (refer to Section 12.1.2 (Glossary of Terms) for 
the definition of intercurrent medical condition). If it is the case, the condition(s) must be 
recorded in the AE section of the eCRF. Intercurrent medical conditions will not be 
collected during the follow-up phase.
At the time of analysis, subjects may be eliminated from the per-protocol cohort for 
immunogenicity if, during the study, they incur a condition that has the capability of 
altering their immune response or are confirmed to have an alteration of their initial 
immune status.
7.7.
Contraindications to subsequent vaccine administration
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 criteria or the criteria listed below, they 
should not receive additional vaccinations. However, the subjects should be encouraged 
to continue other study procedures at the discretion of the investigator (Section 9.2).

Anaphylaxis following the administration of vaccine(s).

Hepatomegaly, right upper quadrant abdominal pain or tenderness.


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
Decreased renal function since baseline, as defined by an increase in blood urea 
nitrogen or creatinine levels from values within normal range at pre-vaccination to 
Grade 2 abnormalities (based on the testing laboratory parameters) at 7 days post-
vaccination.

Any confirmed or suspected immunosuppressive or immunodeficient condition, 
including human immunodeficiency virus (HIV) infection. 

Any condition that in the judgment of the investigator would make IM injection 
unsafe.

An SAE judged to be vaccine-related by the investigator.

Hematology parameters (complete blood cell count [red blood cells, white blood 
cells], white blood cells differential count [lymphocytes, neutrophils and 
eosinophils], platelets count or hemoglobin level) and/or biochemistry parameters 
(creatinine, blood urea nitrogen or liver enzymes [ALT or AST]) outside the normal 
laboratory ranges that persist after the administration of a previous study vaccine, 
unless the laboratory abnormalities are considered not clinically significant by the 
investigator.

Occurrence of a new pIMD or the exacerbation of an existing pIMD that, in the 
opinion of the investigator, may expose the subject to unacceptable risk from 
subsequent vaccination. In such cases, the investigator should use his/her clinical 
judgement prior to administering the next dose of the vaccine. Refer to Section 
12.5.5.1 for the definition of pIMDs.

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.
The following events constitute contraindications to administration of the investigational 
RSV vaccine at that point in time; if any of these events occur at the time scheduled for 
vaccination, the subject may be vaccinated at a later date, within the time window 
specified in the protocol (see Table 2 in Section 2), or the subject may be withdrawn at 
the discretion of the investigator (see Section 9.2).

Acute disease and/or fever at the time of vaccination. 

Fever is defined as temperature 38.0°C. The preferred location for measuring 
temperature in this study will be the oral cavity.

Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory 
infection) without fever can be administered all vaccines.


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8.
STUDY ASSESSMENTS AND PROCEDURES
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.
Adherence to the study design requirements, including those specified in the SoA 
(Section 2), 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 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.
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.
A schedule of activities is provided in Table 1. Time intervals between visits related to 
study procedures performed on subjects participating in the study are presented in Table 
2.
All participants will be closely observed for a minimum of 60 minutes after each 
vaccination.
Refer to Section 8.7 for information about the study holding rules, safety monitoring and 
safety evaluation by the iSRC.
8.1.1.
Informed consent
The signed informed consent of the subject must be obtained before study participation. 
In addition, the signed informed consent of the designee must be obtained, in case a 
designee is assigned by the subject. Refer to Section 12.4.3 for the requirements on how 
to obtain informed consent. Please refer to Section 12.1.2 (Glossary of Terms) for the 
definition of designee.


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8.2.
Screening procedures to check subject eligibility
8.2.1.
Check inclusion and exclusion criteria
When all data from the Screening Visit are available, the investigator will confirm strict 
adherence to all inclusion/exclusion criteria to ensure subjects are qualified for enrolment 
into the study, as described in Sections 6.1 and 6.2. 
8.2.2.
Collect demographic data, medical history, vaccination history 
and perform physical examination
The investigator will obtain the following information at the Screening Visit to confirm 
subject eligibility before enrolment: demographic data (such as age, gender, race and 
ethnicity), medical history and vaccination history. The investigator will also perform a 
physical examination of the subject, including assessment of oral body temperature and 
resting vital signs: systolic/diastolic blood pressure, pulse oximetry, heart rate and 
respiratory rate after at least 10 minutes of rest.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider.
These procedures at the Screening Visit do not need to be recorded into the eCRF.
8.2.3.
Blood sampling for eligibility assessment
At the Screening Visit, a blood sample for eligibility assessment will be drawn from all 
subjects.
In case Visit 1 occurs more than 30 days after the Screening Visit, a re-screening visit 
should be scheduled before Visit 1 during which blood sample collection must be 
repeated (maximum one re-screening per subject is allowed). Medical history, physical 
examination and review of inclusion/exclusion criteria must be repeated if a re-screening 
visit occurs. Only data from the re-screening visit, if it occurs, will be taken into 
consideration and recorded in the eCRF. The subject can however only be randomized 
once the investigator receives the safety assessment results and confirms the eligibility 
criteria.
8.2.4.
Screening conclusion
Complete the Screening Conclusion screen in the eCRF, including the reason for 
screening failure, if applicable.


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8.3.
Pre-vaccination procedures
8.3.1.
Check inclusion and exclusion criteria
Before randomization, the investigator should confirm strict adherence to all 
inclusion/exclusion criteria to ensure subjects are still qualified as described in Sections 
6.1 and 6.2. This does not need to be recorded in the subject’s eCRF.
8.3.2.
Collection of demographic data
Record demographic data such as age, gender, race and ethnicity in the subject’s eCRF.
8.3.3.
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.
8.3.4.
Vaccination history
Obtain the subject’s vaccination history by interview and/or review the subject’s 
vaccination records prior to the first study vaccination. Any vaccination administered up 
to 5 years before administration of the first dose of study vaccine should be recorded in 
the eCRF.
8.3.5.
Physical examination
Perform a physical examination of the subject, including assessment of resting vital 
signs: systolic/diastolic blood pressure, pulse oximetry, heart rate and respiratory rate 
after at least 10 minutes of rest (to be recorded in the eCRF at Visit 1 and at the 
Assessment visit for potential RSV-RTI).
Physical examination at each study visit subsequent to the first vaccination visit will be 
performed only if the subject indicates during questioning that there might be some 
underlying pathology(ies) or if deemed necessary by the investigator.
If the investigator determines that the subject’s health on the day of vaccination 
temporarily precludes vaccination, the visit will be rescheduled.
Treatment of any abnormality observed during physical examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
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In addition, during the assessment visit for potential RSV-RTI, the investigator/study 
staff will evaluate the clinical signs and symptoms of the RTI and measure the subject’s 
resting vital signs (systolic/diastolic blood pressure, pulse oximetry, heart rate, 
respiratory rate after at least 10 minutes of rest) and temperature (refer to Section 8.6.3
for the list of symptoms to be recorded).
8.3.6.
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. 
8.3.7.
Pre-vaccination body temperature
The body temperature of each subjects needs to be measured prior to any study vaccine 
administration and recorded in the eCRF. The preferred location for measuring 
temperature in this study will be the oral cavity. If the subject has fever (fever is defined 
as temperature 38.0°C regardless the location of measurement) on the day of 
vaccination, the vaccination visit will be rescheduled within the allowed interval for this 
visit (see Table 2).
8.3.8.
Study group and treatment number allocation
Study group and treatment number allocation will be performed as described in Section
7.2.2. The number of each administered treatment must be recorded in the eCRF.
8.3.9.
Study vaccine administration
After completing all prerequisite procedures prior to vaccination, one dose of study 
vaccine will be administered IM in the deltoid of the non-dominant arm. If the 
investigator or delegator 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 2).
All 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.
8.3.10.
Check and record concomitant medication/vaccination and 
intercurrent medical conditions 
Concomitant medication/vaccination must be checked and recorded in the eCRF as 
described in Section 7.5.
Intercurrent medical conditions must be checked (up to Visit 6) and recorded in the eCRF 
as described in Section 7.6.


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8.3.11.
Distribution of eDiary devices
eDiary devices will be distributed at Visit 1 (Day 1). At this timepoint, the subjects or 
designees will be instructed on the use of the eDiaries for the capture of solicited AEs (re-
instructions will be provided at Visit 4). Refer to Section 12.5.7 for details regarding the 
completion of the eDiary devices. The devices need to be returned at Visit 6 (Day 91).
8.3.12.
Distribution of paper diary cards
Paper diary cards will be distributed at each vaccination visit for the subjects to note 
down any unsolicited symptom (i.e., any symptom not reported as solicited in the eDiary) 
they may have experienced as well as any medication taken in the 30-day period 
following each vaccination. Refer to Section 12.5.4 for guidelines.
8.3.13.
Recording of AEs and SAEs
Solicited AEs will be recorded by the subjects or their designee in the eDiaries.
Non-serious unsolicited AEs will be recorded by the investigator in the Non-Serious 
Adverse Event section of the eCRF.
Any serious adverse event (SAE), (solicited or unsolicited) will be recorded by the 
investigator in the Expedited Adverse Event report in the eCRF.
Refer to Section 12.5.7 for the detailed procedures for the investigator to record AEs and 
SAEs. Refer to Section 12.5.8 for guidelines and how to report SAE reports to GSK.
8.3.14.
Recording of potential immune-mediated diseases (pIMDs)
pIMDs will be recorded by the investigator in the Expedited Adverse Event report in the 
eCRF.
Refer to Section 12.5.5.1 for the detailed procedures for the investigator to record pIMDs. 
Refer to Section 12.5.8.4 for guidelines and how to report pIMD reports to GSK.
8.3.15.
Study conclusion
The investigator will:

Review data collected to ensure accuracy and completeness.

Complete the Study Conclusion screen in the eCRF.


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8.4.
Efficacy assessments
Please refer to the SPM 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 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 
Japan 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.
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). 
If additional testing is performed, the marker priority ranking given in Section 8.4.4 may 
be changed.
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.
8.4.1.
Use of specified study materials
When materials are provided by GSK, 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 comply with this requirement. However, when GSK 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.


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8.4.2.
Biological samples
Refer to the Module on Biospecimen Management in the SPM for detailed instructions 
for the collection, handling and processing of the samples.
Table 7
Biological samples
Sample type
Timepoint
Subset
Quantity
Unit
Blood for humoral immune response
Visit 1 (Pre-Vacc)
Visit 3 (PI D31)
Visit 4 (PI D61)
Visit 6 (PII D91)
All enrolled subjects
10
ml
Blood for hematology/biochemistry
Screening Visit (Pre-Day 1)
All screened subjects
5.5
ml
Visit 1 (Pre-Vacc)
Visit 2 (PI D8)
Visit 4 (PI D61)
Visit 5 (PII D68)
All enrolled subjects
Nasal swab specimen collected by 
subject at home
Assessment visit for 
potential RSV-RTI
Event-driven
-
-
Combined nasal and throat swab
specimen collected by qualified staff
Assessment visit for 
potential RSV-RTI
Event-driven
-
-
Total quantity of blood for each subject
67.5
mL
8.4.2.1.
Blood sampling for safety or immunogenicity response assessments 
Blood samples will be taken during certain study visits as specified in Section 2. Refer to 
the SPM for more details. Blood sampling at vaccination visits needs to be performed 
before vaccination.

A total volume of approximately 5.5 mL of blood should be drawn from all subjects 
for hematology and biochemistry analysis at each pre-defined time point. After 
centrifugation, serum samples should be kept at room temperature (20 to 25°C) until 
shipment. 

A volume of approximately 10 mL of whole blood (to provide 3.3 mL of serum)
should be drawn from all subjects for analysis of the humoral immune response at 
each pre-defined time point. After centrifugation, serum samples should be kept 
at -20°C or below until shipment. 

The overall volume of blood that will be collected from each subject during the 
entire duration of the study is approximately 67.5 mL. 
8.4.2.2.
Other biological samples
During the assessment visit for potential RSV-RTI, one swab will be collected from both 
nostrils of each subject and another swab will be collected from the throat. Both swabs 
will be placed together in one M4RT medium tube and sent for testing. Refer to the SPM 
for more details about nasal and throat swab sampling.
In case of RTI symptoms (at least 3) reported by the subject, the subject will be asked to 
collect a nasal swab from both nostrils at home within 48 hours after the start of 
symptoms.


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8.4.3.
Laboratory assays
Please refer to Section 12.2 (Appendix 2) for a detailed description of the assays 
performed in the study. Please refer to Section 12.3 (Appendix 3) for the address of the 
clinical laboratories used for sample analysis.
RSV humoral immune responses
Serological assays for the determination of functional antibodies against RSV-A and B 
will be performed by neutralization assays. Further characterization of the humoral 
immune response will be performed by use of enzyme-linked immunosorbent assays 
(ELISAs), including measurement of IgG antibodies binding to the RSVPreF3 protein 
(see Table 8). 
The assays will be performed at a GSK’s laboratory or in a laboratory designated by 
GSK. 
Table 8
Humoral immunity (antibody determination)
System
Component
Method
Kit / 
Manufacturer
Unit
Cut-
off$
Laboratory**
SERUM
Respiratory 
Syncytial Virus A Ab
NEUTRALIZATION
In-house
ED60
18
GSK* or 
NÉOMED-LABS
SERUM
Respiratory 
Syncytial Virus B Ab
NEUTRALIZATION
In-house
ED60
TBD
GSK* or 
NÉOMED-LABS
Serum
RSVPreF3-specific 
IgG antibody 
concentrations
ELISA
In house at 
Neomed Labs
ELU/mL
TBD
NÉOMED-LABS
Ab: antibody; ELISA: enzyme-linked immunosorbent assay; RSV: respiratory syncytial virus; 
ED60: Estimated Dose: serum dilution giving a 60% reduction of the signal compared to a control without serum
TBD: to be determined
*GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium; Marburg, 
Germany.
**Refer to Section 12.3 (Appendix 3) for the laboratory addresses.
$ Assay cut-offs could be subject to change and will be defined in the Statistical Analysis Plan.


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Hematology and biochemistry
Hematology and biochemistry assays for safety assessment will be performed in a central
laboratory (see Table 9). 
Table 9
Hematology/biochemistry
System
Discipline
Component
Method
Scale**
Laboratory***
Whole 
blood
Hematology
Leukocytes (White Blood Cells)
As per central 
laboratory 
procedure
Quantitative
Q2 Solutions
Neutrophils*
Lymphocytes*
Basophils*
Monocytes*
Eosinophils*
Hemoglobin
Platelets
Erythrocytes (Red Blood Cells)
Serum
Biochemistry
Alanine Aminotransferase (ALT)
Aspartate Aminotransferase (AST)
Creatinine
Blood Urea Nitrogen (BUN)
Uric Acid
*For White Blood Cell (WBC) differential count.
**Grading of laboratory parameters will be based on the Food and Drug Administration (FDA) Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
(refer to Section 12.7, Appendix 7). Basophils, monocytes, erythrocytes and uric acid are not included in the FDA 
Toxicity Grading Scale and will not be graded.
***Refer to Section 12.3 (Appendix 3) for the laboratory addresses.
RSV molecular biology
For identified RTI cases under active or passive surveillance, the potential RSV infection 
will be assessed by quantitative reverse transcription PCR (qRT-PCR) testing of swabs
(see Table 10). 
Table 10
Molecular biology (qRT-PCR tests)
Component
Kit / Manufacturer
Method
Unit
Laboratory**
System: Self-collected nasal swab, and combined nasal and throat swab specimen
Respiratory Syncytial Virus A RNA
Respiratory Syncytial Virus B RNA
In-house
Quantitative
RT-PCR
Copies/mL
GSK * or 
designated 
laboratory
Quantitative RT-PCR: quantitative reverse transcription polymerase chain reaction; RSV: respiratory syncytial virus
* GSK laboratory refers to the CLS in Rixensart, Belgium; Wavre, Belgium; Marburg, Germany.
**Refer to Section 12.3 (Appendix 3) for the laboratory addresses.


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Additional testing on blood or swab samples
Additional testing on serum to characterize the immune response to RSV/to the 
investigational RSV vaccine/vaccine components may be performed if deemed necessary 
for accurate interpretation of the data and/or should such test(s) become available in the 
GSK’s laboratory or a laboratory designated by GSK. 
Additional viral/bacterial diagnosis testing on the swabs, such as (but not limited to) 
multiplex PCR, sequencing and/or high-throughput sequencing, may be done, if deemed 
necessary for accurate interpretation of the data and/or should such assays become 
available at GSK’s laboratory or a laboratory designated by GSK.
Additional testing may include, but is not limited to, the following:

Further characterization of the pathogens detected in the swabs (e.g. genotyping, 
strain identification).

Further characterization of the immune response directed against different epitopes 
of RSV F proteins. 

Further characterization of the immune response by evaluation of cross-reactive 
neutralizing antibodies to human metapneumovirus (hMPV).

Characterization of the impact of vaccination on possible new immunological 
markers for protection (e.g. antibody affinity/avidity, ADCC).

Host transcriptome signature: evaluation of mRNA and/or microRNA signatures by 
microarray and/or RNA sequencing.

Translational research using next generation technologies.
Additional testing on the vaccine formulation 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 clinical laboratories have established a Quality System supported by 
procedures. The activities of GSK clinical laboratories are audited regularly for quality 
assessment by an internal (sponsor-dependent) but laboratory-independent Quality 
Department.
8.4.4.
Biological samples evaluation
For blood sample collection, the following ranking applies:
1.
Sample for hematology/biochemistry testing 
2.
Sample for humoral immune responses


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8.4.4.1.
Immunological read-outs
Testing of RSV-A neutralizing antibodies and RSVPreF3 IgG antibodies will be 
performed on blood samples from all subjects.
In case of insufficient blood sample volume to perform assays for all immunological 
read-out components, the samples will be analyzed according to priority ranking provided 
in Table 11. 
Table 11
Immunological read-outs
Blood sampling time point*
Sub-cohort
No. 
subjects
Component
Components 
priority rank 
Type of contact 
and time point
Sampling time 
point
Humoral immunity (on serum samples)
Visit 1 (Day 1)
Pre-Day 1
All subjects
40
RSV-A neutralizing antibody
1
Anti-RSVPreF3-specific IgG antibody
2
RSV-B neutralizing antibody
3
Visit 3 (Day 31)
PI D31
All subjects
40
RSV-A neutralizing antibody
1
Anti-RSVPreF3-specific IgG antibody
2
Visit 4 (Day 61)
PI D61
All subjects
40
RSV-A neutralizing antibody
1
Anti-RSVPreF3-specific IgG antibody
2
Visit 6 (Day 91)
PII D91
All subjects
40
RSV-A neutralizing antibody
1
Anti-RSVPreF3-specific IgG antibody
2
RSV-B neutralizing antibody
3
Pre-Vacc: Pre-vaccination; PI DX= Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X
8.4.4.2.
Hematology/blood chemistry 
Table 12
Hematology and biochemistry read-outs 
Blood sampling time point
Sub-cohort
No. 
subjects
Component
Type of contact and 
time point
Sampling 
time point
Screening Visit * 
Pre-Day 1
All 
screened 
subjects
40
Hematology: leukocytes, neutrophils, lymphocytes, 
basophils, monocytes, eosinophils, hemoglobin, 
platelets, erythrocytes
Biochemistry: ALT, AST, creatinine, BUN, uric acid
Visit 1 (Day 1)
Visit 2 (Day 8 )
Visit 4 (Day 61)
Visit 5 (Day 68)
Pre-Vacc
PI D8
PI D61
PII D68
All enrolled 
subjects
40
Pre-Vacc: Pre-vaccination; PI DX: Post-Dose 1 Study Day X; PII DX: Post-Dose 2 Study Day X
ALT = Alanine Aminotransferase; AST = Aspartate Aminotransferase; BUN = Blood Urea Nitrogen
* In case Visit 1 occurs more than 30 days after the Screening Visit, a re-screening visit should be scheduled before 
Visit 1 during which blood sample collection for safety laboratory assessment must be repeated (maximum one re-
screening per subject is allowed). Only laboratory results from the re-screening visit, if it occurs, will be taken into 
consideration and recorded in the eCRF. Medical history, physical examination and review of inclusion/exclusion 
criteria must be repeated if a re-screening visit occurs. The subject can only be randomized once the investigator 
receives the results and confirms the eligibility criteria.


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8.4.4.3.
Molecular biology
Table 13
Molecular biology tests on combined nasal and throat swab 
specimen
Sampling time point
Sub-cohort
No. subjects
Component
Type of contact (time point)
Sampling time point
Sampling of nasal swab by subject 
at home
Assessment visit for potential RSV-
RTI
Unscheduled
Event-driven* Event-driven*
RSV-A/B RNA
* RSV-A/B quantitative RT-PCR (RSV-A/B RNA) will be performed on all specimen.
8.4.5.
Immunological correlates of protection
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigen used in the investigational RSV vaccine.
8.5.
Safety Assessments
The investigator and any delegators are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE, SAE or pIMD. After the initial report 
of AE, SAE or pIMD (serious or non-serious), the investigator is required to proactively 
follow each subject at subsequent visits/contacts. All SAEs or pIMDs (serious or non-
serious) will be followed until the event is resolved, stabilized, otherwise explained, or 
the subject is lost to follow-up.
8.5.1.
Safety definitions
Please refer to Section 12.5 for safety definitions.
8.5.2.
Time period and frequency for collecting AE, serious adverse 
event (SAE), and pIMD information
An overview of the protocol-required reporting periods for AEs, SAEs and pIMDs is 
given in Table 14. Refer to the Section 12.5.7.1 for details on the time period for 
recording safety information.


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Table 14
Reporting periods for collecting safety information
Event
SCR
Visit 1
Visit 2
Visit 3
Visit 4 Visit 5
Visit 6 Phone call 1Phone call 2
Pre-D1*
Vacc 1
Vacc 2
Study 
Conclusion
Solicited local and 
general AEs
Days 1-7
Days 61-67
Unsolicited AEs
Days 1-30
Days 61-90
AEs/SAEs leading 
to withdrawal from 
the study
Day 1 - Month 14
SAEs 
Day 1 - Month 14
SAEs related to 
study participation 
or concurrent GSK 
medication/vaccine 
Pre-Day 1* - Month 14
pIMDs 
Day 1 - Month 14
Intercurrent 
medical conditions
Day 1 - Day 91
* i.e., consent obtained. 
Pre-D1: Pre-vaccination Day 1; Vacc: Vaccination
SCR: Screening Visit
All SAEs will be recorded and reported via Expedited AE Reporting Form to the sponsor 
or its delegator immediately and under no circumstance should this exceed 24 hours after 
the investigator became aware of it, as indicated in Section 12.5.8. 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 14. 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.
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 12.5.7 and 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 subjects is the preferred method to inquire about 
AE occurrence. 


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8.5.4.
Reporting of serious adverse events 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 15, once the investigator determines that 
the event meets the protocol definition of an SAE.
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 15, once the investigator determines that 
the event meets the protocol definition of a pIMD.
Table 15
Timeframes for submitting serious adverse event, and other events 
reports to GSK
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
pIMDs
24 hours** ‡
electronic Expedited 
Adverse Events Report
24 hours*
electronic Expedited Adverse 
Events Report
* Timeframe allowed after receipt or awareness of the information.
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD.
‡ The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box in the electronic 
Expedited Adverse Events Report within 72 hours of submission of the SAE or pIMD.
8.5.4.1.
Contact information for reporting of serious adverse events (SAEs), 
pIMDs and study holding rules
Table 16
Contact information for reporting of serious adverse events (SAEs), 
pIMDs and study holding rules
Study contact for questions regarding SAEs and pIMDs
Refer to the local study contact information document.
Study Contact for Reporting of study holding rules 
As soon as the investigator is aware that a holding rule is met, he/she must immediately inform the Local Medical 
Lead (LML). 
Back-up Study Contact for Reporting SAEs and pIMDs
24/24 hour and 7/7 day availability:
GSK Clinical Safety & Pharmacovigilance
Outside US & Canada sites:
Fax: 
 or 
Email address: 
PPD
PPD
PPD


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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 an 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 report of AE, SAE or pIMD (serious or non-serious), the investigator is 
required to proactively follow each subject at subsequent visits/contacts. All SAEs or 
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 12.5.10.
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 an SAE or 
pIMD should be recorded in Expedited Adverse Event Report of the subject’s eCRF 
(refer to Section 7.5).
8.5.7.
Clinical safety laboratory assessments
Refer to Section 12.2 (Appendix 2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 2) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with an 
underlying disease, unless judged by the investigator to be more severe than 
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
All laboratory tests with values considered clinically significant abnormal during 
participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. Refer to 
the Section 12.5.6 for clinical laboratory abnormal assessments qualified as AEs or 
SAEs.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
All protocol-required laboratory safety assessments, as defined in Section 12.2 (Appendix 
2), must be conducted in accordance with the laboratory manual and the SoA (Section 2).
8.5.8.
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 delegator) 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.
8.5.9.
Safety follow-up calls
At the Month 8 and Month 14 telephone contacts, subjects will be queried in accordance 
with a template script provided separately by GSK. The subjects will be queried about 
concomitant medications and the occurrence of pIMDs, SAEs, concurrent vaccination, 
SAEs related to study participation or to a concurrent GSK medication/vaccine, and AEs 
or SAEs leading to withdrawal. Information collected will be documented in the source 
document and will be recorded in the eCRF.


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8.6.
RTI Surveillance
RTI surveillance comprises active and passive surveillance. Both active and passive 
surveillance will only be carried out during the RSV seasons (from August until end of 
February), as based on local data. According to a surveillance study assessing the 
seasonality in 19 different countries, the RSV season from 2010 to 2017 in Japan 
specifically was found to start between late July and early November and continue 
through February with a peak seen between early October to early December. 
Information regarding the regional variability was not available [Obando-Pacheco, 2018]. 
These findings are similar to that reported by the Infectious Agents Surveillance Report 
(IASR) in their weekly report detecting RSV from 2007 onward in Japan [IASR, 2014] 
with a seasonality which approximates that of North America [Saijo, 1994]. In most 
recent seasons, RSV epidemics have been observed as beginning earlier, accompanied 
with a rapid increase in the number of reports since early July, 2018 [IDWR, 2018].
8.6.1.
Active surveillance
During the RSV seasons, study participants will be contacted by the investigator/study 
staff every 2 weeks to identify if they experience RTI symptoms (i.e., cough, runny nose, 
fever [37.5°C] or difficulty to breathe). A template script will be provided separately by 
GSK.
In case of RTI symptoms (at least 3; see Section 8.6.3) reported by the subject, the 
subject will be asked to collect a nasal swab at home ideally within 48 hours after the 
start of symptoms. An assessment visit for nasal and throat swab specimen collection by 
qualified staff from the study team will be scheduled. The assessment visit should take 
place as soon as possible after the start of symptoms (ideally within 48 hours, but no later 
than 7 days). Episodes should be treated accordingly to local standard of care.
In the event that it is not possible to schedule an assessment visit, the assessment visit 
page of the eCRF should be filled in as completely as possible using available medical 
records.
8.6.2.
Passive surveillance
Study participants will be instructed to contact the investigator/study staff in case of RTI 
symptoms during the RSV seasons (e.g., cough, runny nose, fever [37.5°C] or difficulty 
to breathe). 
In case of RTI symptoms (at least 3) reported by the subject, the subject will be asked to 
collect a nasal swab at home within 48 hours after the start of symptoms and contact the 
investigator/study staff, who will schedule an assessment visit for nasal and throat swab 
specimen collection by qualified staff from the study team. The assessment visit should 
take place as soon as possible after the start of symptoms (ideally within 48 hours, but no 
later than 7 days). Episodes should be treated according to local standard of care.


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In the event that it is not possible to schedule an assessment visit, the assessment visit 
page of the eCRF should be filled in as completely as possible using available medical 
records.
8.6.3.
Assessment Visit for potential RSV-RTI
The purpose of the Assessment Visit for potential RSV-RTI is to objectively document 
signs and symptoms (e.g., cough, runny nose, fever [37.5°C] or difficulty to breathe) by 
an appropriately qualified person (i.e., medical or nursing) and to take nasal and throat 
swabs for detection of RSV infection. The visit should take place as soon as possible after 
the start of symptoms (ideally within 48 hours, but no later than 7 days). 

Assessment visits may take place in the study participant’s home, the investigator’s 
clinical facility or a medical facility as appropriate to the circumstances in the 
judgment of the investigator.

If the reported symptoms are already of a level of severity that urgent care is 
indicated, the study participant should be redirected to the proper location to receive 
this care (e.g. Emergency Room) and an assessment visit could be scheduled to take 
place there at a suitable time. 

For self-collection as well as staff-collection, swabs for analysis at sponsor 
laboratory should be collected when subjects show at least 3 of the following 
signs/symptoms:

Nasal congestion,

Sore throat,

Earache,

New or worsening cough,

New or worsening sputum,

Dyspnea,

Rhinorrhea,

Wheezing (whistling, musical or puffing sound made on exhalation) or 
worsening of wheezing,

Rales (crackles),

Rhonchi (sound with musical pitch during inspiration or expiration),

Fever (temperature of 37.5°C) or feeling feverish. 


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
During the assessment visit, the investigator/study staff will evaluate the clinical 
signs and symptoms of the RTI and measure the subject’s resting vital signs 
(systolic/diastolic blood pressure, pulse oximetry, heart rate, respiratory rate after at 
least 10 minutes of rest) and temperature. RTI symptoms include, but may not be 
limited to, the following:

Upper respiratory symptoms: nasal congestion, sore throat, rhinorrhea, 
earache.

Lower respiratory symptoms: new or worsening cough, new or worsening of 
sputum production, dyspnea, wheezing or worsening of wheezing, rales 
(crackles), rhonchi.

Systemic symptoms: myalgia, arthralgia, fatigue, headache, decreased appetite, 
feverishness, pain (localized at chest or abdomen at respiration).
Signs and symptoms, resting vital signs, temperature and onset date of first symptom 
should be recorded within the RTI episode screen in the eCRF.

Following the assessment visit, study participants will be instructed to contact the 
study staff if the severity of the already existing symptoms increases or if they 
develop difficulty in breathing or wheezing, and this may lead to a repeat assessment 
visit upon the judgment of the investigator.

The status and evolution of the case will be followed until case resolution, as per 
routine practice.

RTI data will be entered in the eCRF:

A new episode number and section will be created in the eCRF for each RTI 
episode.

All data pertaining to a same episode (including date of onset and end date) will 
be entered under the same eCRF episode number, even if observations are 
consolidated from several visits or contacts.
8.7.
Holding rules and safety monitoring
An iSRC will be appointed and operating under a charter, in addition to the existing 
project’s Safety Review Team. Safety holding rules have been defined (Table 17, Table 
18). The iSRC will review the protocol and Statistical Analysis Plan (SAP). Meetings 
will be documented and in case open sessions are held at the iSRC meetings, the minutes 
from these open sessions will be made available to the study team. The iSRC may, if 
deemed necessary, convene a meeting with, or request further information from GSK’s 
designated project representatives at any stage of the study.
The iSRC will conduct unblinded reviews of all available safety data (as clean as 
possible) from the present study, while taking into account any other findings that could 
have an impact on the safety of the subjects, and will determine whether there is a safety 
signal that needs to be escalated to the sponsor. 


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Other GSK studies evaluating the same antigen in the RSV older adults or RSV maternal 
program may be running at a time that can overlap with the conduct of this study. Any 
relevant safety information from these other GSK studies with the same antigen will be 
shared with the iSRC of the Japan study; the holding rules of these other studies might 
also impact the Japan study, and vice versa.
Overview of safety monitoring:

All participants will be closely observed for a minimum of 60 minutes after each 
vaccination.

All available data from the participants vaccinated with the first dose will be 
reviewed in a first iSRC meeting. This iSRC will perform a safety evaluation of all 
available data collected up to 7 days post-Dose 1. Holding rules described in Table 
18 will apply. 

If the outcome of the first iSRC evaluation is favorable, participants will receive the 
second dose.

A second iSRC meeting will review all available safety data up to 30 days post-Dose 
2. 

During the follow-up phase, 2 iSRC meetings will be planned with an interval of 
approximately 6 months. For the last of these iSRC evaluations, the end-of-study 
Clinical Study Report will be provided to the iSRC for review.  

If any safety concern is identified by the investigator (i.e., meeting of holding rules 
1a-1c see Table 17] or any other safety concern), he/she should hold vaccination 
and inform GSK immediately (within 24 hours). GSK will confirm the hold of the 
vaccination and call for an ad-hoc iSRC if needed.
8.7.1.
Outcome of safety evaluation

If no safety signal is observed, the favorable outcome of the safety evaluations will 
be documented and provided in writing, authorizing the investigator to start 
vaccination of subjects with the subsequent dose.

If a safety signal is observed during the safety evaluations or if any of the holding 
rules 2a-d is met, the iSRC Chair (or his/her representative) is responsible for the 
urgent communication to GSK, including the rationale for the decision to put the 
vaccination on hold or not. 

The study Clinical Research and Development Lead (CRDL) will be accountable for 
notifying all investigators of the decision whether to suspend, modify or continue the 
conduct of the study. 
Refer to Section 8.7.2 for an overview of the communication flow in case a holding rule 
is met, as identified by the Investigator or iSRC.


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8.7.1.1.
Process of stopping the vaccination
In the event that a safety signal is observed, the sponsor might decide to cancel 
vaccination.
In this case:

Subjects who were already vaccinated will not receive the second study vaccine dose 
(if not yet administered) and continue all other visits as planned.

Subjects who signed an informed consent but did not receive any study vaccine will 
be informed that their study participation will be stopped.
8.7.2.
Study holding rules
The safety holding rules are defined in Table 17 and Table 18. 
Holding rules 1a-1c from Table 17 will be assessed by the investigator on a continuous 
basis and meeting any of these holding rules will trigger a hold of vaccination, 
irrespective of the number of subjects enrolled and/or timing of the event relative to 
vaccination. The safety holding rules 2a – 2d from Table 18 will be assessed by iSRC 
during the first safety evaluation on unblinded data. These holding rules have been 
written under the assumption that the safety data from all subjects will be available. If the 
data from all subjects are not available (i.e. in case a subject is lost to follow-up), then the 
holding rules will be assessed by the iSRC on a pro-rata basis. 
Of note, no formal holding rules will be applied for other safety data such as non-life-
threatening SAEs that cannot reasonably be attributed to the study vaccination (non-life-
threatening non-related SAEs), missed visits due to vaccine-related AEs, Grade 1 and 
Grade 2 solicited, unsolicited AEs in the 7-day follow-up period, unsolicited AEs 
collected from Day 8 to Day 30 after vaccination. However, these data, if available, will 
also be reviewed by the iSRC in order to allow for an overall assessment of the benefit/ 
risk ratio of vaccination.
Table 17
Study holding rules identifiable by the investigator
Holding 
Rule
Event
Number of 
subjects
1a
Death or any life-threatening SAE
≥ 1
1b
Any non-life-threatening SAE that cannot reasonably be attributed to a cause 
other than vaccination (non-life-threatening related SAEs)
≥ 1
1c
Any local or general solicited AE leading to hospitalization, or fever > 40°C
that cannot reasonably be attributed to a cause other than vaccination, or 
necrosis at the injection site, within the 7-day (Day 1-7) post-vaccination period
≥ 1


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Table 18
Study holding rules identifiable by the iSRC
Holding 
Rule
Event
Percentage 
(number of 
subjects/group/ 
dose)
2a
Any withdrawal from the study (by investigator or subject request) following a 
Grade 3 AE that cannot reasonably be attributed to a cause other than 
vaccination
≥ 25% (5/20)
2b
Any Grade 3 solicited local AE lasting 48h or more in an investigational RSV 
vaccine group, within the 7-day (Day 1-7) post-vaccination period 
≥ 25% (5/20)
2c
Any Grade 3 solicited general AE lasting 48h or more in an investigational 
RSV vaccine group, that cannot reasonably be attributed to a cause other than 
vaccination, within the 7-day (Day 1-7) post-vaccination period
≥ 25% (5/20)
2d
Any Grade 3 unsolicited AE in an investigational RSV vaccine group, that 
cannot reasonably be attributed to a cause other than vaccination, within the 7-
day (Day 1-7) post-vaccination period
OR
Any Grade 3 abnormality in pre-specified hematological or biochemical 
laboratory parameters in an investigational RSV vaccine group, up to the Day 
8 post-vaccination visit.†
≥ 25% (5/20)
† Grading of laboratory parameters will be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy 
Adults and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (Refer to Section 12.7, Appendix 7). 
Those laboratory parameters not included in the FDA Toxicity Grading Scale will not be graded.
The investigator is not permitted to start the administration of the next dose until receipt 
of the favorable outcome of the safety evaluation, documented and provided in writing, 
authorizing the investigator to proceed. 
Moreover, if the investigator becomes aware of a holding rule being met, he/she will 
suspend vaccination and will inform GSK immediately (e.g. meeting of holding rules 1a-
c).
The below flow of communication has to be followed:
In order to provide an effective study conduct, a proper communication plan will be set 
up between investigators, Local Operating Company (LOC) personnel, Central functions 
and the iSRC. This communication plan will allow an effective vaccination halt as well 
as restart or suspend of vaccination. 
Holding rules identified by Investigators 
If a holding rule is met at the site level, vaccination must be put on hold immediately in 
each study center and the study Local Medical Lead (LML) in the LOC should be 
informed. The LOC will inform the central study team (study CRDL, Study Delivery 
Lead, and Safety Physician). All other procedures relating to safety and immunology will 
continue. 
Following an internal review as well as review by the iSRC, the Sponsor will decide to 
continue the conduct of, suspend or modify the study. This decision will be documented 
and provided in writing to the investigators. 


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Holding rules identified by the iSRC
If a holding rule is met following safety evaluation by the iSRC, the iSRC Chairman must 
notify the primary GSK contact immediately. The central study team (study CRDL, 
Study Delivery Lead, or Safety Physician) will subsequently inform the LOC and 
Investigators from each study center. All vaccinations will cease immediately, but all 
other procedures relating to safety and immunology will continue.
Following additional assessment by the iSRC, the Sponsor will decide to continue the 
conduct of, suspend or modify the study. This decision will be documented and provided 
in writing to the investigators.
8.7.3.
Risk assessment
Figure 2 gives the probability of not meeting each holding rule 1 and 2 for 20 subjects per 
group. 
Figure 2
Evaluations based on 20 subjects per group - risk assessment curve
for 1 group based on the proposed safety holding rules


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The above figure illustrates that, with 20 subjects per study group:

Each holding rule 1a-c has more than 90% chance of not being met for vaccination 
with a true incidence rate below 1% and has more than 88% chance of being met for 
vaccination with a true incidence rate above 10%.

Each holding rule 2a-d has more than 80% chance of not being met for vaccination 
with a true incidence rate below 16% and more than 60% chance of being met for 
vaccination with a true incidence rate above 25%.
8.8.
Genetic Research (Pharmacogenetics)
Genetics are not evaluated in this study.


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9.
DISCONTINUATION CRITERIA

Refer to the Section 7.7 for contraindications to subsequent vaccination.

All AEs/SAEs leading to withdrawal from the study will be collected and recorded 
from the time of the first study vaccine (refer to Section 12.5, Appendix 5).
9.1.
Discontinuation from the study
From an analysis perspective, a ‘withdrawal’ from the study refers to any subject who 
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 to contact those subjects who do not return for 
scheduled visits or follow-up (e.g., 3 telephone calls and a certified letter to the last 
known address). 
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 12.5.8.2 for details)

Unsolicited non-serious adverse event

Solicited adverse event

Protocol deviation (specify)

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 an SAE/AE until 
resolution of the event (see Section 12.5.10).


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9.2.
Discontinuation of study vaccine
A ‘withdrawal’ from the study vaccine(s) 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 vaccine(s) 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 vaccine(s) 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 delegator 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.
Sample size calculation
A sample size of 20 subjects per group would provide a probability of 80% or 90% to 
observe at least one AE, if the true AE rate is 7.8% or 10.9%, respectively.
Considering a sample size of 20 subjects per group, Table 19 below illustrates the exact 
95% Confidence Intervals (CIs) for the different possible numbers of AEs within each 
group.
Table 19
Two-sided 95% exact confidence intervals based on the percentage 
of subjects with adverse events following vaccination of 20 subjects 
per group
Number (%) of subjects
with an AE
Exact 95% Confidence Interval (CI)
Lower Limit (%)
Upper limit (%)
0 (0%)
0.00
16.84
1 (5%)
0.13
24.87
2 (10%)
1.23
31.70
3 (15%)
3.21
37.89
4 (20%)
5.73
43.66
5 (25%)
8.66
49.10
6 (30%)
11.89
54.28
7 (35%)
15.39
59.22
8 (40%)
19.12
63.95
9 (45%)
23.06
68.47
10 (50%)
27.20
72.80
11 (55%)
31.53
76.94
12 (60%)
36.05
80.88
13 (65%)
40.78
84.61
14 (70%)
45.72
88.11
15 (75%)
50.90
91.34
16 (80%)
56.34
94.27
17 (90%)
62.11
96.79
18 (95%)
68.30
98.77
19 (95%)
75.13
99.87
20 (100%)
83.16
100.00
Exact 95% CI computed based on Clopper/Pearson formula.


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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.
Per Protocol 
All subjects who received at least 1 dose of the study treatment to which they 
are randomized and have post-vaccination data minus subjects with protocol 
deviations that lead to exclusion.
10.3.
Statistical analyses
The analyses will be descriptive with the aim to characterize the safety/reactogenicity and
immunogenicity of the vaccine group with respect to the placebo. 
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the final study report.
10.3.1.
Demography and baseline characteristics analyses
The demography analysis will be performed on the Exposed Set (ES) and on the Per 
Protocol (PP) set.
Demographic characteristics (age at vaccination in years, gender, race and ethnicity) will 
be summarized by group using descriptive statistics:

Frequency tables will be generated for categorical variable such as race.

Mean, median, standard deviation and range will be provided for continuous data 
such as age.
The distribution of subjects will be tabulated as a whole and per group and for each age 
category (60-69 years and 70-80 years).
Withdrawal status will be summarized by group using descriptive statistics:

The number of subjects enrolled into the study as well as the number of subjects 
excluded from PP analyses will be tabulated. 

The numbers of withdrawn subjects will be tabulated according to the reason for 
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10.3.2.
Safety analyses
The primary analysis will be performed on the ES.
Endpoint
Statistical Analysis Methods
Primary
The percentage of subjects with at least one local AE (solicited and unsolicited), with at least one 
general AE (solicited and unsolicited) and with any AE during the 7-day or 30-day follow-up period 
will be tabulated with exact 95% confidence interval (CI) after each dose and overall. The same 
computations will be done for Grade 3 AEs, for any AEs considered related to vaccination, for 
Grade 3 AEs considered related to vaccination and for Grade 3 non-serious AEs.
The percentage of subjects with any AE (solicited and unsolicited) resulting in a medically attended 
visit during the 30-day follow-up period will also be tabulated after each dose and overall.
The percentage of subjects reporting each individual solicited local AE (any grade and Grade 3) and 
solicited general AE (any grade, Grade 3, any related and Grade 3 related) during the 7-day follow-
up period (i.e., on the day of vaccination and 6 subsequent days) will be tabulated for each group 
after each dose and overall. 
For fever, the number and percentage of subjects reporting fever by half degree (°C) cumulative 
increments during the 7-day follow-up period (i.e., on the day of vaccination and 6 subsequent 
days) will be tabulated for each group after each dose and overall. Similar tabulations will be 
performed for any fever with a causal relationship to vaccination and for Grade 3 (> 39.0°C) 
causally related fever. In addition, the prevalence of any and Grade 3 fever will be presented 
graphically over time after each vaccination.
For each group and for each hematology and biochemistry parameter:
•
The percentage of subjects having hematology and biochemistry results below or above 
the laboratory normal ranges will be tabulated by time point.
•
The summary of grading post-vaccination will be tabulated versus baseline. Grades will 
be based on the FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adults and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”, see section 12.7 (Appendix 
7). The laboratory parameters not included on FDA Toxicity Grading Scale will not be graded.
The percentage of subjects with any unsolicited AEs during the 30-day follow-up period (i.e., on the 
day of vaccination and 29 subsequent days) with its exact 95% CI will be tabulated by group and by 
Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Similar tabulation will be
done for Grade 3 unsolicited AEs, for any causally related unsolicited AEs, for Grade 3 causally 
related unsolicited AEs and for unsolicited AEs resulting in a medically attended visit. The verbatim 
reports of unsolicited AEs will be reviewed by a qualified person and the signs and symptoms will 
be coded according to the MedDRA Dictionary for Adverse Reaction Terminology. Every verbatim 
term will be matched with the appropriate Preferred Term.
The percentage of subjects with at least one report of SAE classified by the MedDRA Preferred 
Terms and reported from Dose 1 up to 30 days after the second vaccine dose (Day 91) will be 
tabulated with exact 95% CI. 
The percentage of subjects with at least one pIMD classified by the MedDRA Preferred Terms and 
reported from Dose 1 up to 30 days after the second vaccine dose (Day 91) will be tabulated with 
exact 95% CI. 
Secondary
The percentage of subjects with at least one report of SAE classified by the MedDRA Preferred 
Terms and reported during the entire study period will be tabulated with exact 95% CI. SAEs will 
also be described in detail.
The percentage of subjects with at least one pIMD classified by the MedDRA Preferred Terms and 
reported during the entire study period will be tabulated with exact 95% CI. pIMDs will also be 
described in detail.
Tertiary
N/A


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The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (i.e., on the day of vaccination and 6 subsequent days) and during the 
30-day follow-up period (i.e., on the day of vaccination and 29 subsequent days) will be 
summarized by group after each vaccine dose and overall.
The analysis of safety might also be performed by age category (60-69 years and 70-80 
years).
10.3.3.
Immunogenicity analyses
The primary analysis will be based on the PP set for analysis of immunogenicity. If, in 
any study group and at any timepoint, the percentage of vaccinated subjects with 
serological results excluded from the PP set for analysis of immunogenicity is 10% or 
more, a second analysis based on the ES will be performed to complement the PP
analysis.
Endpoint
Statistical Analysis Methods
Primary
N/A
Secondary
For each group, at each time point that blood samples are collected for humoral immune 
response and for each assay (unless otherwise specified): 

Percentage of subjects above pre-defined threshold and their exact 95% CI will be 
tabulated.

Geometric mean concentrations (GMCs)/ geometric mean titers (GMTs) and their 95% 
CI will be tabulated and represented graphically.

Antibody titer/concentration will be displayed using reverse cumulative curves. 

The distributions of antibody titers/concentrations will be tabulated.

Geometric mean of ratios of antibody titer/concentrations at each post-vaccination time 
point over pre-vaccination (Day 1) will be tabulated with 95% CI.

Individual post-vaccination results (at Days 31, 61 and 91) versus pre-vaccination results 
(Day 1) will be plotted using scatter plots. Results of the placebo group will be used as a 
reference.

Distribution of the fold increase of the antibody titers/concentrations (post- over pre-
vaccination titers) will be tabulated.

The ratio of the fold-increase of RSVPreF3 ELISA antibody concentrations over the fold-
increase of RSV-A neutralizing antibody titers will be computed and tabulated using 
descriptive statistics (Ratio of fold increase Post- over Pre-vaccination).
The kinetics of GMT/GMCs will be plotted as a function of time for subjects with results 
available at all time points.
Tertiary
Will be described in a Statistical Analysis Plan finalized before database unblinding/freezing
The immunogenicity analysis might also be performed by age category (60-69 years and 
70-80 years).


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10.3.4.
Other analyses
10.3.4.1.
Analysis of RTI 
The analysis will be performed on the ES. 
Endpoint
Statistical Analysis Methods
Primary
N/A
Secondary/Tertiary
A listing of RTI cases and their respective viral load results assessed by qRT-PCR will be 
provided by group.
10.3.5.
Interim analyses 
All analyses will be conducted on final data and therefore no statistical adjustment for 
interim analyses is required.
10.4.
Sequence of analyses
In preparation of the planned iSRC evaluations, analyses of all available safety data (as 
clean as possible) will be performed. The blinded analyses will be distributed to the study 
team. The unblinded analyses will be done by an Independent External Statistician to 
maintain the study blind and will be shared with iSRC members through a secured folder 
(refer to the iSRC charter). Only the recommendations of the iSRC reviews will be 
communicated to the RSV OA study team. No clinical study report will be written at this 
stage.
The following analyses will be performed stepwise:

A first analysis will be performed on all data available and as clean as possible, when 
data for at least primary and secondary endpoints up to Day 91 are available (except 
for the occurrence of RSV RTI). This analysis will be considered as final for those 
endpoints. A statistical report will be written.
At this point, the statistician will be unblinded (i.e., individual subject treatment 
assignments will be available), but no individual listings will be provided to the 
study team. Given that summary safety results may unblind some specific subjects, 
the study will be considered as single-blind from this point onwards, with subjects 
remaining blinded up to study end (Month 14). The investigators will not be 
provided with the individual data listings or with the randomization listings until the 
end of study analysis.

The end of study analysis will be performed when all data for primary and secondary 
endpoints up to study conclusion are available (Month 14). Individual listings will 
only be provided at this stage. An integrated clinical study report containing all 
available data will be written and made available to the investigators.
The final 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 and will be made available to the investigators at that time.


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11.
REFERENCES
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from a combinatorial library bind to respiratory syncytial virus F glycoprotein and 
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Bates JT, Keefer CJ, Slaughter JC, et al. Escape from neutralization by the respiratory 
syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by 
changes in on-rate of binding to the fusion protein. Virology. 2014; 454-455: 139-44.
Borchers AT, Chang C, Gershwin ME, et al. Respiratory syncytial virus – a 
comprehensive review. Clin Rev Allergy Immunol. 2013; 45: 331-79.
CDC website. March 2017. http://www.cdc.gov/rsv/research/us-surveillance.html
Chlibek R, Bayas JM, Collis H, et al. Safety and immunogenicity of an AS01-adjuvanted 
varicella-zoster virus subunit candidate vaccine against herpes zoster in adults 50 years 
of age. J Infect Dis. 2013; 208:1953-61.
Chlibek R, Smetana J, Pauksens K, et al. Safety and immunogenicity of three different 
formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older 
adults: A phase II, randomized, controlled study. Vaccine. 2014; 32:1745-53.
Chlibek R, Pauksens K, Rombo L, et al. Long-term immunogenicity and safety of an 
investigational herpes zoster subunit vaccine in older adults. Vaccine. 2016; 34:863-868.
Doi, I, Nagata, N, Tsukagoshi, H, et al. An outbreak of acute respiratory infections due to 
human respiratory syncytial virus in a nursing home for the elderly in Ibaraki, Japan, 
2014. Jpn J Infect Dis. 2014; 67: 326–328.
Falsey AR, McElhaney JE, Beran J, et al. Respiratory syncytial virus and other 
respiratory viral infections in older adults with moderate to severe influenza-like illness. J 
Infect Dis. 2014;209:1873-81.
Graham BS. Biological challenges and technological opportunities for respiratory 
syncytial virus vaccine development. Immunol Rev. 2011; 239:149-166.
Ikematsu H, Hideyuki Y, Rosenlund M, et al. The post-infection outcomes of influenza 
and acute respiratory infection in patients above 50 years of age in Japan: an 
observational study. Influenza Other Respir Viruses. 2012; 6(3): 211-217.
Kanou K, Arima Y, Kinoshita H, et al. Respiratory Syncytial Virus Surveillance System 
in Japan: Assessment of Recent Trends, 2008–2015. Jpn J Infect Dis. 2018; 71(3): 250-
255.
Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. 
Expert Rev. Anti. Infect. Ther. 2011; 9: 27–32.


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Kurai D, Sasaki Y, Saraya T, et al. Pathogen profiles and molecular epidemiology of 
respiratory viruses in Japanese inpatients with community-acquired pneumonia. Respir 
Investig. 2016; 54(4): 255-63.
Kwakkenbos MJ, Diehl SA, Yasuda E, et al. Generation of stable monoclonal antibody-
producing B cell receptor-positive human memory B cells by genetic programming. Nat 
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placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of 
an investigational non-typeable Haemophilus influenza (NTHi) protein vaccine in adults. 
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vaccine for respiratory syncytial virus. Science 2013;6158:592-8.
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pneumonia in the aging Japanese population: a multicenter prospective study. PLoS One. 
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Steff AM, Monroe J, Friedrich K, et al. Pre-fusion RSV F strongly boosts pre-fusion 
specific neutralizing responses in cattle pre-exposed to bovine RSV. Nat Commun. 2017; 
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of the Japanese Association for Infectious Diseases). 2016; 90(5): 645-51.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations, glossary of terms and 
trademarks
12.1.1.
List of abbreviations
AE:
Adverse Event
ALT:
Alanine Aminotransferase
AS01B:
MPL, QS-21, liposome based Adjuvant System (50 g 
MPL and 50 g QS-21)
AST:
Aspartate Aminotransferase
BUN:
Blood Urea Nitrogen
CDC:
Centers for Disease Control
CI:
Confidence Interval
CLS:
Clinical Laboratory Sciences
CoP:
Correlate of Protection
COP:
Community-Onset Pneumonia
COPD:
Chronic Obstructive Pulmonary Disease
eCRF:
electronic Case Report Form
eDiary:
electronic Diary
ELISA:
Enzyme-Linked Immunosorbent Assay
eTDF:
Electronic Temperature excursion Decision Form
EoS:
End of Study
ES:
Exposed Set
FDA:
Food and Drug Administration, United States of America
GCP:
Good Clinical Practice
gE:
glycoprotein E
GM:
Geometric Mean


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GMC:
Geometric Mean Concentration
GMT:
Geometric Mean Titer
GSK:
GlaxoSmithKline
HIV:
Human Immunodeficiency Virus
hMPV:
Human Metapneumovirus
HZ/su:
Herpes Zoster subunit vaccine
IASR:
Infectious Agents Surveillance Report
IB:
Investigator Brochure
ICF:
Informed Consent Form
ICH:
International Council on Harmonization
IDMC:
IEC:
Independent Data Monitoring Committee
Independent Ethics Committee
IgG:
Immunoglobulin G
IL:
Interleukin
IM:
Intramuscular(ly)
IMP:
Investigational Medicinal Product
IND:
Investigational New Drug
IRB:
Institutional Review Board
iSRC:
Internal Safety Review Committee
LML:
Local Medical Lead 
LOC:
Local Operating Company
LRTD:
Lower Respiratory Tract Disease
LSLV:
Last Subject Last Visit
MACDP:
Metropolitan Atlanta Congenital Defects Program
MedDRA:
Medical Dictionary for Regulatory Activities


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PCD:
Primary Completion Date
PCR:
Polymerase Chain Reaction
PP:
Per protocol
PT:
Preferred Term
pIMD:
Potential Immune-Mediated Disease
qRT-PCR:
Quantitative Reverse Transcription Polymerase Chain 
Reaction
QS-21:
Quillaja saponaria Molina, fraction 21 (Licensed by 
GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation)
RNA:
Ribonucleic Acid
RSV:
Respiratory Syncytial Virus
RTI:
Respiratory Tract Infection
SAE:
Serious Adverse Event
SAP:
Statistical Analysis Plan
SBIR:
Source data Base for Internet Randomization
SDV:
Source Document Verification
SmPC:
Summary of Product Characteristics
SoA
Schedule of Activities
SPM:
Study Procedures Manual
US:
United States
WBC:
White Blood Cells


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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 unfavorable
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.
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 a 
single-blind study, the investigator and/or his staff are 
aware of the treatment assignment but the subject is not. 
In an observer-blind study, the subject and the site and 
sponsor personnel involved in the clinical evaluation of 
the subjects are blinded while other study personnel may 
be aware of the treatment assignment (see Section 7.3 for 
details on observer-blinded studies). 
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.
Designee:
A person who helps the subject with performing some of 
the study procedures if the subject has difficulties to 
perform them alone (such as completion of the eDiary, 
receiving phone calls and planning of the study visits), 
e.g. a relative of the subject, a field worker who is linked 
to this study. Designees are appointed by the subject for 
help with the study procedures solely and cannot make 
decisions on behalf of the subject.
Delegator:
A qualified person appointed by the investigator or 
sponsor to take over a specific part of their trial-related 
duties or responsibilities.


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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, 
the EoS is defined as Last subject last visit (Phone Call 
2), or Last testing results released of samples collected up 
to Phone Call 2*
* In this case EoS must be achieved no later than 8 
months after LSLV. 
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).
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.
Intercurrent medical 
condition:
A condition that has the capability of altering the immune 
response to the study vaccine or is confirmed to have an 
alteration of the subject’s initial immune status.
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. 


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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.
Pharmacogenomics
The International Council on Harmonization (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, 
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 etiology.
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.


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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).
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.


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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
The following trademarks are used in the present protocol.
Note: In the body of the protocol, the names of the vaccines/products and/or medications
and/or assays are written without the superscript symbol ™ or ® and in italics.
Trademarks of the GSK group of 
companies
Generic description
Cervarix
Human Papillomavirus vaccine Types 16 
and 18 (Recombinant, AS04 adjuvanted)
Shingrix
Zoster vaccine (Recombinant, adjuvanted)
Trademarks not owned by the GSK group 
of companies
Generic description
Fluad (Seqirus Inc.)
Influenza virus vaccine (Surface antigen, 
inactivated, adjuvanted with MF59)
MF59 adjuvant (Novartis)
Oil-in-water emulsion of squalene oil
TrueBlue peroxidase substrate (SeraCare)
Chromagenic substrate for visualization of 
horseradish peroxidase-labeled reporter 
reagents


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12.2.
Appendix 2: Clinical and safety laboratory tests
The tests detailed in Table 20 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 6 of the protocol.
The investigator is not allowed to do extra testing on samples outside of what has been 
agreed upon by the ethic committees.
Table 20
Protocol-required safety laboratory assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Clinical 
Chemistry
Alanine Aminotransferase (ALT)
Blood Urea nitrogen (BUN)
Aspartate Aminotransferase (AST)
Creatinine
Uric Acid
12.2.1.
Laboratory assays
Assay descriptions for RSV-specific read-out are provided below. Assays may possibly 
be adapted during assay development and/or qualification.
RSV A/B neutralization assay
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize the cytopathic effects of RSV on the host cell line, hence RSV 
replication.
First, virus neutralization is performed by incubating a fixed amount of RSV (A long 
strain [ATCC No. VR-26] or B strain 18537 [ATCC N°. VR-1580]) with serial dilutions 
of the test serum. Then, the serum-virus mixture is transferred onto a monolayer of Vero 
cells (African Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL-81) and 
incubated for 2 days to allow infection of Vero cells by non-neutralized viruses and the 
formation of plaques in the cell monolayer. Following the fixation period, RSV-infected 
cells are detected using a primary antibody directed against RSV (anti-RSV IgG) and a 
secondary antibody conjugated with horse-radish peroxidase (HRP), allowing the 
visualization of plaques after coloration with TrueBlue peroxidase substrate. Viral 
plaques are counted using an automated microscope coupled to an image analyzer 
(Scanlab system with Axiovision software). 


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For each serum dilution, a ratio, expressed as a percentage, is calculated between the 
number of plaques at that dilution and the number of plaques in the virus control wells 
(no serum added). The serum neutralizing antibody titer is expressed in ED60 (Estimated 
Dilution 60) and corresponds to the inverse of the interpolated serum dilution that yields 
a 60% reduction in the number of plaques compared to the virus control wells as 
described by others [Barbas, 1992; Bates, 2014].
RSVPreF3 ELISA
The RSVPreF3 IgG ELISA is under development. The assay will be based on an indirect 
ELISA allowing the detection and the quantification of total IgG antibodies directed 
against RSVPreF3 in human serum samples.
The principle of this assay will be as follows. The RSVPreF3 antigen will be adsorbed 
onto a 96-well polystyrene microplate. After a washing and a blocking step, dilutions of 
serum samples, controls and standards will be added to the coated microplate. A 
reference standard curve will be prepared using a pool of commercial human serum 
containing anti-RSV antibodies. After incubation, the microplate will be washed to 
remove unbound primary antibodies. Bound IgG will be detected by the addition of a 
secondary anti-human antibody conjugated to horseradish peroxidase (HRP). Bound 
antibodies are quantified by the addition of the HRP substrate, tetramethylbenzidine and 
hydrogen peroxide, whereby a colored product develops proportionally to the amount of 
anti-RSV F3 IgG antibodies present in the serum sample. The optical density of each 
sample dilution is then interpolated on the reference standard. The corresponding 
antibody concentration, corrected for the dilution factor, is expressed in arbitrary ELISA 
Laboratory Units per milliliter (ELU/mL).
qRT-PCR

Quantitative PCR able to discriminate RSV-A and RSV-B subtypes
Briefly, RSV A and RSV B RNAs extracted from the nasal and throat swabs are 
detected in a duplex PCR format using specific amplification primers and fluorescent 
probes designed in the RSV N gene, encoding the RSV nucleocapsid protein. The 
process involves nucleic acids extraction, conversion of RNA to complementary 
deoxyribonucleic acid by reverse transcription and detection by real-time PCR 
reaction using a calibration curve (absolute quantitation). The RSV viral load is 
reported as copies of RSV RNA per mL of sample.


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12.3.
Appendix 3: Clinical laboratories
Table 21
GSK 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 22
Outsourced laboratories
Laboratory
Address
NÉOMED-LABS Inc.
525, Cartier Ouest Laval
Quebec Canada H7V 3S8
NÉOMED-LABS Inc.
Q2 Solutions Clinical Trials (US)
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Tan Tock Seng Hospital
Dept of Laboratory Medicine
Level 2, Podium Block
Tan Tock Seng Hospital
11 Jalan Tan Tock Seng
Singapore 308433
DDL Diagnostic Laboratory B.V.
Fonteijnenburghlaan 7
Voorburg
Netherland
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 Organizations 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), Investigator, 
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. 


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
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/IEC.

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 center 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. 
12.4.3.
Informed consent process
The investigator or his/her representative will explain the nature of the study to the 
subject and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. 
Freely given and written 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 center.
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. 


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A copy of the ICF(s) must be provided to the subject. 
The ICF contains a specific section that addresses the use of remaining leftover samples 
for future use. The investigator or authorized delegator will inform each subject of the 
possibility of future use of left-over samples not related to the study/disease. Subjects will 
be told that they are free to refuse and may withdraw their consent at any time and for 
any reason during the storage period. A separate tick box will be required to document a 
subject's agreement to allow any remaining leftover samples to be used for future use not 
related to the study/disease. Subjects who decline the use of left-over samples for 
objectives not related to the study/disease will tick the corresponding box.
12.4.4.
Data protection
Subject 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’s
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 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.
GSK will also ensure the protection of personal data of investigator and the site staff 
which will be collected within the frame and for the purpose of the study. 
12.4.5.
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 
studies and from the completion of the analysis for non-interventional studies and follows 
the guidance from the International Committee of Medical Journal Editors.
12.4.6.
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. 


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In addition, for studies that are in scope of the EU Clinical Trial Directive, summaries of 
the results of GSK interventional studies (phase I-IV) in adult population will be posted 
within defined timelines on the publicly available 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 pediatric
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 will also provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary 
results with the study subjects, as appropriate.
12.4.7.
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 its delegator 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/eCRF. 
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. 


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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 its delegator 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. 
12.4.8.
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.
Data 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
Section 12.1.2 (Glossary of Terms).
12.4.9.
Study and site closure
GSK or its delegator 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.


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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 unfavorable 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 

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.

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).

Signs, symptoms that require medical attention (e.g. Hospital stays, physician visits 
and emergency room visits).
AEs to be recorded as solicited AEs are described in Section 12.5.3. All other AEs within 
30 days post-vaccination will be recorded as unsolicited AEs.


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12.5.1.3.
Events NOT meeting the AE definition 

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE/SAE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

Pre-existing conditions or signs and/or symptoms present in a subject prior to the 
first study vaccination. These events will be recorded in the medical history section 
of the eCRF.
12.5.2.
Definition of SAE
An SAE is any untoward medical occurrence that:
a.
Results in death,
b.
Is life-threatening,
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalization 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, diarrhea, 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.


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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. 
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 AEs (see Table 23 and Table 24) occurring during the 7-day follow-up period 
after each vaccination (day of vaccination and 6 subsequent days) will be recorded by the 
subjects or designees in the eDiaries. The data will be made available for site follow-up 
on the eDiary web-portal. 
The investigator will assess the causality of the general symptoms on the web-portal, 
after a discussion with the subject. 
a.
Solicited local (injection-site) adverse events
The following local (injection-site) AEs will be solicited:
Table 23
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 24
Solicited general adverse events
Fatigue
Fever
Gastrointestinal symptoms†
Headache
Myalgia
Shivering
Arthralgia
†Gastrointestinal symptoms include nausea, vomiting, diarrhea and/or abdominal pain.
Note: subjects will be instructed to measure and record the body temperature (preferably 
oral) in the evening. Should additional temperature measurements be performed at other 
times of day, subjects will be instructed to record the highest temperature in the eDiary.


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12.5.4.
Unsolicited adverse events
An unsolicited AE is 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. Unsolicited 
adverse events will be collected up to 30 days after each vaccination. Note that solicited 
symptoms with onset in the specified period of follow-up, but continuing until after the 7-
day follow-up period after vaccination, do not become unsolicited AEs but should 
continue to be reported as solicited AE until resolved.
Potential unsolicited AEs may be medically attended (defined as symptoms or illnesses 
requiring hospitalization, or emergency room visit, or visit to/by a health care provider), 
or were of concern to the subjects. In case of such events, subjects will be instructed to 
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.
All unsolicited AEs up to 30 days after each vaccination have to be reported via paper 
diary or orally, and detailed information about the reported unsolicited AEs will be 
collected by the qualified site personnel and will be documented in the subject’s records.
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 etiology. AEs that need to be recorded and 
reported as pIMDs include those listed in the Table 25 (Please refer to section 12.5.8.2
for reporting details).
However, the investigator will exercise his/her medical and scientific judgement in 
deciding whether other diseases have an autoimmune origin (i.e. pathophysiology 
involving systemic or organ-specific pathogenic autoantibodies) and should also be 
recorded as a pIMD.


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Table 25
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 hemolytic anemia.

Autoimmune thrombocytopenia.

Antiphospholipid syndrome.

Pernicious anemia.

Autoimmune aplastic anemia.

Autoimmune neutropenia.

Autoimmune pancytopenia.

Autoimmune glomerulonephritis including:

IgA nephropathy, 

Glomerulonephritis rapidly progressive, 

Membranous glomerulonephritis, 

Membranoproliferative glomerulonephritis, 

Mesangioproliferative glomerulonephritis. 

Tubulointerstitial nephritis and uveitis 
syndrome.

Ocular autoimmune diseases including:

Autoimmune uveitis 

Autoimmune retinitis.

Autoimmune myocarditis.

Sarcoidosis.

Stevens-Johnson syndrome.

Sjögren’s syndrome.

Alopecia areata.

Idiopathic pulmonary fibrosis.

Goodpasture syndrome.

Raynaud’s phenomenon.
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis.

Primary biliary cirrhosis.

Primary sclerosing cholangitis.

Autoimmune cholangitis.

Inflammatory Bowel disease, including:

Crohn’s disease, 

Ulcerative colitis, 

Microscopic colitis, 

Ulcerative proctitis.

Celiac disease.

Autoimmune pancreatitis.

Autoimmune thyroiditis (Hashimoto 
thyroiditis).

Grave's or Basedow’s disease.

Diabetes mellitus type I.

Addison’s disease.

Polyglandular autoimmune syndrome.

Autoimmune hypophysitis.


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When there is enough evidence to make any of the above diagnoses, the AE must be reported as a pIMD. Symptoms, signs or conditions 
which might (or might not) represent the above diagnoses, should be recorded and reported as AEs but not as pIMDs until the final or 
definitive diagnosis has been determined, and alternative diagnoses have been eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard questionnaire and a list of preferred terms (PTs) and PT 
codes corresponding to the above diagnoses will be available to investigators at study start.


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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, 
hematology, urinalysis) or other abnormal assessments (e.g. physical examination signs 
or symptoms) 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.
As for other AEs/ SAEs, treatment for clinically significant abnormal laboratory findings 
or other assessments is at the sole discretion of the investigator and according to good 
medical practice.
In case of invalid or missing results or clinically significant abnormal laboratory findings 
that cannot be reasonably explained (e.g. due to a pre-existing or current medical 
condition), the investigator will be recommended to recall the subject in a timely manner 
(preferably within 7 days after investigator’s awareness/assessment of the abnormal 
findings, if applicable) for a repeat test to confirm the result. 


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12.5.7.
Detecting and recording adverse events and serious adverse 
events
Electronic Diaries (eDiaries) will be used to capture solicited adverse events.
Paper diary cards will be used by the subjects or their designee to capture the details of 
the unsolicited signs or symptoms. They will be reviewed by the investigator at the 
subsequent study visits (Day 8, Day 31, Day 68 or Day 91) and then reported as 
applicable in the AE section of the eCRF. 
The subjects should be trained on how and when to complete each field of the electronic 
and paper diary. If a subject is unable or not willing to complete the electronic and/or the 
paper diary him/herself, he/she may be helped by a designee (refer to the Section 12.1.2
(Glossary of Terms) for the definition of designee). This person’s identity must then be 
documented in the subject’s source record and be trained. The training will be given at 
the visit when the electronic and paper diaries are dispensed and will be documented in 
the subject’s source record. This person also needs to sign an ICF.
The subjects will be instructed to contact the investigator immediately should the subjects 
manifest any signs or symptoms they perceive as serious. 

The same individual should complete the eDiary throughout the course of the study.

The subject should be trained on how to self-measure local solicited adverse events 
and body temperature. 

The measurement of solicited local adverse events is to be performed using the ruler 
provided by the site.

Subjects will be instructed to measure and record the body temperature (preferably 
oral) in the evening. Should additional temperature measurements be performed at 
other times of day, subjects will be instructed to record the highest temperature in the 
eDiary.
eDiary assignment and use:

Each subject or designee will be assigned a eDiary and shown how to use the device 
– this will include how to access the diary, performing test data entry on sample 
questions, and how to charge and store the device.

The subject or designee will self-select a numeric access code secret to themselves. 
The same individual should make the assessments and complete the eDiary 
throughout the course of the study. 

The subject or designee will select an alarm time that suits their daily routines whilst 
ensuring compliance with protocol requirements.


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eDiary instructions must ensure that the subject understands the following:

Timely completion of the eDiary on a daily basis is a critical component to study 
participation.

The eDiary will allow certain time windows for completion of each day’s 
observations.

The eDiary employs the use of audio-visual alarms to ensure timely completion of 
data entry.

The trained and assigned user of the eDiary must not share access codes with 
anyone.

A helpdesk will be provisioned for users of eDiary in case of technical issues, though 
it must be stressed that the Helpdesk is not a replacement for normal medical care 
and no medical issues can be discussed with the agents.

The eDiary itself must never be considered a substitute for direct medical care and 
any concerns must be communicated to site staff as soon as possible.

Any new safety information reported during the safety follow-up phone call or site
visits (including a solicited adverse event) cannot be entered into the eDiary. Such
information must be described in the source documents as a verbally-reported event.
Any adverse event reported in this fashion must be described as an unsolicited
adverse event and therefore entered into the eCRF.
12.5.7.1.
Time period for detecting and recording adverse events and serious 
adverse events 
All solicited AEs during 7 days following administration of each dose of study vaccine
(the day of vaccination and 6 subsequent days) must be recorded in the eDiary, 
irrespective of intensity or whether or not they are considered vaccination-related.
All unsolicited AEs during 30 days following administration of each dose of study 
vaccine (the day of vaccination and 29 subsequent days) recorded by the subjects on their 
paper diary cards or reported orally must be recorded into the appropriate section of the 
eCRF, irrespective of intensity or whether or not they are considered vaccination-related.
The time period for collecting and recording SAEs will begin at the first receipt of study 
vaccine and will end 12 months following administration of the last dose of study vaccine 
for each subject. See Section 12.5.8 for instructions on reporting of SAEs to GSK.
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study vaccine.
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.


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The time period for collecting and recording of pIMDs will begin at the first receipt of 
study vaccine and will end 12 months following administration of the last dose of study 
vaccine. See section 12.5.8.4 for instructions on reporting of pIMDs.
12.5.7.2.
Evaluation of adverse events and serious adverse events
12.5.7.2.1. 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 instead of appropriately completing the eCRF.
However, there may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers will be blinded on the copies of 
the medical records prior to submission to GSK.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs/symptoms.


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12.5.7.2.2. Assessment of adverse events
Assessment of intensity
The intensity of the following solicited AEs will be assessed as described:
Table 26
Intensity scales for solicited symptoms in adults 
Adults
Adverse Event
Intensity 
grade
Parameter
Pain at injection site
0
None
1
Mild: Any pain neither interfering with nor preventing normal every day 
activities.
2
Moderate: Painful when limb is moved and interferes with every day 
activities.
3
Severe: Significant pain at rest. Prevents normal every day activities.
Redness at injection site
Record greatest surface diameter in mm
Swelling at injection site
Record greatest surface diameter in mm
Fever*
Record temperature in °C (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, diarrhea 
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
Arthralgia
0
Normal
1
Mild: Arthralgia that is easily tolerated
2
Moderate: Arthralgia that interferes with normal activity
3
Severe: Arthralgia that prevents 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
Shivering
0
Normal
1
Mild: Shivering that is easily tolerated
2
Moderate: Shivering that interferes with normal activity
3
Severe: Shivering that prevents normal activity
*Fever to be reported as AE is defined as temperature 38.0°C. The preferred location for measuring temperature in 
this study will be the oral cavity.


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The maximum intensity of local injection site redness/swelling and fever will be scored at 
GSK as follows:
Redness/swelling
Fever
0:
20 mm
< 38.0°C 
1:
> 20 - 50 mm
≥ 38.0°C - 38.5°C
2:
> 50 - 100 mm
> 38.5°C - 39.0°C 
3:
> 100 mm
> 39.0°C 
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.
In adults, such an AE would, for example, prevent attendance at 
work and would necessitate the administration of corrective 
therapy.)
An AE that is assessed as Grade 3 (severe) should not be confused with an 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.
Assessment of causality
The investigator is obligated to assess the relationship between study vaccine and the 
occurrence of each AE/SAE using clinical judgement. 
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 an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. 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. The investigator may change his/her 
opinion of causality in light of follow-up information and update the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.


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All solicited local (injection site) reactions will be considered causally related to 
vaccination. Causality of all other AEs should be assessed by the investigator using the 
following question:
Is there a reasonable possibility that the AE may have been caused by the study vaccine?
YES
:
There is a reasonable possibility that the study vaccine contributed 
to the AE. 
NO
:
There is no reasonable possibility that the AE is causally related to 
the administration of the study vaccine. There are other, more 
likely causes and administration of the study vaccine is not 
suspected to have contributed to the AE.
If an event meets the criteria to be determined as ‘serious’ (see Section 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.

Lack of efficacy of the vaccine, if applicable.

Erroneous administration.

Other cause (specify).
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).
12.5.7.2.3. Medically attended visits
The subject will be asked if he/she received medical attention defined as hospitalization, 
or an otherwise unscheduled visit to or from medical personnel for any reason, including 
emergency room visits.


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12.5.8.
Reporting of serious adverse events, and other events
12.5.8.1.
Prompt reporting of serious adverse events, and other events to GSK
SAEs that occur in the time period defined in Section 12.5.7 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 an SAE.
pIMDs that occur in the time period defined in Section 12.5.7 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 pIMD.
12.5.8.2.
SAEs requiring expedited reporting to GSK
Once an investigator becomes aware that an SAE has occurred in a study subject, the 
investigator (or delegator) 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 an 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.
12.5.8.3.
Back-up system in case the electronic reporting system does not work
If the electronic reporting system does not work, the investigator (or delegator) 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 
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 delegator) 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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12.5.8.4.
Reporting of pIMDs to GSK
Once a pIMD is diagnosed (serious or non-serious) in a study subject, the investigator (or 
delegator) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS after he/she becomes aware of the diagnosis. The report 
allows to specify that the event is a pIMD and whether it is serious or non-serious. The 
report will always be completed as thoroughly as possible with all available details of the 
event, in accordance with the AESIs standard questionnaire provided. Even if the 
investigator does not have all information regarding an 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 12.5.8.3 for back-up system in case the electronic reporting system does 
not work.
12.5.9.
Updating of SAE and pIMD information after removal of write 
access to the subject’s eCRF
When additional SAE 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 Clinical Safety and Pharmacovigilance department within 
the designated reporting time frames specified in Table 15.
12.5.10.
Follow-up of adverse events and serious adverse events
12.5.10.1. Follow-up of adverse events and serious adverse events
12.5.10.1.1.
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 
(within 24 hours for SAEs; refer to Table 15).
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 contact with the subject in the context of the 
study. In case any SAEs or pIMDs remain not resolved at this last contact, these SAEs or 
pIMDs will continue to be followed after study end (refer to section 12.5.10.1.2).


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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.
12.5.10.1.2.
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. 
If the investigator receives additional relevant information on a previously reported SAE, 
he/she will provide this information to GSK using a paper/electronic Expedited Adverse 
Events Report as applicable.
GSK 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 will be 
provided with any available post-mortem findings, including histopathology.


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12.6.
Appendix 6: Country-specific requirements
12.6.1.
Regulatory and ethical considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and Law for Ensuring the Quality, Efficacy, and Safety 
of Drugs and Medical Devices.
The statement “I agree to assume responsibility for the proper conduct of the study at this 
site.” on the Investigator Protocol Agreement Page means the investigator’s 
responsibility as defined by Japanese GCP.
GSK Japan will submit the CTN to the regulatory authorities in accordance with Law for 
Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Device before 
conclusion of any contract for the conduct of the study with study sites.
12.6.2.
Informed consent
Prior to participation in the study, the investigator (or sub-investigator) should fully 
inform the potential subject or designee including the written approval given by the IRB. 
The investigator (or sub-investigator) should provide the subject or designee ample time 
and opportunity to inquire about details of the study. The subject or designee should sign 
and personally date the consent form. If the subject wishes to consider the content of the 
written information at home, he/she may sign the consent form at home. The person who 
conducted the informed consent discussion and the study collaborator giving 
supplementary explanation, where applicable, should sign and personally date the consent 
form. The investigator (or delegator) should retain this signed and dated form (and other 
written information) together with the source medical records, such as clinical charts (in 
accordance with the rules for records retention, if any, at each medical institution) and 
give a copy to the subject or designee
12.6.3.
Study administrative structure
Sponsor Information and List of Medical Institutions and Investigators are included in 
Exhibit 1 and Exhibit 2, respectively.
12.6.4.
Unapproved medical device
If unapproved medical devices are used in the study, further details will be added in 
Exhibit 3. In case no unapproved medical devices are used, Exhibit 3 will not be attached.


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12.7.
Appendix 7:
FDA guidance for industry: toxicity grading 
scale for healthy adult and adolescent volunteers enrolled in 
preventive vaccine clinical trials (September 2007) - Tables 
for laboratory abnormalities
The laboratory values provided in the tables below serve as guidelines and are dependent 
upon institutional normal parameters. Institutional normal reference ranges should be 
provided to demonstrate that they are appropriate.
Table 27
FDA toxicity grading scales for hematology/ biochemistry 
parameters evaluated in the current study RSV OA=ADJ-003
Serum *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)**
Blood Urea Nitrogen 
BUN mg/dL 
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Liver Function Tests –ALT, AST 
increase by factor 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (Grade 4).
*** “ULN” is the upper limit of the normal range.
Hematology *
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life 
Threatening (Grade 4)
Hemoglobin (Female) - gm/dL 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0
Hemoglobin (Female) 
change from baseline value -
gm/dL 
Any decrease 
– 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0
Hemoglobin (Male) - gm/dL 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5
Hemoglobin (Male) 
change from baseline value –
gm/dL 
Any decrease 
– 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0
WBC Increase - cell/mm
3
10 800 –
15 000 
15 001 –
20 000 
20 001 – 25 000 
> 25 000
WBC Decrease - cell/mm
3
2 500 – 3 500 
1 500 – 2 499 
1 000 – 1 499 
< 1 000
Lymphocytes Decrease -
cell/mm
3
750 – 1 000 
500 – 749 
250 – 499 
< 250
Neutrophils Decrease -
cell/mm
3
1 500 – 2 000 
1 000 – 1 499 
500 – 999 
< 500
Eosinophils - cell/mm
3
650 – 1 500 
1 501 - 5 000 
> 5 000 
Hypereosinophilic
Platelets Decreased -
cell/mm
3
125 000 –
140 000 
100 000 –
124 000 
25 000 – 99 000 
< 25 000
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.
** “ULN” is the upper limit of the normal range.

SAP_001.pdf: 
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Statistical Analysis Plan
Detailed Title:
A phase I, randomized, placebo-controlled, observer-
blind study to evaluate the safety, reactogenicity and 
immunogenicity of GSK’s investigational respiratory 
syncytial virus (RSV) vaccine (adjuvanted with 
AS01B) when administered intramuscularly according 
to a 0, 2-month schedule in Japanese adults 60-80 
years of age.
eTrack study number and 
Abbreviated Title
209699 (RSV OA=ADJ-003)
Scope:
All data pertaining to the above study (except iSRC 
analysis).
Date of Statistical Analysis 
Plan
Final 23 September 2019
APP 9000058193 Statistical Analysis Plan Template V4 (Effective date: 3June2019)


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................6
1.
DOCUMENT HISTORY............................................................................................8
2.
OBJECTIVES/ENDPOINTS .....................................................................................8
3.
STUDY DESIGN ......................................................................................................9
4.
ANALYSIS SETS ...................................................................................................12
4.1.
Definition.....................................................................................................12
4.2.
Criteria for eliminating data from Analysis Sets...........................................12
4.2.1.
Elimination from Exposed Set (ES)..............................................12
4.2.2.
Elimination from Per-protocol analysis Set (PPS) ........................12
4.2.2.1.
Excluded subjects ......................................................12
5.
STATISTICAL ANALYSES.....................................................................................14
5.1.
Demography...............................................................................................14
5.1.1.
Analysis of demographics/baseline characteristics planned 
in the protocol..............................................................................14
5.1.2.
Additional considerations.............................................................15
5.2.
Exposure ....................................................................................................15
5.2.1.
Analysis of exposure planned in the protocol...............................15
5.2.2.
Additional considerations.............................................................15
5.3.
Immunogenicity...........................................................................................15
5.3.1.
Analysis of immunogenicity planned in the protocol.....................15
5.3.1.1.
Humoral immune response.........................................15
5.4.
Analysis of safety and reactogenicity ..........................................................16
5.4.1.
Analysis of safety and reactogenicity planned in the 
protocol........................................................................................16
5.4.2.
Additional considerations.............................................................17
5.4.2.1.
Solicited Adverse Events............................................18
5.4.2.2.
Unsolicited Adverse Events........................................18
5.4.2.3.
Combined Solicited and Unsolicited Adverse 
Events ........................................................................19
5.4.2.4.
Clinical Safety Laboratory Investigations ....................20
5.4.2.5.
Concomitant Medication .............................................20
5.5.
Analysis of RTI............................................................................................20
5.5.1.
Analysis of RTI planned in the protocol........................................20
5.5.2.
Additional considerations.............................................................20
6.
ANALYSIS INTERPRETATION..............................................................................20
7.
CONDUCT OF ANALYSES....................................................................................20
7.1.
Sequence of analyses.................................................................................20
7.2.
Statistical considerations for interim analyses.............................................21
8.
CHANGES FROM PLANNED ANALYSES.............................................................21


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9.
NON-STANDARD DATA DERIVATION RULES AND STATISTICAL 
METHODS .............................................................................................................21
9.1.
Handling of missing data.............................................................................21
9.1.1.
Dates...........................................................................................21
10. ANNEXES..............................................................................................................23
10.1.
Business rules for standard data derivations and statistical methods..........23
10.1.1.
Attributing events to vaccine doses..............................................23
10.1.2.
Handling of missing data..............................................................23
10.1.2.1.
Dates..........................................................................23
10.1.2.2.
Laboratory data ..........................................................23
10.1.2.3.
Daily recording of solicited adverse events.................23
10.1.2.3.1.
Studies with electronic diaries.................23
10.1.2.4.
Unsolicited adverse events.........................................23
10.1.3.
Data derivation ............................................................................24
10.1.3.1.
Age at vaccination in years.........................................24
10.1.3.2.
Numerical serology results .........................................24
10.1.3.3.
Geometric mean titres (GMTs) and 
concentrations (GMCs)...............................................24
10.1.3.4.
Onset day...................................................................24
10.1.3.5.
Duration of events ......................................................25
10.1.3.6.
Counting rules for combining solicited and 
unsolicited adverse events .........................................25
10.1.3.7.
Counting rules for occurrences of solicited 
adverse events...........................................................25
10.1.4.
Display of decimals......................................................................25
10.1.4.1.
Percentages ...............................................................25
10.1.4.2.
Demographic/baseline characteristics statistics..........26
10.1.4.3.
Serological summary statistics ...................................26
10.1.5.
Statistical methodology................................................................27
10.1.5.1.
Exact confidence intervals around proportions ...........27
10.2.
TFL TOC.....................................................................................................27
11. REFERENCES.......................................................................................................27


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LIST OF TABLES
PAGE
Table 1
Study objectives and endpoints................................................................8


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LIST OF FIGURES
PAGE
Figure 1
Study design overview .............................................................................9


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LIST OF ABBREVIATIONS
AE
Adverse event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AS01B:
MPL, QS-21, liposome based Adjuvant System (50g MPL and 50g 
QS-21)
AST
Aspartate Aminotransferase
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
CTRS
Clinical Trial Registry Summary
eCRF
Electronic Case Report Form
eDiary
electronic Diary
ELU/mL
ELISA unit per milliliter
Eli Type
Internal database code for type of elimination code
EoS
End of Study
ES
Exposed Set
eTMF
Electronic Trial Master File
GMC
Geometric mean antibody concentration
GMT
Geometric mean antibody titer
GSK
GlaxoSmithKline
HR
Hazard Ratio
IU/mL
International Units per milliLiter
LL
Lower Limit of the confidence interval


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Mcg or μg
Microgram
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not Applicable
PD
Protocol Deviation
PPS
Per-Protocol Set
RR
Relative Risk
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBIR
GSK Biological’s Internet Randomization System
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SR
Study Report
SUSAR
Suspected Unexpected Serious Adverse Reaction
TFL
Tables Figures and Listings 
ToC
Table of Content
UL
Upper Limit of the confidence interval
WBR
Web-based Randomization


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1.
DOCUMENT HISTORY
Date
Description
Protocol Version
23 SEP 2019
First version
Final: 30 APR 2019
2.
OBJECTIVES/ENDPOINTS
Table 1
Study objectives and endpoints
Objectives
Endpoints
Primary

To evaluate the safety and reactogenicity of 2 doses 
of the investigational RSV vaccine administered IM 
according to a 0, 2-month schedule, up to one 
month after the last dose (Day 91, Visit 6).

Occurrence of AEs from first vaccination up to 30 
days after the second vaccination (Day 91):

Occurrence of each solicited local and general 
AE during a 7-day follow-up period (i.e., on the 
day of vaccination and 6 subsequent days) 
after each vaccination.

Occurrence of any unsolicited AE during a 30-
day follow up period (i.e., on the day of 
vaccination and 29 subsequent days) after 
each vaccination.

Occurrence of any hematological 
(erythrocytes, WBC and differential count, 
platelets count and hemoglobin level) and 
biochemical (ALT, AST, creatinine, BUN and 
uric acid) laboratory abnormalities at Days 1, 
8, 61 and 68.

Occurrence of all Grade 3 non-serious AEs 
(solicited and unsolicited) during the 30-day 
follow-up period after each vaccination.

Occurrence of SAEs from Dose 1 up to 30 
days after the second vaccine dose (Day 91).

Occurrence of pIMDs from Dose 1 up to 30 
days after the second vaccine dose (Day 91).
Secondary

To evaluate the humoral immune responses of the 
investigational RSV vaccine administered IM 
according to a 0, 2-month schedule, up to one 
month after the last dose (Day 91, Visit 6).

Humoral immune response with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1), 30 days post-Dose 1 (Day 31), 
on the day of second vaccination (Day 61) and 30 
days post-Dose 2 (Day 91):

Neutralizing antibody titers against RSV-A.

RSVPreF3-specific IgG antibody 
concentrations.

To evaluate the safety of 2 doses of the 
investigational RSV vaccine administered IM 
according to a 0, 2 -month schedule, up to the end 
of follow-up (Month 14, Phone call 2).

Occurrence of SAEs from Dose 1 up to the end of 
follow-up.

Occurrence of pIMDs from Dose 1 up to the end of 
follow-up.

To evaluate the occurrence of RSV-associated 
respiratory tract infections (RTI) during the RSV 
seasons in combined nasal and throat swab 
samples collected during the assessment visit for 
potential RSV-RTI.

Occurrence of qRT-PCR confirmed RSV-associated 
RTI in the combined nasal and throat swabs
collected during the assessment visit for potential 
RSV-RTI during the RSV seasons, up to the end of 
follow-up.


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Objectives
Endpoints
Tertiary

To further characterize immune responses to 
investigational RSV vaccine formulation.

Humoral immune response with respect to 
components of the investigational vaccine at pre-
vaccination (Day 1) and 30 days post-Dose 2 (Day 
91):

Neutralizing antibody titers against RSV
serotype B.

Any further exploratory immunology to detect RSV-
related immune responses, such as but not limited 
to:

Antibodies against specific protein F epitopes.

Potential new immunological markers for 
protection.

Cross-reactive neutralizing antibody titers 
against hMPV.

To evaluate the occurrence of RSV-associated RTI 
during the RSV seasons using self-collected nasal 
swabs.

Occurrence of qRT-PCR confirmed RSV-associated 
RTI in self-collected nasal swab samples during the 
RSV seasons, up to the end of follow-up.
IM: intramuscular; RSV: respiratory syncytial virus; AE: adverse event; WBC: white blood cells; ALT: alanine 
aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; SAE: serious adverse event; pIMD: 
potential immune-mediated disease; RTI: respiratory tract infection; qRT-PCR: quantitative reverse transcription 
polymerase chain reaction, hMPV: Human metapneumovirus
3.
STUDY DESIGN
Figure 1
Study design overview
BS S: Blood sample for safety evaluation (hematology/biochemistry)
BS H: Blood sample for humoral immune responses
qRT-PCR: quantitative reverse transcription polymerase chain reaction
* Visit 1 should take place no longer than 30 days after the Screening Visit. In case Visit 1 occurs more than 30 days 
after the Screening Visit, a re-screening visit should be scheduled before Visit 1 during which blood sample collection 
for safety laboratory assessment must be repeated (maximum one re-screening per subject is allowed). Only


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laboratory results from the re-screening visit, if it occurs, will be taken into consideration and recorded in the eCRF. 
Medical history, physical examination and review of inclusion/exclusion criteria must be repeated if a re-screening visit 
occurs. The subject can only be randomized once the investigator receives the results and confirms the eligibility 
criteria.
** An internal Safety Review Committee (iSRC) evaluation of safety data up to Day 8 from all subjects will be 
performed before proceeding with administration of Dose 2. Additional iSRC evaluations will happen during the 
conduct of the study.
† In case of RTI symptoms during the RSV seasons (from August until end of February), the subject will be asked to 
collect a nasal swab at home and contact the investigator/study staff to schedule an assessment visit for collection of 
an additional nasal swab and a throat swab at the site. The assessment visit should take place as soon as possible 
after the start of symptoms (ideally within 48 hours, but no later than 7 days).
£ A first analysis will be performed on all data collected up to Day 91 for at least primary and secondary endpoints
(except for the occurrence of RSV RTI). The analysis will be based on data as clean as possible.

Type of study: self-contained.

Experimental design: A phase I, observer-blind, randomized, placebo-controlled, 
single-country study with 2 parallel groups (see Figure 1):

Duration of the study: approximately 14 months per subject. 

Epoch 001: Screening Visit (Day -30 to -3)

Epoch 002: Primary (vaccination phase) starting at Visit 1 (Day 1) and ending at 
Visit 6 (Day 91) 

Epoch 003: Follow-up starting after Visit 6 (Day 91) and ending at Phone Call 2 
(Month 14)

Primary Completion Date (PCD): last visit of the vaccination phase (Visit 6 
[Day 91]). 

End of Study (EoS): Last testing results released of samples collected up to Phone 
call 2 (Month 14) (for assays related to secondary endpoints only), or Last subject 
last Phone Call, whichever comes last.
While no samples will be collected at Phone calls 1 and 2, nasal and throat swabs 
may be collected in case of RTI symptoms up to the Phone call 2 (Month 14) 
timepoint, if this timepoint falls within the RSV season.

Study groups:

RSV Group: subjects receiving 2 doses of the investigational RSV vaccine 
containing 120 g RSVPreF3 adjuvanted with AS01B.

Placebo: subjects receiving 2 doses of placebo as control.

Vaccination schedule: Two vaccine doses administered intramuscularly at Day 1 
and Day 61.

Treatment allocation: Subjects will be randomized using a centralized 
randomization system on internet (SBIR) on Day 1. 


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A total of approximately 40 participants are planned to be enrolled in this study in a 
1:1 ratio. The target is to enrol approximately 28 eligible participants aged 60-69 
years (approximately 14 per group) and approximately 12 (and minimum 10) eligible 
participants aged 70-80 years (approximately 6 per group). The randomization 
algorithm will use a minimization procedure accounting for age, center and gender.

Blinding: observer-blind.
The vaccination phase (Epoch 002) will be observer-blind. A first statistical analysis 
will be performed on data available up to one-month post-Dose 2 (Visit 6, Day 91). 
Given that summary safety results may unblind some specific subjects, the follow-up 
phase (Epoch 003) will be considered as single-blind with subjects remaining 
blinded up to study end (Phone Call 2 [Month 14]). The investigators will not be 
provided with the individual data listings or with the randomization listings until the 
end of study analysis.

RTI surveillance: Active and passive surveillance will only be carried out during 
RSV seasons (from August until end of February) throughout the entire study:

Active surveillance: study participants will be contacted by the 
investigator/study staff every 2 weeks to identify if they experienced an RTI.

Passive surveillance: study participants are instructed to contact the 
investigator/study staff as soon as they experience an RTI.
At the beginning of the RSV season, study participants will be reminded of the start 
of the RTI surveillance.

Safety monitoring: The study will be conducted with oversight by an internal Safety 
Review Committee (iSRC). An iSRC evaluation of safety data up to Day 8 from all 
subjects will be performed before proceeding with administration of Dose 2. The 
investigator is not permitted to start the administration of the next dose until receipt 
of the favourable outcome of the safety evaluation by the iSRC. A second data 
review iSRC meeting will be held to review all available safety data up to 30 days 
post-Dose 2. During the follow-up phase, 2 iSRC meetings will be planned with an 
interval of approximately 6 months.

Group description for analysis
For the analysis by age category, the following sub-group names will be used in the TFLs
Sub-group label in tables 
Sub-group definition for footnote
60-69Y
60 to 69 years old subjects
70-80Y
70 to 80 years old subjects


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4.
ANALYSIS SETS
4.1.
Definition
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.
Per Protocol 
All subjects who received at least 1 dose of the study treatment to which they 
are randomized and have post-vaccination data minus subjects with protocol 
deviations that lead to exclusion.
4.2.
Criteria for eliminating data from Analysis Sets
Elimination codes are used to identify subjects to be eliminated from analysis. Detail is 
provided below for each set. 
4.2.1.
Elimination from Exposed Set (ES)
Code 1030 (Study vaccine not administered at all), 800 (Fraudulent data) and code 900 
(invalid informed consent or other GCP noncompliance) will be used for identifying 
subjects eliminated from ES.
4.2.2.
Elimination from Per-protocol analysis Set (PPS)
4.2.2.1.
Excluded subjects
A subject will be excluded from the PPS analysis under the following conditions 

For codes 800, 900, 1030, 1050 and 1060: subjects will be eliminated for all visits.

For codes 1040, 1070, 1080, 1090, 2010, 2040, 2060, 2080: subjects will be 
eliminated from a specific visit (at which the condition is met) onwards.

For codes 2090, 2100, 2120: subjects will be eliminated for the specific visit at 
which the condition is met.
Code
Condition under which the code is used
Visit (timepoints) 
where the code is 
applicable
Applicable for analysis set
800
Fraudulent data
All
ES and PPS for analysis of 
immunogenicity
900
Invalid informed consent or other GCP non-
compliance
All
ES and PPS for analysis of 
immunogenicity
1030
Study vaccine not administered at all
All
ES and PPS for analysis of 
immunogenicity
1040
Administration of concomitant vaccine(s) 
forbidden in the protocol
Any investigational or non-registered vaccine 
other than the study vaccine used during the 
study period
All
PPS for analysis of 
immunogenicity


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Code
Condition under which the code is used
Visit (timepoints) 
where the code is 
applicable
Applicable for analysis set
A vaccine not foreseen by the study protocol 
administered during the period starting 30 
days before the first dose and ending 30 
days after the last vaccine dose, except for 
inactivated and subunit influenza vaccines 
which can be administered up to 14 days 
before or from 30 days after each 
vaccination.
1050
Randomization failure
All
PPS for analysis of 
immunogenicity
1060
Randomization code was broken
All
PPS for analysis of 
immunogenicity
1070
Vaccination not according to protocol
Incomplete vaccination course
Subject was vaccinated with the correct 
vaccine but containing a lower volume
Wrong replacement or study vaccine 
administered (not compatible with the vaccine 
regimen associated to the treatment number)
Route of the study vaccine is not 
intramuscular
Wrong reconstitution of administered vaccine
Vaccination visits 1 
and 4
PPS for analysis of 
immunogenicity
1080
Vaccine temperature deviation
Vaccine administered despite a Good 
Manufacturing Practices (GMP) no-go 
temperature deviation
Vaccination visits 1 
and 4
PPS for analysis of 
immunogenicity
1090
Expired vaccine administered
Vaccination visits 1 
and 4
PPS for analysis of 
immunogenicity
2010
Protocol violation (inclusion/exclusion criteria)
All
PPS for analysis of 
immunogenicity
2040
Administration of any medication forbidden by 
the protocol
Any investigational or non-registered 
medication used during the study period
Immunosuppressants or other immune-
modifying drugs administered chronically 
(i.e., more than 14 consecutive days in total) 
during the study period
Long-acting immune-modifying drugs 
administered at any time during the study 
period
Immunoglobulins and/or any blood products 
administered during the study period
All
PPS for analysis of 
immunogenicity
2060
Intercurrent medical condition 
Subjects may be eliminated from the PPS 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 (other 
than RSV infection).
All
PPS for analysis of 
immunogenicity
2080
Subjects did not comply with vaccination 
schedule
number of days between dose 1 and dose 2 
is outside [55-65 days]
Visit 4
PPS for analysis of 
immunogenicity


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Code
Condition under which the code is used
Visit (timepoints) 
where the code is 
applicable
Applicable for analysis set
2090
Subjects did not comply with blood sample 
schedule
Number of days between dose 1 and visit 3 
blood sample is outside [30-37 days]
Number of days between dose 2 and visit 6 
blood sample is outside [30-37 days]
Visits 3 and 6
PPS for analysis of 
immunogenicity
2100
Serological results not available post-
vaccination
No immunological result at visit x for all 2
following tests: RSV A Neutralising antibody 
titer and RSVPreF3-specific IgG antibody 
concentration 
Visits 3, 4, 6
PPS for analysis of 
immunogenicity
2120
Obvious incoherence or abnormality or error 
in data
Unreliable released data as a result of 
confirmed sample mismatch or confirmed 
inappropriate sample handling at lab
Visits 1, 3, 4, 6
PPS for analysis of 
immunogenicity
5.
STATISTICAL ANALYSES
That standard data derivation rules and stat methods are described in Section 10.1 while
the study specific data derivation rules and statistical methods are described in Section 9.
5.1.
Demography
5.1.1.
Analysis of demographics/baseline characteristics planned in the 
protocol
The analysis of demographic characteristics by group will be performed on the ES and on 
the PPS.
Demographic characteristics (age at vaccination in years, sex, race and ethnicity) will be 
summarized by group using descriptive statistics:

Frequency tables will be generated for categorical variables such as race.

Mean, median, standard deviation and range will be provided for continuous data 
such as age.
The distribution of subjects will be tabulated as a whole and per group and for each age 
category (60-69 years and 70-80 years).
Withdrawal status will be summarized by group using descriptive statistics:

The number of subjects enrolled into the study as well as the number of subjects 
excluded from Per Protocol (PP) analyses will be tabulated. 

The numbers of withdrawn subjects will be tabulated according to the reason for 
withdrawal.


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5.1.2.
Additional considerations
Vital signs (heart rate, respiratory rate, systolic/diastolic blood pressure, pulse oximetry) 
reported at visit 1 will be summarized by study group using descriptive statistics. 
5.2.
Exposure
5.2.1.
Analysis of exposure planned in the protocol
NA
5.2.2.
Additional considerations
The number of doses of study vaccines administered will be tabulated by group and by 
vaccine.
5.3.
Immunogenicity
The primary analysis will be based on the Per Protocol set for analysis of immunogenicity.
If in any study group and at any timepoint, the percentage of vaccinated subjects with 
serological results excluded from the Per Protocol set for analysis of immunogenicity is 
10% or more, a second analysis based on the Exposed set will be performed to complement 
the Per Protocol analysis.
5.3.1.
Analysis of immunogenicity planned in the protocol
5.3.1.1.
Humoral immune response
For each group, at each time point that blood samples are collected for humoral immune 
response and for each assay (unless otherwise specified): 

Percentage of subjects above pre-defined threshold and their exact 95% CI will be 
tabulated.

Geometric mean concentrations (GMCs)/ geometric mean titers (GMTs) and their 
95% CI will be tabulated and represented graphically.

Antibody titer/concentration will be displayed using reverse cumulative curves.

The distributions of antibody titers/concentrations will be tabulated.

Geometric mean of ratios of antibody titer/concentrations at each post-vaccination 
time point over pre-vaccination (Day 1) will be tabulated with 95% CI.

Individual post-vaccination results (at Days 31, 61 and 91) versus pre-vaccination 
results (Day 1) will be plotted using scatter plots. Results of the placebo group will 
be used as a reference.

Distribution of the fold increase of the antibody titers/concentrations (post- over pre-
vaccination titers) will be tabulated.


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
The ratio of fold increase (post over pre-vaccination) of RSVPreF3 ELISA antibody 
concentrations over the fold increase (post over pre-vaccination) of RSV-A and 
RSVB neutralizing antibody titers will be computed and tabulated using descriptive 
statistics.

The kinetics of GMT/GMCs will be plotted as a function of time for subjects with 
results available at all time points.
The immunogenicity analysis might also be performed by age category (60-69 years and 
70-80 years). 
5.4.
Analysis of safety and reactogenicity
The primary analysis will be performed on the Exposed Set.
5.4.1.
Analysis of safety and reactogenicity planned in the protocol

The percentage of subjects with at least one local AE (solicited and unsolicited), with 
at least one general AE (solicited and unsolicited) and with any AE during the 7-day 
or 30-day follow-up period will be tabulated with exact 95% confidence interval (CI) 
after each dose and overall. The same computations will be done for Grade 3 AEs, 
for any AEs considered related to vaccination, for Grade 3 AEs considered related to 
vaccination and for Grade 3 non-serious AEs.

The percentage of subjects with any AE (solicited and unsolicited) resulting in a 
medically attended visit during the 30-day follow-up period will also be tabulated 
after each dose and overall.

The percentage of subjects reporting each individual solicited local AE (any grade 
and Grade 3) and solicited general AE (any grade, Grade 3, any related and Grade 3 
related) during the 7-day follow-up period (i.e., on the day of vaccination and 6 
subsequent days) will be tabulated for each group after each dose and overall. 

For fever, the number and percentage of subjects reporting fever by half degree (°C) 
cumulative increments during the 7-day follow-up period (i.e., on the day of 
vaccination and 6 subsequent days) will be tabulated for each group after each dose 
and overall. Similar tabulations will be performed for any fever with a causal 
relationship to vaccination and for Grade 3 (> 39.0°C) causally related fever. In 
addition, the prevalence of any and Grade 3 fever will be presented graphically over 
time after each vaccination.

For each group and for each hematology and biochemistry parameter:
i.
The percentage of subjects having hematology and biochemistry results below 
or above the laboratory normal ranges will be tabulated by time point.
ii.
The summary of grading post-vaccination will be tabulated versus baseline. 
Grades will be based on the FDA Guidance for Industry “Toxicity Grading 
Scale for Healthy Adults and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials”, see Protocol Section 12.7 The laboratory parameters 
not included on FDA Toxicity Grading Scale will not be graded.


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
The percentage of subjects with any unsolicited AEs during the 30-day follow-up 
period (i.e., on the day of vaccination and 29 subsequent days) with its exact 95% CI 
will be tabulated by group and by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term. Similar tabulation will be done for Grade 3 unsolicited 
AEs, for any causally related unsolicited AEs, for Grade 3 causally related 
unsolicited AEs and for unsolicited AEs resulting in a medically attended visit. The 
verbatim reports of unsolicited AEs will be reviewed by a qualified person and the 
signs and symptoms will be coded according to the MedDRA Dictionary for Adverse 
Reaction Terminology. Every verbatim term will be matched with the appropriate 
Preferred Term.

The percentage of subjects with at least one report of SAE classified by the 
MedDRA Preferred Terms and reported from Dose 1 up to 30 days after the second 
vaccine dose (Day 91) will be tabulated with exact 95% CI. 

The percentage of subjects with at least one pIMD classified by the MedDRA 
Preferred Terms and reported from Dose 1 up to 30 days after the second vaccine 
dose (Day 91) will be tabulated with exact 95% CI. 

The percentage of subjects with at least one report of SAE classified by the 
MedDRA Preferred Terms and reported during the entire study period will be 
tabulated with exact 95% CI. SAEs will also be described in detail.

The percentage of subjects with at least one pIMD classified by the MedDRA 
Preferred Terms and reported during the entire study period will be tabulated with 
exact 95% CI. pIMDs will also be described in detail.
The analysis of safety might also be performed by age category (60-69 years and 70-80 
years).
5.4.2.
Additional considerations

Compliance in completing solicited adverse events information will be tabulated after 
each dose and overall.

The percentage of subjects using concomitant medication (any medication, any 
antipyretic and any antipyretic taken prophylactically, respectively) during the 7-day 
follow-up period (i.e., on the day of vaccination and 6 subsequent days) and during 
the 30-day follow-up period (i.e., on the day of vaccination and 29 subsequent days) 
will be summarized by group after each vaccine dose and overall.

The percentage of subjects reporting each individual solicited local AE (any grade and 
Grade 3) and solicited general AE (any grade, Grade 3, any related and Grade 3 
related) during the 4-day follow-up period (i.e., on the day of vaccination and 3
subsequent days) will be tabulated for each group after each dose and overall.

The percentage of subjects with at least one local solicited AE, with at least one general 
solicited AE and with any solicited AE during the 7-day and 4-day follow-up period 
will be tabulated with exact 95% confidence interval (CI) after each dose and overall. 
The same computations will be done for Grade 3 AEs, for any AEs considered related 
to vaccination, and for Grade 3 AEs considered related to vaccination.


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
The number of days with solicited symptoms reported during the 7-day follow-up 
period will be tabulated for each solicited adverse event, after each dose using 
descriptive statistics (mean, min, Q1, median, Q3, maximum). The same tabulation 
will be done for Grade 3 symptoms, and also during the whole post-vaccination 
period (to include the total number of days for symptoms ongoing beyond the 
follow-up period). 

The incidence of each solicited symptom (any grade and grade 3) will also be 
represented graphically per group and per dose.
5.4.2.1.
Solicited Adverse Events
Solicited adverse events will be reported daily during the 7-day follow up period after each 
vaccination by the subject in the eDiaries. Missing or non-evaluable measurements will not 
be replaced. The data will be made available for site follow-up on the eDiary web-portal. 
In order to summarize the data, the maximum intensity of local injection site 
redness/swelling (in mm) and fever (in °C) will be categorized as follows
Grading
Redness/swelling
Fever
0:
20 mm
< 38.0°C 
1:
> 20 - 50 mm
≥ 38.0°C - 38.5°C 
2:
> 50 - 100 mm
> 38.5°C - 39.0°C 
3:
> 100 mm
> 39.0°C 
Fever is defined as temperature 38.0°C (regardless of the location of measurement). 
The preferred location for measuring temperature in this study will be the oral cavity.
Body temperature will also be summarized by 0.5°C increments as follows: 
≥38.0, >38.5, >39.0, >39.5, >40.0 °C.
Each subject’s data will be summarized according to the maximal severity observed 
during the follow-up period for each adverse event and each dose, followed by a 
summary across subjects and across doses.
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.
In adults, such an AE would, for example, prevent attendance at 
work and would necessitate the administration of corrective 
therapy.
5.4.2.2.
Unsolicited Adverse Events
When an unsolicited adverse event occurs more than once for a subject, the maximal 
severity and strongest relationship to the vaccine group will be counted. The selection of 
unsolicited AEs reported during the follow-up period will be done using the day of onset.
The analysis of unsolicited adverse events includes the following categories:


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
Any unsolicited adverse event

Possibly related unsolicited adverse events

Grade 3 unsolicited adverse events

Grade 3 possibly related unsolicited adverse events 

Serious adverse events (SAEs)

Possibly related SAEs

Potential immune-mediated disease (pIMD)

Medically attended adverse events
SAEs and pIMDs reported during the entire study period will be tabulated.
In addition, the following time periods will be considered to report SAEs/pIMDs at the 
first and end of study analyses (E1_02 and E1_01, see section 7.1):

from Dose 1 up to 30 days post-dose 2 (or up to 90 days post-dose 1 for subjects who 
did not received the second dose)
* months will be converted in days in order to select the events for the output tables.

Listing of AEs/SAEs leading premature withdrawal from study or to interruption of 
vaccination will be described in detail.
5.4.2.3.
Combined Solicited and Unsolicited Adverse Events
A summary of subjects with all combined solicited (regardless of their duration) and 
unsolicited adverse events will be provided. Solicited adverse events will be coded by 
MedDRA as per the following codes:
Solicited symptom
Lower level term code
Corresponding Lower level term decode 
Pain
10022086
Injection site pain
Erythema
10015150
Erythema
Swelling
10053425
Swelling at injection site
Fatigue
10016256
Fatigue
Fever
10016558
Fever
Gastrointestinal symptoms
10017944
Gastrointestinal disorder
Headache
10019211
Headache
Myalgia
10028411
Myalgia
Shivering
10040558
Shivering
Arthralgia
10003239
Arthralgia
For clinicaltrials.gov and EudraCT posting purposes, a summary of combined solicited 
and unsolicited non-serious adverse events will be produced by System Organ Class and 
preferred terms and according to occurrence of each event. 


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5.4.2.4.
Clinical Safety Laboratory Investigations
In case of invalid or missing results or clinically significant grade 3 and above abnormal 
laboratory findings, a repeat testing may be done to confirm the first result (see Protocol 
section 12.5.6). For the analysis, the following rules will be applied:

In general, the first result will be considered, except if this result is missing.

In case of retesting for a grade 3 and above at pre-vaccination, the retesting will be 
considered if the result is < grade 3.
5.4.2.5.
Concomitant Medication
Medications will be coded using the GSKDRUG dictionary. 
5.5.
Analysis of RTI
5.5.1.
Analysis of RTI planned in the protocol
The analysis will be performed on the ES.
Any RTI episode for which a visit for the assessment of potential RSV-RTI has been 
performed (with nasal/throat swab sampling) will be described in detail in a listing. This 
will present the results of the qRT-PCR performed on the nasal swab collected by the 
subject and on the nasal/throat swab collected by an appropriately qualified person (i.e., 
medical or nursing) at the assessment visit.
5.5.2.
Additional considerations
Information collected at assessment visit will be further described for RSV RTI episodes 
versus Non-RSV RTI episodes. An RTI episode will be considered as associated to RSV
when the qRT-PCR test performed on nasal/throat swabs collected at assessment visit is 
positive. It will include: vital signs, clinical signs and symptoms, self-collected nasal 
swab result, medically attended visit and SAE related to the episode.
6.
ANALYSIS INTERPRETATION
The analyses will be descriptive with the aim to characterize the safety/reactogenicity and 
immunogenicity of the RSV group with respect to the placebo. 
7.
CONDUCT OF ANALYSES
7.1.
Sequence of analyses
The following analyses will be performed stepwise:

A first analysis will be performed on all data available and as clean as possible, when 
data for at least primary and secondary endpoints up to Day 91 are available (except 
for the occurrence of RSV RTI). This analysis will be considered as final for those 
endpoints. A statistical report will be written.


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At this point, the statistician will be unblinded (i.e., individual subject treatment 
assignments will be available), but no individual listings will be provided to the 
study team. Given that summary safety results may unblind some specific subjects, 
the study will be considered as single-blind from this point onwards, with subjects 
remaining blinded up to study end (Month 14). The investigators will not be 
provided with the individual data listings or with the randomization listings until the 
end of study analysis.

The end of study analysis will be performed when all data for primary and secondary 
endpoints up to study conclusion are available (Month 14). Individual listings will 
only be provided at this stage. An integrated clinical study report containing all 
available data will be written and made available to the investigators.
The final 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 and will be made available to the investigators at that time.
7.2.
Statistical considerations for interim analyses
All analyses will be conducted on final data (as clean as possible) and therefore no 
statistical adjustment for interim analyses is required.
8.
CHANGES FROM PLANNED ANALYSES
NA
9.
NON-STANDARD DATA DERIVATION RULES AND 
STATISTICAL METHODS
The following sections describe additional derivation rules and statistical methods which 
are not presented in section 10.1.
9.1.
Handling of missing data
9.1.1.
Dates
When partially completed dates (i.e. with missing day or month) are used in calculations, 
the following rules will be applied:

Adverse event start dates with missing day:

If the month is not the same as the vaccine dose, then the imputed start date will 
be the 1st of the month.
Description
Analysis
ID
Disclosure Purpose
(CTRS=public posting, SR=study report, 
internal)
Reference for TFL
TOC
End of study analysis
E1_01
CTRS, SR
See column 5 in TFL TOC
Analysis up to Day 91
E1_02
Internal
See column 5 in TFL TOC


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
If the event starts in the same month as the vaccine dose, the flag indicating if 
the event occurred before or after vaccination (AE.AESTRTPT) will be used to 
complete the date. If ‘after vaccination’ is selected, the imputed start date will 
match the vaccine dose given during that month. If ‘before vaccination’ is 
selected, the imputed date will be one day before the vaccine dose given during 
that month.

Adverse event start dates with missing day and month:

If the year is not the same as the vaccine dose, then the imputed start date will be 
the 1st of January.

If the event starts in the same year as the vaccine dose, the flag indicating if the 
event occurred before or after vaccination (AE.AESTRTPT) will be used to 
complete the date. If ‘after vaccination’ is selected, the imputed start date will 
match the first vaccine dose given during that year. If ‘before vaccination’ is 
selected, the imputed date will be one day before the first vaccine dose given 
during that year.

Adverse event end dates with missing day: the imputed end date will be the last day 
of the month (30 or 31) or the study conclusion date whichever comes first.

Adverse event end dates with missing day and month: the imputed end date will be 
the last day of the year (31st of December) or the study conclusion date whichever 
comes first.
All other cases of incomplete AE or concomitant medication/vaccination start date will 
follow the standard rules above.


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10.
ANNEXES 
10.1.
Business rules for standard data derivations and statistical 
methods
This section contains GSK Vaccines’ standard rules for data display and derivation for 
clinical and epidemiological studies. These rules will be applied along with those detailed 
in section 9 (additional study-specific rules).
10.1.1.
Attributing events to vaccine doses
The dose relative to an event is the most recent study dose given to a subject prior to the 
start of a given event. For example, if the start date of an adverse event is between Dose 1 
and Dose 2, the relative dose will be Dose 1.
If an event starts on the same day as a study dose, the relative dose will be derived from 
the additional information provided in the CRF using the contents of the flag indicating if 
the event occurred before or after vaccination. If ‘after vaccination’ is selected, the 
relative dose for the event will be the one administered on the start day of the event. If 
‘before vaccination’ is selected, the relative dose for the event will be the dose prior to 
this one.
10.1.2.
Handling of missing data
10.1.2.1.
Dates
When partially completed dates (i.e. with missing day or month) are used in calculations, 
the following standard rules will be applied:

A missing day will be replaced by 15

A missing day and month will be replaced by June 30th.
See also exceptions in section 9.1.
10.1.2.2.
Laboratory data
Missing laboratory results (including immunological data) will not be replaced.
10.1.2.3.
Daily recording of solicited adverse events
10.1.2.3.1. Studies with electronic diaries
For studies using electronic diaries for the collection of solicited adverse events, a 
solicited adverse event will be considered present only when a daily recording of grade 1 
or more is present.
10.1.2.4.
Unsolicited adverse events
Missing severity, relationship with study vaccine, and outcome of unsolicited adverse 
events will not be replaced and will appear as ‘UNKNOWN’ in all statistical output.


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10.1.3.
Data derivation
10.1.3.1.
Age at vaccination in years
When age at vaccination is to be displayed in years, it will be calculated as the number of 
complete calendar years between the date of birth and the date of vaccination. For 
example:
DOB = SEP1983, Date of vaccination = 14SEP2018
-> Derived DOB=15SEP1983 and derived Age = 34 years
DOB = SEP1983, Date of vaccination = 15SEP2018
-> Derived DOB=15SEP1983 and derived Age = 35 years
10.1.3.2.
Numerical serology results
Numerical serology results will be derived from the content of IS.ISORRES in the SDTM 
dataset. For assays with a specific cut-off, the following derivation rules apply:
IS.ISORRES
Derived value
“NEG”, “-“, or “(-)”
cut-off/2
“POS”, “+”, or “(+)”
cut-off
“< value” and value is <= assay cut-off
cut-off/2
“< value” and value is > assay cut-off
value
“> value” and value is < assay cut-off
cut-off/2
“> value” and value is >= assay cut-off
value
“value” and value is < cut-off
cut-off/2
“value” and value is >= cut-off and value is <=ULOQ
“value” and value is > ULOQ
value
ULOQ
All other cases
missing
10.1.3.3.
Geometric mean titres (GMTs) and concentrations (GMCs)
Geometric Mean Titre (GMT) or Concentration (GMC) calculations are performed by 
taking the inverse logarithm of the mean of the log titeror concentration transformations. 
Antibody titeror concentrations below the cut-off of the assay will be given an arbitrary 
value of half the cut-off of the assay for the purpose of GMT/GMC calculation. The cut-
off value is defined by the laboratory before the analysis and is described in the protocol.
10.1.3.4.
Onset day
The onset day for an event (e.g. AE, medication, vaccination) is the number of days 
between the last study vaccination and the start date of the event. This is 1 for an event 
occurring on the same day as a vaccination (and reported as starting after vaccination).


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10.1.3.5.
Duration of events
The duration of an event with a start and end date will be the number of days between the 
start and end dates plus one day, i.e. an event that starts on 03MAR2018 and ends on 
12MAR2018 has a duration of 10 days.
The duration of solicited events will be calculated as the sum of the individual days with 
the adverse event reported at grade 1 or higher during the solicited adverse event period.
10.1.3.6.
Counting rules for combining solicited and unsolicited adverse events
For output combining solicited and unsolicited adverse events, all serious adverse events 
will be considered general events since the administration site flag is not included in the 
expedited adverse event CRF pages.
Multiple events with the same preferred term which start on the same day are counted as 
only one occurrence.
10.1.3.7.
Counting rules for occurrences of solicited adverse events
When the occurrences of solicited adverse events are summarized, each event recorded as 
having occurred during a specific period will be counted as only one occurrence 
regardless of the number of days on which it occurs. Also, in the case of co-administered 
study vaccines, an injection site reaction recorded for a subject following multiple 
vaccines will be counted as only one occurrence.
10.1.4.
Display of decimals
10.1.4.1.
Percentages
Percentages and their corresponding confidence limits will be displayed with:

no decimals when there are fewer than 50 subjects in each tabulated group

one decimal when there are at least 50 subjects in at least one tabulated group

Exceptions will be made for percentages that are not 0% or 100% but appear as 
0% or 100% due to rounding. For these specific cases the number of decimals 
will be increased until the displayed value is no longer 0% or 100%. Examples 
are given in the following table.


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n/N
Displayed percentage
10/45
22%
1/45
2%
10/55
18.2%
1/55
1.8%
1/300
0.3%
1/3000
0.03%
1/30000
0.003%
299/300
99.7%
2999/3000
99.97%
29999/30000
99.997%

The display of additional decimals for values close to 0% or 100% will be 
applied only to point estimates and not confidence limits, which can be rounded 
and displayed as 0% or 100%.

Values of exactly 0% or 100% will be presented with no decimals regardless of 
the number of subjects per tabulated group.
10.1.4.2.
Demographic/baseline characteristics statistics
The mean, median, and standard deviation for continuous baseline characteristics will be 
presented with one decimal.
The minimum and maximum values and quartile values (if required) will be presented 
with the same number of decimals as the observed values. 
10.1.4.3.
Serological summary statistics
The number of decimals used when displaying geometric mean titers (GMT) or 
concentrations (GMC) and their confidence limits is shown in the following table:
GMT or GMC value
Number of decimals to display
<0.1
3
>=0.1 and <10
2
>=10 and <1000
1
>=1000
0
When multiple categories of GMT or GMC values are present in the same table, the 
number of decimals displayed should match that of the smallest category (i.e. the one 
with the higher number of decimals). For example, if GMT or GMC values of <0.1 
appear in the same table as values of >=0.1 and <10, 3 decimals should be displayed for 
both.
GMT or GMC ratios and their confidence limits will be displayed with 2 decimals 
regardless of the actual values.


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10.1.5.
Statistical methodology
10.1.5.1.
Exact confidence intervals around proportions
The exact confidence intervals around within-group proportions are derived using the 
method of Clopper and Pearson [Clopper, 1934].
10.2.
TFL TOC
The Table Figure Listing (TFL) Table Of Content (TOC) which itemizes the planned list 
of TFL and their associated lay-out is developed as a separate document.
11.
REFERENCES
Clopper CJ, Pearson E. The Use of Confidence or Fiducial Limits Illustrated in the case 
of the Binomial. Biometrika. 1934;26:404-13.