A Phase 3, Open-label, Randomized, Controlled, Multi-country Study to Evaluate the Immune Response, Safety and Reactogenicity of RSVPreF3 OA Investigational Vaccine When Co-administered With FLU-QIV Vaccine in Adults Aged 60 Years and Above
Phase: PHASE3
Conditions: Respiratory Syncytial Virus Infections
Sponsor: GlaxoSmithKline

 
 
 
 
 
 
 
 
Protocol 
A Phase 3, open-label, randomized, controlled, multi-country study to evaluate the 
immune response, safety and reactogenicity of RSVPreF3 OA investigational vaccine 
when co-administered with FLU-QIV vaccine in adults aged 60 years and above. 
 
214488 
 
Date of Document: 27 November 2020 
 

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Clinical Study Protocol 
Sponsor: 
GlaxoSmithKline Biologicals SA (GSK) 
Rue de l’Institut, 89 
1330 Rixensart, Belgium 
Primary study intervention 
and number 
GlaxoSmithKline Biologicals SA (GSK)’s 
investigational respiratory syncytial virus (RSV) 
vaccine BIO RSV OA=ADJ (GSK3844766A) 
Other study interventions 
GSK’s Fluarix Quadrivalent or Fluarix Tetra 
(quadrivalent seasonal influenza vaccine) 
eTrack study number and 
abbreviated title 
214488 (RSV OA=ADJ-007) 
Date of protocol 
Final: 19 October 2020 
Date of protocol amendment 
Amendment 1 Final: 24 November 2020 
Title  
A Phase 3, open-label, randomized, controlled, 
multi-country study to evaluate the immune 
response, safety and reactogenicity of RSVPreF3 OA 
investigational vaccine when co-administered with 
FLU-QIV vaccine in adults aged 60 years and above. 
Brief title  
A study on the immune response and safety elicited 
by a vaccine against respiratory syncytial virus 
(RSV) when given alone and together with a vaccine 
against influenza in adults aged 60 years and above.  
Based on GlaxoSmithKline Biologicals SA Protocol WS v17.1 
©2020 GSK group of companies or its licensor. 
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Protocol Amendment 1 Sponsor Signatory Approval 
eTrack study number and 
abbreviated title 
214488 (RSV OA=ADJ-007) 
Date of protocol 
Final: 19 October 2020 
Date of protocol amendment 
Amendment 1 Final: 24 November 2020 
Title  
A Phase 3, open-label, randomized, controlled, 
multi-country study to evaluate the immune 
response, safety and reactogenicity of RSVPreF3 
OA investigational vaccine when co-administered 
with FLU-QIV vaccine in adults aged 60 years and 
above. 
Sponsor signatory  
(Amended 24 November 2020) 
Marie Van Der Wielen, MD 
Clinical and Epidemiology R&D Project Lead  
RSV Older Adults 
Signature 
 
 
 
Date 
 
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Protocol Amendment 1 Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments or protocol administrative changes, with the terms of the clinical trial 
agreement and with any other study conduct procedures and/or study conduct 
documents provided by GlaxoSmithKline (GSK) Biologicals 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 intervention 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 participant.  
• 
To perform no biological assays on the clinical samples other than those described in 
the protocol or its amendment(s).  
• 
To co-operate with representative(s) 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 intervention(s), 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 
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 all other documents 
required by regulatory agencies for this study. 
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eTrack study number and 
abbreviated title 
214488 (RSV OA=ADJ-007) 
Date of protocol 
Final: 19 October 2020 
Date of protocol amendment 
Amendment 1 Final: 24 November 2020 
Title  
A Phase 3, open-label, randomized, controlled, 
multi-country study to evaluate the immune 
response, safety and reactogenicity of RSVPreF3 
OA investigational vaccine when co-administered 
with FLU-QIV vaccine in adults aged 60 years and 
above. 
Investigator name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
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SPONSOR INFORMATION 
1. Sponsor 
GlaxoSmithKline Biologicals SA (GSK)  
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 Events (SAEs) 
GSK central back up study contact for reporting SAEs: refer to the protocol Section 
8.3.3.1.  
Study contact for reporting SAEs: refer to the local study contact information 
document. 
5. GSK Helpdesk for Emergency Unblinding 
Refer to the protocol section 6.3.5.1. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document history 
Document 
Date 
Original Protocol 
19 October 2020 
Amendment 1: 24 November 2020 
Overall Rationale for the Amendment:  
The protocol is amended to address the comments from the Center for Biologics 
Evaluation and Research (CBER), United States Food and Drug Administration (US 
FDA). Specifically, the non-inferiority (NI) margins have been updated, and accordingly 
the power calculations associated with the co-primary objectives have been updated 
while the sample size remains the same. The formulation of the FLU vaccine has also 
been added based on WHO recommendations for the 2021 influenza season in the 
Southern Hemisphere, and a typographical error has been corrected, in Table 7 (Study 
interventions administered).  
List of main changes in the protocol and their rationale 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 Study 
interventions 
administered 
The formulation of the FLU 
vaccine has been added. 
The formulation has been added based on WHO 
recommendations for the 2021 influenza season in 
the Southern Hemisphere. 
Section 9.1 
Statistical 
hypotheses 
The NI margins associated with 
each co-primary objective have 
been changed from 2.0 to 1.5. 
These changes are made to acknowledge CBER’s 
recommendation of a NI margin of 1.5 for 
demonstrating NI based on influenza hemagglutinin 
inhibition and RSV-A neutralizing antibody geometric 
mean titers.  
Section 9.2 Sample 
size determination 
The power calculations have 
been updated to reflect the 
updated NI margin. 
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TABLE OF CONTENTS 
PAGE 
SPONSOR INFORMATION ............................................................................................ 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 7 
Document history ..................................................................................................... 7 
List of main changes in the protocol and their rationale ............................................ 7 
1. 
PROTOCOL SUMMARY ........................................................................................ 15 
1.1. 
Synopsis ..................................................................................................... 15 
1.2. 
Schema ...................................................................................................... 15 
1.3. 
Schedule of Activities (SoA) ........................................................................ 16 
2. 
INTRODUCTION .................................................................................................... 20 
2.1. 
Study rationale ............................................................................................ 20 
2.2. 
Background ................................................................................................ 20 
2.3. 
Benefit/Risk assessment ............................................................................. 21 
2.3.1. 
Risk Assessment ......................................................................... 21 
2.3.2. 
Benefit Assessment ..................................................................... 21 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................... 22 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 22 
4. 
STUDY DESIGN .................................................................................................... 24 
4.1. 
Overall design ............................................................................................. 24 
4.1.1. 
Overview of the recruitment plan ................................................. 25 
4.1.2. 
Enrolment rules............................................................................ 26 
4.2. 
Scientific rationale for study design ............................................................. 26 
4.3. 
Justification for dose ................................................................................... 27 
4.4. 
End of Study definition ................................................................................ 27 
5. 
STUDY POPULATION ........................................................................................... 27 
5.1. 
Inclusion criteria .......................................................................................... 27 
5.2. 
Exclusion criteria ......................................................................................... 28 
5.2.1. 
Medical conditions ....................................................................... 28 
5.2.2. 
Prior/Concomitant therapy ........................................................... 29 
5.2.3. 
Prior/Concurrent clinical study experience ................................... 29 
5.2.4. 
Other exclusions .......................................................................... 30 
5.2.5. 
Caregiver support ........................................................................ 30 
5.3. 
Lifestyle considerations ............................................................................... 30 
5.4. 
Screen failures ............................................................................................ 30 
5.5. 
Criteria for temporarily delaying enrolment/ Study intervention 
administration ............................................................................................. 31 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 32 
6.1. 
Study interventions administered ................................................................ 32 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 32 
6.3. 
Measures to minimize bias: randomization and blinding ............................. 33 
6.3.1. 
Participant identification ............................................................... 33 
6.3.2. 
Randomization to study intervention ............................................ 33 
6.3.3. 
Intervention allocation to the participant ....................................... 33 
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6.3.4. 
Allocation of participants to assay subsets ................................... 33 
6.3.5. 
Blinding and unblinding ................................................................ 34 
6.3.5.1. 
Emergency unblinding ................................................ 34 
6.4. 
Study intervention compliance .................................................................... 35 
6.5. 
Dose modification ....................................................................................... 35 
6.6. 
Continued access to study intervention after the end of the study ............... 35 
6.7. 
Treatment of overdose ................................................................................ 35 
6.8. 
Concomitant therapy ................................................................................... 35 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 36 
7.1. 
Discontinuation of study interventions ......................................................... 36 
7.1.1. 
Contraindications to subsequent study intervention 
administration .............................................................................. 36 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 37 
7.3. 
Lost to follow-up.......................................................................................... 37 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 38 
8.1. 
Immunogenicity assessments ..................................................................... 39 
8.1.1. 
Biological samples ....................................................................... 39 
8.1.2. 
Laboratory assays ....................................................................... 40 
8.1.3. 
Immunological read-outs .............................................................. 40 
8.1.4. 
Immunological correlates of protection ......................................... 41 
8.2. 
Safety assessments .................................................................................... 42 
8.2.1. 
Pre-vaccination procedures ......................................................... 42 
8.2.1.1. 
Collection of demographic data .................................. 42 
8.2.1.2. 
Medical history ........................................................... 42 
8.2.1.3. 
Vaccination history ..................................................... 42 
8.2.1.4. 
History directed physical examination ......................... 42 
8.2.1.5. 
Warnings and precautions to vaccination ................... 43 
8.2.1.6. 
Pre-vaccination body temperature .............................. 43 
8.2.2. 
Post-vaccination procedures ........................................................ 43 
8.2.2.1. 
Safety contact at 6 months post-last 
vaccination ................................................................. 43 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and other 
safety reporting ........................................................................................... 44 
8.3.1. 
Time period and frequency for collecting AE, SAE and 
other safety information ............................................................... 44 
8.3.2. 
Method of detecting AEs, SAEs, and other events ....................... 45 
8.3.3. 
Regulatory reporting requirements for SAEs and other 
events .......................................................................................... 45 
8.3.3.1. 
Contact information for reporting SAEs and 
pIMDs ......................................................................... 46 
8.3.4. 
Treatment of adverse events ....................................................... 46 
8.3.5. 
Participant card ............................................................................ 46 
8.4. 
Pharmacokinetics ....................................................................................... 46 
8.5. 
Genetics ..................................................................................................... 47 
8.6. 
Biomarkers ................................................................................................. 47 
8.7. 
Immunogenicity........................................................................................... 47 
8.8. 
Health outcomes ......................................................................................... 47 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 47 
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9.1. 
Statistical hypotheses (Amended 24 November 2020) ................................ 47 
9.2. 
Sample size determination (Amended 24 November 2020) ........................ 48 
9.3. 
Analysis sets ............................................................................................... 49 
9.3.1. 
Criteria for elimination from analysis ............................................ 49 
9.4. 
Statistical analyses (Amended 24 November 2020) .................................... 50 
9.4.1. 
Co-primary endpoints (Amended 24 November 2020) ................. 50 
9.4.2. 
Secondary endpoints ................................................................... 51 
9.5. 
Interim analyses .......................................................................................... 52 
9.5.1. 
Sequence of analyses.................................................................. 52 
9.5.2. 
Statistical consideration for interim analysis ................................. 52 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 52 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 52 
10.1.1. 
Regulatory and ethical considerations ......................................... 52 
10.1.2. 
Financial disclosure ..................................................................... 53 
10.1.3. 
Informed consent process ............................................................ 53 
10.1.4. 
Data protection ............................................................................ 53 
10.1.5. 
Committees structure ................................................................... 54 
10.1.6. 
Dissemination of clinical study data ............................................. 54 
10.1.7. 
Data quality assurance ................................................................ 55 
10.1.8. 
Source documents ....................................................................... 56 
10.1.9. 
Study and site start and closure ................................................... 56 
10.1.10. Publication policy ......................................................................... 56 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 57 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of AE .................. 58 
10.3.1. 
Definition of an Adverse Event (AE) ............................................. 58 
10.3.1.1. Events Meeting the AE Definition ............................... 58 
10.3.1.2. Events NOT Meeting the AE Definition ....................... 59 
10.3.2. 
Definition of an SAE ..................................................................... 59 
10.3.3. 
Solicited events............................................................................ 60 
10.3.4. 
Unsolicited adverse events .......................................................... 61 
10.3.5. 
Adverse events of special interest (AESIs) .................................. 61 
10.3.5.1. Potential immune-mediated diseases ......................... 61 
10.3.6. 
Clinical laboratory parameters and other abnormal 
assessments qualifying as AEs or SAEs ...................................... 64 
10.3.7. 
Recording and follow-up of AEs, SAEs, and pIMDs ..................... 64 
10.3.7.1. Time period for collecting and recording AEs, 
SAEs, and pIMDs ....................................................... 65 
10.3.7.2. Follow-up of AEs, SAEs, and pIMDs .......................... 65 
10.3.7.2.1. Follow-up during the study ...................... 65 
10.3.7.2.2. Follow-up after the participant is 
discharged from the study ...................... 65 
10.3.7.3. Updating of SAE and pIMD information after 
removal of write access to the participant’s 
eCRF .......................................................................... 66 
10.3.8. 
Assessment of intensity and toxicity ............................................. 66 
10.3.8.1. Assessment of intensity .............................................. 66 
10.3.8.2. Assessment of causality ............................................. 67 
10.3.8.3. Medically attended visits ............................................. 68 
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10.3.8.4. Assessment of outcomes............................................ 69 
10.3.9. 
Reporting of SAEs and pIMDs ..................................................... 69 
10.3.9.1. Events requiring expedited reporting to GSK .............. 69 
10.3.9.2. Backup system in case the electronic reporting 
system does not work ................................................. 69 
10.4. 
Appendix 4: Abbreviations and glossary of terms ........................................ 70 
10.4.1. 
List of abbreviations ..................................................................... 70 
10.4.2. 
Glossary of terms ......................................................................... 72 
10.5. 
Appendix 5: Protocol Amendment history ................................................... 76 
11. REFERENCES ....................................................................................................... 79 
 
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LIST OF TABLES 
PAGE 
Table 1 
SoA for Co-Ad group .............................................................................. 16 
Table 2 
SoA for Control group ............................................................................. 18 
Table 3 
Intervals between study visits (Co-Ad group) ......................................... 19 
Table 4 
Intervals between study visits (Control group) ........................................ 19 
Table 5 
Study objectives and endpoints .............................................................. 22 
Table 6 
Study groups and intervention ................................................................ 25 
Table 7 
Study interventions administered (Amended 24 November 2020) .......... 32 
Table 8 
Contact information for emergency unblinding ....................................... 34 
Table 9 
Biological samples ................................................................................. 39 
Table 10 
Laboratory assays .................................................................................. 40 
Table 11 
Immunological read-outs ........................................................................ 40 
Table 12 
Timeframes for collecting and reporting of safety information ................. 44 
Table 13 
Timeframes for submitting SAE and other events reports to GSK .......... 46 
Table 14 
Contact information for reporting SAEs and pIMDs ................................ 46 
Table 15 
Study objectives and null hypothesis (Amended 24 November 
2020) ...................................................................................................... 47 
Table 16 
Overall power to demonstrate co-primary objectives: non-
inferiority of the immunogenicity of RSVPreF3 OA investigational 
vaccine when co-administered with FLU vaccine as compared to 
when administered alone- assuming 393 participants are 
available in each group (Amended 24 November 2020) ......................... 48 
Table 17 
Evaluation of non-inferiority in terms of HI antibody SCR when 
the FLU vaccine is co-administered with the RSVPreF3 OA 
investigational vaccine as compared to FLU when administered 
alone assuming 393 participants are available in each group for 
a range of plausible SCRs ...................................................................... 49 
Table 18 
Analysis sets .......................................................................................... 49 
Table 19 
Definitions of seroconversion rate, seroprotection rate and mean 
geometric increase ................................................................................. 51 
Table 20 
Solicited administration site events......................................................... 60 
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Table 21 
Solicited systemic events ....................................................................... 60 
Table 22 
List of potential immune-mediated diseases (pIMDs) ............................. 62 
Table 23 
Intensity scales for solicited events ........................................................ 66 
 
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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 24 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Rationale:  
GSK is developing a new RSV PreFusion protein 3 Older Adult (RSVPreF3 OA) 
investigational vaccine against respiratory syncytial virus (RSV)-associated (subtypes A 
and B) disease in adults ≥60 years of age (YOA). The vaccine development is currently 
in phase 3, and immunogenicity, safety and reactogenicity of the candidate vaccine when 
co-administered with an influenza vaccine are not known. 
The current study will assess the immunogenicity, safety and reactogenicity of the 
RSVPreF3 OA investigational vaccine when co-administered with the seasonal 
quadrivalent influenza vaccine FLU-QIV in adults ≥60 YOA. The FLU-QIV vaccine is a 
quadrivalent inactivated split virion influenza vaccine manufactured in Dresden 
(Germany), containing 2 influenza A-like viruses (H1N1 and H3N2) and 2 influenza B-
like viruses (1 from the Yamagata lineage and 1 from the Victoria lineage). The FLU-
QIV vaccine is registered under the name Fluarix Quadrivalent or Fluarix Tetra (United 
States and other countries), Influsplit Tetra (Germany) and Alpharix Tetra (Belgium). It 
is indicated for active immunization for the prevention of disease caused by influenza A 
subtype viruses and type B viruses contained in the vaccine. The vaccine is approved for 
use in individuals as of 6 months of age. 
Note: for readability, at some places in this protocol, the “RSVPreF3 OA investigational 
vaccine” is also referred to as “RSV investigational vaccine”. 
Objectives and endpoints: Refer to Table 5. 
1.2. 
Schema 
Refer to Figure 1 for a schematic presentation of the study design.  
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1.3. 
Schedule of Activities (SoA) 
Table 1 
SoA for Co-Ad group  
Type of contact 
Visit 1 
Visit 2* 
Contact 
Notes 
Timepoints 
Day 1 
Day 31 
Month 61 
Informed consent 
● 
 
 
See Section 10.1.3 for details 
Distribution of participant card 
O 
 
 
See Section 8.3.5 for details  
Check inclusion/exclusion criteria 
● 
 
 
See Sections 5.1 and 5.2 for 
Inclusion and Exclusion criteria 
Check with participant if he/she will 
appoint a caregiver and distribute 
caregiver information letter, when 
applicable 
O 
O 
 
See Sections 5.2.5 and 10.1.3 
for details 
Randomization  
● 
 
 
See Section 6.3 for more 
information 
Baseline and demography assessments 
Collect demographic data 
● 
 
 
See Section 8.2.1.1 for more 
information 
Recording of medical and vaccination 
history  
● 
 
 
See Sections 8.2.1.2 and 8.2.1.3 
for more information 
Perform history directed physical 
examination  
O 
 
 
See Section 8.2.1.4 for more 
information 
Laboratory assessment  
 
 
 
 
Blood sampling from all participants for 
antibody determination (~10 mL) 
●2 
●3 
 
See Section 8.1.1 for more 
information 
Study interventions 
 
 
 
 
Check contraindications, warnings and 
precautions to study interventions 
administration 
O 
 
 
See Sections 7.1.1 and 8.2.1.5 
for more information 
Check criteria for temporary delay of 
study interventions administration 
O 
 
 
See Section 5.5 for more 
information 
Study group allocation 
O 
 
 
See Sections 6.3.2, 6.3.3 and 
6.3.4 for more information 
Recording of body temperature before 
study interventions administration4 
● 
 
 
The location for measuring 
temperature can be the oral 
cavity/axillary/tympanic 
membrane. 
Study interventions administration (FLU 
vaccine + RSV investigational vaccine) 
(including 30-minute post-vaccination 
observation) 
● 
 
 
See Section 6.1 for more 
information 
Recording of administered study 
interventions numbers 
● 
 
 
 
Safety assessments 
 
 
 
 
Distribution of diary cards for solicited 
events and unsolicited adverse events 
O 
 
 
See Section 10.3.7 for more 
information 
Return of diary cards  
 
O 
 
See Section 10.3.7 for more 
information 
Recording of solicited events (Days 1–4 
after study intervention administration)  
● 
● 
 
See Sections 10.3.3 and 10.3.7 
for more information 
Recording of unsolicited adverse events 
(Days 1-30 after study intervention 
administration) 
● 
● 
 
See Sections 10.3.4 and 10.3.7 
for more information 
Recording of concomitant 
medications/vaccinations 
● 
● 
● 
See Section 6.8 for more 
information 
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Type of contact 
Visit 1 
Visit 2* 
Contact 
Notes 
Timepoints 
Day 1 
Day 31 
Month 61 
Recording of intercurrent medical 
conditions  
● 
● 
● 
See Section 9.3.1 for more 
information 
Recording of SAEs and pIMDs 
● 
● 
● 
See Section 10.3.7 for more 
information 
Recording of AEs/SAEs leading to 
withdrawal from the study 
● 
● 
● 
See Section 10.3.7 for more 
information 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine5 
● 
● 
● 
See Section 10.3.7 for more 
information 
Contact for safety follow-up  
 
 
● 
See Sections 8.2.2 and 10.3.7.2 
for more information 
Study Conclusion 
 
 
● 
See Section 4.4 for more 
information 
Note: The double-line borders indicate analyses which will be performed on all data obtained up to these time points. 
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF 
AE = adverse event; pIMDs = potential immune-mediated diseases; SAE = Serious Adverse Event; eCRF = electronic 
case report form. 
FLU vaccine = FLU-QIV.  
* Visit 2 should preferably be done on site but if deemed necessary (during special circumstances such as Coronavirus 
Disease 2019 [COVID-19] pandemic), this study visit can be replaced by a home visit conducted by authorized staff . 
Any further information from the participant, not collected during the home visit, can be obtained by means of a phone 
call conducted by the site staff. 
1 Month 6 = 6 months after study interventions administration. For this contact, multiple formats can be proposed by the 
study site. Please refer to Section 8.2.2.1 for more details. 
2 Sample collected at Day 1 will be used as baseline for FLU and RSV vaccination.  
3 Sample collected at Day 31 will be used for the post-vaccination FLU vaccine- and RSV vaccine-related testing. 
4 The route for measuring temperature can be oral, axillary or tympanic. Fever is defined as temperature ≥38.0°C 
regardless of the location of measurement. 
5 SAEs related to study participation, or to a concurrent GSK medication/vaccine should be collected from the time of 
consent obtained (prior to study vaccine administration) up to study end. 
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Table 2 
SoA for Control group  
Type of contact 
Visit 1 Visit 2 Visit 3* 
Contact 
Notes 
Timepoints 
Day 1 Day 31 Day 61 Month 71 
Informed consent 
● 
 
 
 
See Section 10.1.3 for details 
Distribution of participant card 
O 
 
 
 
See Section 8.3.5 for details 
Check inclusion/exclusion criteria 
● 
 
 
 
See Sections 5.1 and 5.2 for Inclusion 
and Exclusion criteria 
Check with participant if he/she will 
appoint a caregiver and distribute 
caregiver information letter, when 
applicable 
O 
O 
O 
 
See Sections 5.2.5 and 10.1.3 for 
details 
Randomization 
● 
 
 
 
See Section 6.3 for more information 
Baseline and demography assessments 
Collect demographic data 
● 
 
 
 
See Section 8.2.1.1 for more 
information 
Recording of medical and vaccination 
history 
● 
 
 
 
See Section 8.2.1.2 and 8.2.1.3 for 
more information 
Perform history directed physical 
examination  
O 
 
 
 
See Section 8.2.1.4 for more 
information 
Laboratory assessment  
 
 
 
 
 
Blood sampling from all participants 
for antibody determination (~10 mL) 
●3 
●4 
●5 
 
See Section 8.1.1 for more information 
Study interventions 
 
 
 
 
 
Check contraindications, warnings and 
precautions to study intervention 
administration 
O 
O 
 
 
See Sections 7.1.1 and 8.2.1.5 for 
more information 
Check criteria for temporary delay of 
study intervention administration 
O 
O 
 
 
See Section 5.5 for more information 
Study group allocation 
O 
 
 
 
See Sections 6.3.2, 6.3.3 and 6.3.4 for 
more information 
Recording of body temperature before 
study intervention administration2 
● 
● 
 
 
The location for measuring 
temperature can be the oral 
cavity/axillary/tympanic membrane. 
Study intervention administration: FLU 
vaccine (including 30-minute post-
vaccination observation) 
● 
 
 
 
See Section 6.1 for more information 
Study intervention administration: RSV 
investigational vaccine (including 30-
minute post-vaccination observation) 
 
● 
 
 
See Section 6.1 for more information 
Recording of administered study 
intervention number 
● 
● 
 
 
 
Safety assessments 
 
 
 
 
 
Distribution of diary cards for solicited 
events and unsolicited adverse events 
O 
O 
 
 
See Section 10.3.7 for more 
information 
Return of diary cards  
 
O 
O 
 
See Section 10.3.7 for more 
information 
Recording of solicited events  
(Days 1–4 after study intervention 
administration)  
● 
● 
● 
 
See Sections 10.3.3 and 10.3.7 for 
more information 
Recording of unsolicited events (Days 
1-30 after study intervention 
administration) 
● 
● 
● 
 
See Sections 10.3.4 and 10.3.7 for 
more information 
Recording of concomitant 
medications/vaccinations 
● 
● 
● 
● 
See Section 6.8 for more information 
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Type of contact 
Visit 1 Visit 2 Visit 3* 
Contact 
Notes 
Timepoints 
Day 1 Day 31 Day 61 Month 71 
Recording of intercurrent medical 
conditions  
● 
● 
● 
● 
See Section 9.3.1 for more information 
Recording of SAEs and pIMDs 
● 
● 
● 
● 
See Section10.3.7 for more information 
Recording of AEs/SAEs leading to 
withdrawal from the study 
● 
● 
● 
● 
See Section10.3.7 for more information 
Recording of SAEs related to study 
participation, or to a concurrent GSK 
medication/vaccine6 
● 
● 
● 
● 
See Section 10.3.7 for more 
information 
Contact for safety follow-up  
 
 
 
● 
See Sections 8.2.2 and 10.3.7.2 for 
more information 
Study Conclusion 
 
 
 
● 
See Section 4.4 for more information 
Note: The double-line borders indicate analyses which will be performed on all data obtained up to these time points. 
● is used to indicate a study procedure that requires documentation in the individual eCRF 
○ is used to indicate a study procedure that does not require documentation in the individual eCRF 
AE = adverse event; pIMDs = potential immune-mediated diseases; SAE = Serious Adverse Event; eCRF = electronic 
case report form. 
FLU vaccine = FLU-QIV.  
*Visit 3 should preferably be done on site but if deemed necessary (during special circumstances such as COVID-19 
pandemic), this study visit can be replaced by a home visit conducted by authorized staff. Any further information from 
the participant, not collected during the home visit, can be obtained by means of a phone call conducted by the site 
staff.   
1 Month 7 = 6 months after administration of RSV investigational vaccine. For this contact, multiple formats can be 
proposed by the study site. Please refer to Section 8.2.2.1 for more details 
2 The route for measuring temperature can be oral, axillary or tympanic. Fever is defined as temperature ≥38.0°C 
regardless the location of measurement. 
3Sample collected at Day 1 will be used as baseline for the FLU vaccination in the Control group. 
4 Sample collected at Day 31 will be used for the post-vaccination FLU vaccine-related testing. This sample will also be 
used as baseline for the RSV vaccination in the Control group. 
5 Sample collected at Day 61 will be used for the post-vaccination RSV vaccine-related testing. 
6SAEs related to study participation, or to a concurrent GSK medication/vaccine should be collected from the time of 
consent obtained (prior to study vaccine administration) up to study end. 
Table 3 
Intervals between study visits (Co-Ad group) 
Interval 
Planned visit interval  
Allowed interval range 
Visit 1 →Visit 2 
30 days 
30-42 days 
Visit 1 → Contact  
180 days 
180-210 days 
Table 4 
Intervals between study visits (Control group) 
Interval 
Planned visit interval  
Allowed interval range 
Visit 1 → Visit 2 
30 days 
30-42 days 
Visit 2 → Visit 3  
30 days 
30-42 days 
Visit 2 → Contact  
180 days 
180-210 days 
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2. 
INTRODUCTION 
2.1. 
Study rationale 
GSK is developing a new RSV PreFusion protein 3 Older Adult (RSVPreF3 OA) 
investigational vaccine against respiratory syncytial virus (RSV)-associated (subtypes A 
and B) disease in adults ≥60 years of age (YOA). The vaccine development is currently 
in phase 3, and immunogenicity, safety and reactogenicity of the candidate vaccine when 
co-administered with an influenza vaccine are not known. 
The current study will assess the immunogenicity, safety and reactogenicity of the 
RSVPreF3 OA investigational vaccine when co-administered with the seasonal 
quadrivalent influenza vaccine FLU-QIV in adults ≥60 YOA. The FLU-QIV vaccine is a 
quadrivalent inactivated split virion influenza vaccine manufactured in Dresden 
(Germany), containing 2 influenza A-like viruses (H1N1 and H3N2) and 2 influenza B-
like viruses (1 from the Yamagata lineage and 1 from the Victoria lineage). The FLU-
QIV vaccine is registered under the name Fluarix Quadrivalent or Fluarix Tetra (United 
States and other countries), Influsplit Tetra (Germany) and Alpharix Tetra (Belgium). It 
is indicated for active immunization for the prevention of disease caused by influenza A 
subtype viruses and type B viruses contained in the vaccine. The vaccine is approved for 
use in individuals as of 6 months of age. 
Note: for readability, at some places in this protocol, the “RSVPreF3 OA investigational 
vaccine” is also referred to as “RSV investigational vaccine”. 
2.2. 
Background 
RSV is a ribonucleic acid virus of which 2 antigenically distinct subgroups exist, RSV-A 
and RSV-B [Borchers, 2013]. It is a highly contagious pathogen that causes respiratory 
tract infections in people of all ages. In temperate climates throughout the world, it 
predictably causes fall-winter epidemics. In (sub)tropical regions, viral activity is more 
endemic, and outbreaks are less temporally focused. 
As the global population ages, the morbidity and mortality from respiratory infections 
appear to be steadily increasing in the older adult population [Lee, 2013; Binder, 2017]. 
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 with influenza-like illness is 7.4%, with values 
between 0% and 17.1% across countries [Falsey, 2014]. In 2015, an estimated 1.5 million 
episodes of RSV-related acute respiratory illness occurred in older adults in industrialized 
countries; approximately 14.5% of these episodes involved a hospital admission [Nam, 
2019]. Further information on RSV incidence and disease burden can be found in the 
Investigator’s Brochure (IB). 
There is currently no vaccine or other prophylactic treatment available against RSV in 
older adults. Currently available treatment for RSV in this age group is generally 
supportive in nature, as detailed in the IB.  
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Please refer to the current IB for information regarding pre-clinical and clinical studies of 
the RSVPreF3 OA investigational vaccine. 
2.3. 
Benefit/Risk assessment 
2.3.1. 
Risk Assessment 
Information about the known and expected benefits and potential risks (syncope, 
hypersensitivity, potential immune-mediated diseases) and reasonably expected adverse 
events (AEs) of the RSVPreF3 OA investigational vaccine can be found in the IB and 
Development Safety Update Report.  
Important Potential/Identified Risk 
Mitigation Strategy 
RSV investigational vaccine 
Potential immune-mediated diseases (pIMDs) are 
considered a potential risk, as for all vaccines 
containing an adjuvant system. 
Refer to Section 10.3.5.1 for details. 
FLU-QIV 
Anaphylaxis, febrile seizures, Bell’s palsy, Guillain-
Barré syndrome (GBS), injection site hemorrhage in 
individuals with thrombocytopenia or any coagulation 
disorder, administration error due to mix-up of 
vaccine brands and narcolepsy are important 
potential risks under close monitoring for Fluarix 
Tetra. 
All participants will remain under observation at the clinical 
center for at least 30 minutes after vaccination. pIMDs 
(including GBS, Bell’s palsy and narcolepsy) will be 
monitored as described above and in Section 10.3.5.1   
Study procedures 
Intramuscular vaccination commonly precipitates a 
transient and self-limiting local inflammatory reaction. 
This may typically include pain at injection site, 
erythema/redness, and swelling. 
As a mitigation strategy, a topical analgesic may be applied 
to the site of injection. 
Pain and bruising may occur at the site where blood 
is drawn. 
As a mitigation strategy, a topical analgesic may be applied 
to the site where blood will be taken. 
Syncope (fainting) can occur following or even before 
any blood draw as a psychogenic response to the 
needle insertion. 
All participants will remain under observation at the clinical 
center for at least 30 minutes after vaccination. 
For details of study procedures, dose, and study design justification, refer to Sections 1.3 
and 4.2.  
2.3.2. 
Benefit Assessment  
The participants may not directly benefit from vaccination with the RSVPreF3 OA 
investigational vaccine because vaccine efficacy has not been established yet. Hence it is 
not known whether the RSVPreF3 OA investigational vaccine is effective in protecting 
against RSV disease. 
An indirect benefit is that the information obtained in this study will aid the development 
of an RSV investigational vaccine, which is intended to prevent disease associated with 
RSV infection in older adults. 
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Another benefit for all study participants may include gaining information about their 
general health status through the medical evaluations/assessments associated with this 
study (i.e., physical examination). 
All participants will receive the seasonal FLU vaccination as part of the study. By 
receiving FLU vaccine as part of standard medical care, the participant may have the 
benefit of being protected against circulating strains of influenza during the active season. 
2.3.3. 
Overall Benefit/Risk Conclusion 
The RSVPreF3 OA investigational vaccine is in clinical development. Considering the 
measures taken to minimize the risk to participants in this study, the potential risks are 
justified by the potential benefits linked to the development of this vaccine. 
The benefits of Fluarix Tetra appear to outweigh its potential risks. The established 
favorable benefit-risk profile for Fluarix Tetra remains unchanged for the active 
immunization of individuals as of 6 months of age against influenza disease caused by 
influenza virus types A and B contained in the vaccine. 
3. 
OBJECTIVES AND ENDPOINTS  
Table 5 
Study objectives and endpoints 
Objectives 
Endpoints 
Co-Primary 
• 
To demonstrate the non-inferiority of RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine compared to RSVPreF3 OA 
investigational vaccine administered alone. 
• 
RSV-A neutralization antibody titers expressed as 
group GMT ratio, 1 month after the RSVPreF3 OA 
investigational vaccine dose. 
• 
To demonstrate the non-inferiority of FLU vaccine 
when co-administered with the RSVPreF3 OA 
investigational vaccine compared to FLU vaccine 
administered alone. 
• 
HI antibody titers for each of the FLU vaccine strains 
expressed as group GMT ratio, 1 month after the 
FLU vaccine dose. 
Secondary 
• 
To evaluate the non-inferiority of FLU vaccine when 
co-administered with the RSVPreF3 OA 
investigational vaccine compared to FLU vaccine 
administered alone. 
• 
HI seroconversion status for each of the FLU 
vaccine strains expressed as SCR, 1 month after 
the FLU vaccine dose. 
• 
To evaluate the humoral immune response to 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine or administered 
alone. 
• 
RSV-A neutralization antibody titers expressed as 
MGI at 1 month after the RSVPreF3 OA 
investigational vaccine dose. 
• 
RSV-B neutralizing antibody titers expressed as 
group GMT ratio and MGI at 1 month after the 
RSVPreF3 OA investigational vaccine dose in a 
subset. 
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Objectives 
Endpoints 
• 
To evaluate the humoral immune response to the 
FLU vaccine when co-administered with the 
RSVPreF3 OA investigational vaccine or 
administered alone. 
• 
HI antibody titers for each of the FLU vaccine strains 
expressed as GMT, at Day 1 and Day 31. 
• 
HI seroconversion status for each of the FLU 
vaccine strains expressed as SCR, from Day 1 to 
Day 31. 
• 
HI seroprotection status for each of the FLU vaccine 
strains expressed as SPR, at Day 1 and Day 31. 
• 
HI antibody titers for each of the FLU vaccine strains 
expressed as MGI, 1 month after the FLU vaccine 
dose. 
• 
To evaluate the safety and reactogenicity following 
administration of the RSVPreF3 OA investigational 
vaccine and FLU vaccine, co-administered or 
administered alone. 
• 
Percentage of participants reporting each solicited 
event with onset within 4 days after vaccine 
administration (i.e. the day of vaccination and 
3 subsequent days). 
• 
Percentage of participants reporting unsolicited 
adverse events (pIMD, non-serious AE or serious 
AE) within 30 days after vaccine administration (i.e. 
the day of vaccination and 29 subsequent days). 
• 
Percentage of participants reporting SAEs after 
vaccine administration (Day 1) up to study end (6 
months after last vaccination). 
• 
Percentage of participants reporting pIMDs after 
vaccine administration (Day 1) up to study end (6 
months after last vaccination). 
Tertiary 
• 
To further evaluate the humoral immune response to 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine or administered 
alone. 
• 
RSVPreF3-specific IgG concentrations expressed 
as group GMC ratio and MGI at 1 month after the 
RSVPreF3 OA investigational vaccine dose in a 
subset. 
FLU vaccine is referring to FLU-QIV; IgG: Immunoglobulin G; GMT: Geometric Mean Titer; GMC: Geometric Mean 
Concentration; HI: Hemagglutinin Inhibition; pIMD: potential immune-mediated disease. AE: adverse event; SAE: 
serious adverse event.  
SCR: Seroconversion rate: the percentage of vaccinees who have either a HI pre-dose titer < 1:10 and a post-dose 
titer ≥ 1:40 or a pre-dose titer ≥ 1:10 and at least a four-fold increase in post-dose titer.  
SPR: Seroprotection rate: The percentage of vaccinees with a serum HI titer ≥ 1:40 that usually is accepted as 
indicating protection.  
MGI: The geometric mean of the within participant ratios of the post-dose titer over the pre-dose titer.  
 
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* Blood sample only from participants in Control group. 
FLU = FLU-QIV; RSV = RSVPreF3 OA investigational vaccine; BS = Blood sample from all participants (except for blood sample at Visit 3 which is only applicable for Control group). 
Note: Unsolicited AEs will be collected from first dose to 30 days post-dose. SAEs and pIMDs will be collected from first dose through the entire study period. SAEs related to study 
participation will be collected from the time of consent. 
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• 
Type of study: self-contained. 
• 
Experimental design: phase 3, randomized, open-label, multi-country study with 2 
parallel groups (see Figure 1). 
• 
Duration of the study: ~ 6 months for participants in Co-Ad group; ~ 7 months for 
participants in Control group. 
• 
Primary completion date: Day 61 (1 month after the RSVPreF3 OA investigational 
vaccine dose in Control group). 
• 
Control: active comparator, i.e. staggered administration of licensed FLU vaccine 
and RSVPreF3 OA investigational vaccine. 
• 
Blinding: open-label. Refer to Section 6.3.5 for details. 
• 
Data collection: standardized electronic Case Report Form (eCRF). Solicited events 
and unsolicited AEs will be collected using a participant Diary card (paper Diary 
card). 
• 
Study groups: Refer to Figure 1 and Table 6 for an overview of the study groups. 
Table 6 
Study groups and intervention  
Study groups 
Number of participants 
Age 
(Min-Max) 
Study interventions  
Co-Ad 
~440 
≥60 years 
RSVPreF3 OA investigational vaccine 
FLU-QIV 
Control 
~440 
≥60 years 
RSVPreF3 OA investigational vaccine 
FLU-QIV 
4.1.1. 
Overview of the recruitment plan 
No screening visit is planned for this study. The study is planned to be conducted at sites 
in multiple countries. The recruitment plan will be defined by each participating site. 
The recruitment plan may be adapted based on the actual number of participants enrolled 
in each country. In case a site would fall behind in participant recruitment, a 
redistribution of the enrolment target per site in the participating countries may be made. 
This would allow the other participating sites to enroll additional participants to ensure 
full and timely enrolment of the overall targeted number of participants specified in this 
protocol. 
The procedures for participants identification/recruitment must be approved by the 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) together with the 
material intended for participants identification/recruitment and participants use. Refer to 
the Study Procedures Manual (SPM) for additional details. 
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4.1.2. 
Enrolment rules 
Overall, participants will be enrolled in 3 age categories reflecting an approximate age 
distribution in the general population with a balance between males and females. It is 
therefore intended to enroll: 
• 
Approximately 40% of participants 60-69 YOA, approximately 30% of participants 
70-79 YOA and approximately 10% of participants ≥80 YOA. The remaining 
approximately 20% can be distributed freely across the 3 age categories. 
• 
Approximately 40% of participants from each sex; the remaining approximately 20% 
can be distributed freely between the 2 sexes. 
4.2. 
Scientific rationale for study design 
The influenza season coincides with the RSV season in temperate countries. Influenza 
vaccination begins at the start of the Flu season, at around the same time when the 
RSVPreF3 OA investigational vaccine may potentially be recommended for 
immunization against RSV infection. Till date, there is no data available on the safety and 
immunogenicity of the RSVPreF3 OA investigational vaccine when it is co-administered 
with an influenza vaccine.  
The current study is therefore designed to assess the safety, reactogenicity and 
immunogenicity of the RSVPreF3 OA investigational vaccine when it is co-administered 
with a FLU vaccine, compared to administration of the vaccines separately. There are 2 
parallel arms: 
• 
Co-Ad group: Participants will receive a single dose of RSV investigational vaccine 
and a single dose of FLU vaccine at Visit 1 (Day 1).  
• 
Control group: Participants will receive a single dose of FLU vaccine at Visit 1 
(Day 1), followed by a single dose of the RSV investigational vaccine at Visit 2 (Day 
31).  
The study will enroll older adults ≥60 YOA who are primarily responsible for self-care 
and activities of daily living. Participants may have one or more chronic medical 
conditions but should be medically stable in the opinion of the investigator. 
As the RSVPreF3 OA investigational vaccine is adjuvanted, all participants will be 
followed up for safety for 6 months post-RSV investigational vaccine administration.  
The 120µg RSVPreF3/AS01E vaccine formulation was selected in a previous study 
(RSV OA=ADJ-002), where the vaccine was administered intramuscularly according to a 
0, 2-month vaccination schedule. Please refer to the IB for details. 
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4.3. 
Justification for dose 
A 2-dose vaccination regimen with an interval of 2 months between doses was evaluated 
in the RSV OA=ADJ-002 study. This regimen was supported by available data from 
several clinical studies in GSK’s Herpes Zoster and chronic obstructive pulmonary 
disease vaccine development programs [Chlibek, 2013; Leroux-Roels, 2016] conducted 
with an AS01-adjuvanted recombinant protein vaccine in older adults. 
In the RSV OA=ADJ-002 study, the peak response for both IgG and neutralizing 
antibodies was observed at 1-month post-Dose 1. Comparisons of the mean responses 1 
month post-Dose 2 versus 1 month post-Dose 1, in terms of neutralizing antibodies 
against RSV-A and in terms of frequencies of RSVPreF3-specific CD4+ T cells 
expressing at least 2 activation markers did not show any added value of the second dose.  
Based on safety, reactogenicity and immunogenicity data (humoral and cellular immune 
response) of the RSV OA=ADJ-002 study, the 120µg RSVPreF3/AS01E formulation as a 
single dose was selected for the phase 3 clinical development.  
In the current study, the FLU vaccine will be administered as a single dose 
(recommended standard of care). 
4.4. 
End of Study definition 
A participant is considered to have completed the study if he/she returns for the last visit 
or is available for the last scheduled contact as described in the protocol. 
End of Study (EoS): Last subject last visit (LSLV) (Contact at 6 months post-last dose). 
5. 
STUDY POPULATION 
Adherence to the inclusion and exclusion criteria specified in the protocol is essential. 
Deviations from these criteria are not allowed because they can jeopardize the scientific 
integrity, regulatory acceptability of the study or safety of the participant. 
5.1. 
Inclusion criteria 
All participants must satisfy ALL the following criteria at study entry: 
• 
Participants, who, in the opinion of the investigator, can and will comply with the 
requirements of the protocol (e.g. completion of the diary cards, return for follow-up 
visits, ability to access and utilize a phone or other electronic communications). 
Note: In case of physical incapacity that would preclude the self-completion of the 
diary cards, either site staff can assist the participant (for activities performed 
during site visits) or the participant may assign a caregiver to assist him/her with 
this activity (for activities performed at home). However, at no time will the site staff 
or caregiver evaluate the participant’s health status while answering diaries or make 
decisions on behalf of the participant. Refer to the Glossary of terms for the 
definition of caregiver. 
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• 
A male or female ≥60 YOA at the time of the first study intervention administration. 
• 
Participants living in the general community or in an assisted-living facility that 
provides minimal assistance, such that the participant is primarily responsible for 
self-care and activities of daily living. 
• 
Written or witnessed informed consent obtained from the participant prior to 
performance of any study-specific procedure. 
• 
Participants who are medically stable in the opinion of the investigator at the time of 
first vaccination. Participants with chronic stable medical conditions with or without 
specific treatment, such as diabetes, hypertension or cardiac disease, are allowed to 
participate in this study if considered by the investigator as medically stable.  
5.2. 
Exclusion criteria 
The following criteria should be checked at the time of study entry. The potential 
participant MAY NOT be included in the study if ANY exclusion criterion applies: 
5.2.1. 
Medical conditions 
• 
Any confirmed or suspected immunosuppressive or immunodeficient condition 
resulting from disease (e.g. current malignancy, human immunodeficiency virus) or 
immunosuppressive/cytotoxic therapy (e.g., medication used during cancer 
chemotherapy, organ transplantation, or to treat autoimmune disorders), 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 vaccines.  
• 
Hypersensitivity to latex. 
• 
History of GBS, anaphylaxis, febrile seizures, Bell’s palsy and narcolepsy. 
• 
Serious or unstable chronic illness.  
• 
Any history of dementia or any medical condition that moderately or severely 
impairs cognition.  
Note: If deemed necessary for clinical evaluation, the investigator can use tools such 
as Mini-Mental State Examination (MMSE), Mini-Cog or Montreal Cognitive 
Assessment (MoCA) to determine cognition levels of the participant. 
• 
Recurrent or un-controlled neurological disorders or seizures. Participants with 
medically-controlled active or chronic neurological diseases can be enrolled in the 
study as per investigator assessment, provided that their condition will allow them to 
comply with the requirements of the protocol (e.g. completion of diary cards, attend 
regular phone calls/study site visits).  
• 
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 up to study end).  
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• 
Any medical condition that in the judgment of the investigator would make 
intramuscular injection unsafe.  
5.2.2. 
Prior/Concomitant therapy 
• 
Use of any investigational or non-registered product (drug, vaccine or medical 
device) other than the study interventions during the period beginning 30 days before 
the first dose of study vaccines and ending 30 days after the last vaccine 
administration, or planned use during the study period. 
• 
Administration of an influenza vaccine during the 6 months preceding the study FLU 
vaccine administration. 
• 
Planned or actual administration of a vaccine not foreseen by the study protocol in 
the period starting 30 days before the first study intervention administration and 
ending 30 days after the last study intervention administration.  
Note: In case an emergency mass vaccination for an unforeseen public health threat 
(e.g.: a pandemic) is recommended and/or 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 used according to 
the local governmental recommendations and that the Sponsor is notified 
accordingly. 
• 
Previous vaccination with an RSV vaccine.  
• 
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 or plasma derivatives 
during the period starting 90 days before the first dose of study vaccine or planned 
administration during the study period.  
• 
Chronic administration (defined as more than 14 consecutive days in total) of 
immunosuppressants or other immune-modifying drugs during the period starting 90 
days prior to the first study vaccination or planned administration during the study 
period. For corticosteroids, this will mean prednisone ≥20 mg/day, or equivalent. 
Inhaled and topical steroids are allowed.  
5.2.3. 
Prior/Concurrent clinical study experience 
• 
Concurrently participating in another clinical study, at any time during the study 
period, in which the participant has been or will be exposed to an investigational or a 
non-investigational intervention (drug/invasive medical device). 
Note: EEC directive 93/42/EEC defines an invasive medical device as ‘A device 
which, in whole or in part, penetrates inside the body, either through a body orifice 
or through the surface of the body’.  
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5.2.4. 
Other exclusions 
• 
History of chronic alcohol consumption and/or drug abuse as deemed by the 
investigator to render the potential participant unable/unlikely to provide accurate 
safety reports or comply with study procedures.  
• 
Planned move during the study conduct that prohibits participation until one month 
post-last vaccine administration.  
• 
Bedridden participants. 
• 
Participation of any study personnel or their immediate dependents, family, or 
household members.  
5.2.5. 
Caregiver support 
Study participants may decide to assign a caregiver to help them fulfilling the study 
procedures. Please refer to the Glossary of terms for the definition of a caregiver. 
A caregiver can be appointed by the participant at any time during the study, when the 
participant feels it is necessary. Each caregiver should receive the caregiver information 
letter before providing support to the study participant. Ideally, a single caregiver should 
be appointed by the participant but, in some situations, it may happen that several 
caregivers will support a study participant throughout the conduct of the study. This 
should be recorded in the source documents. 
Caregivers may help the study participants with performing some practical study 
procedures such as receiving or making phone calls to site staff, planning study visits, 
transcribing responses to diaries, transportation to and from the study site etc. However, 
at no time, the caregiver should evaluate the participant’s health status while answering 
diaries or make decisions on behalf of the participant. At the first study visit (Visit 1) the 
site staff should inform the participant of the possibility to appoint a caregiver. Then at 
subsequent study visit(s), the site staff should check again with the participant if he/she 
wishes to appoint a caregiver or if there were or will be changes of caregiver. 
5.3. 
Lifestyle considerations 
Not applicable for this study. 
5.4. 
Screen failures 
Not applicable for this study. 
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5.5. 
Criteria for temporarily delaying enrolment/ Study 
intervention administration 
Study intervention administration may be postponed within the permitted time interval 
until transient conditions cited below are resolved:  
• 
Acute disease and/or fever at the time of study intervention administration. Refer to 
Section 1.3 (SoA) for definition of fever and location for measuring temperature in 
this study.  
• 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be dosed at the discretion of the investigator.  
• 
Participants with symptoms suggestive of active Coronavirus Disease 2019 (COVID-
19) infection (e.g., fever, cough, etc.). The return of the participant to the site will 
follow the specific guidance from local public health and other competent authorities 
(e.g. free of symptoms, COVID-19 negative testing, etc.). 
• 
Participants with known COVID-19 positive contacts may be vaccinated at least 14 
days after the exposure, provided that the participant remains symptom-free, and at 
the discretion of the investigator.  
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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Refer to the Glossary of terms for the definition of study intervention. 
6.1. 
Study interventions administered  
Table 7 
Study interventions administered (Amended 24 November 2020) 
Study intervention name: 
RSVPreF3 OA investigational vaccine 
FLU-QIV 
Study intervention 
formulation: 
RSVPreF3 (120 µg) 
FLU Quadrivalent Influenza vaccine, 15µg 
hemagglutinin (HA) per strain/dose** 
AS01E: QS-21* (25 µg), MPL (25 
µg), liposomes; Water for injection 
q.s. 0.5 mL 
Presentation: 
RSVPreF3: Vial; Powder for 
suspension for injection 
Syringe, suspension for injection 
AS01E: Vial; Suspension for 
suspension for injection 
Type: 
Biologic 
Biologic 
Route of administration:  
Intramuscular (IM) injection 
IM injection 
Location 
Deltoid 
Deltoid 
Directionality 
Upper 
Upper 
Laterality  
Non-Dominant 
Co-Ad group: Dominant 
Control group: Non-Dominant 
Number of doses to be 
administered: 
1 
1 
Volume to be 
administered***: 
0.5 mL 
0.5 mL 
Packaging, labeling and 
TM: 
(when applicable) 
Refer to the SPM for more details 
Refer to the SPM for more details 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
* QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation)  
**The strains used in the FLU Quadrivalent Influenza vaccine are A/Victoria/2570/2019 (H1N1), IVR-215 (15 µg 
HA); A/Hong Kong/2671/2019 (H3N2), NIB-121 (15 µg HA); B/Washington/02/2019, wild type (15 µg HA); 
B/Phuket/3073/2013, wild type (15 µg HA) 
*** Refer to the SPM for the volume after reconstitution  
Study participants must be observed closely for at least 30 minutes after the 
administration of the study interventions. Appropriate medical treatment must be readily 
available during the observation period in case of anaphylaxis, syncope. 
6.2. 
Preparation/Handling/Storage/Accountability 
The study interventions must be stored in a secured place within the temperature range 
specified on the study intervention’s label. The storage temperature should be 
continuously monitored and recorded with a calibrated (if not validated) temperature 
monitoring device(s).  
Only authorized study personnel should be allowed access to the study interventions. 
Storage conditions will be assessed by a sponsor study contact during pre-study activities. 
Refer to the SPM for more details on storage and handling of the study interventions. 
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6.3. 
Measures to minimize bias: randomization and blinding  
6.3.1. 
Participant identification 
Participant identification numbers will be assigned sequentially to the individuals who 
have consented to participate in the study. Each study center will be allocated a range of 
participant identification numbers.  
6.3.2. 
Randomization to study intervention 
Approximately 880 eligible participants will be randomly assigned (1:1) to the study 
groups (Co-Ad or Control). 
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, United States [US]) by GSK. Entire blocks will be shipped to the study 
centers/ warehouse(s). 
To allow GSK to take advantage of greater rates of recruitment in this multi-center study 
and thus to reduce the overall study recruitment period, an over-randomization of 
supplies will be prepared. 
6.3.3. 
Intervention allocation to the participant 
An automated Internet-based system, Source data Base for Internet Randomization 
(SBIR) will be used for randomization and for identification of intervention material. The 
randomization algorithm will use a minimization procedure accounting for age (60-69, 
70-79 or ≥80 years), center, country and sex. Minimization factors will have equal weight 
in the minimization algorithm. Refer to Section 4.1.2 for the enrolment rules. 
Once a participant identification number is allocated, the randomization system will 
determine study group and will provide the study intervention number to be used for the 
first dose. The study intervention number(s) to be used for subsequent dosing will be 
provided by the same automated Internet-based system (SBIR). 
When SBIR is not available, please refer to the SBIR user guide or SPM for specific 
instructions. 
Refer to the SPM for additional information relative to the intervention number 
allocation. 
6.3.4. 
Allocation of participants to assay subsets 
Testing of RSV-B neutralizing antibodies and RSVPreF3 IgG will be performed on a 
random subset of participants (approximately 220 participants each from the Co-Ad 
group and the Control group). 
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6.3.5. 
Blinding and unblinding 
This is an open-label study 
The laboratory in charge of sample testing will be blinded to the study intervention 
assignment. Codes will be used to link the participant and study to each sample. There 
will be no link between the study intervention and the identity of the participant. 
6.3.5.1. 
Emergency unblinding 
Unblinding a participant’s individual study intervention number should occur ONLY in 
case of a medical emergency when this information is essential for the clinical 
management or welfare of the participant. 
The emergency unblinding process enables the investigator to have unrestricted, 
immediate and direct access to the participant’s individual study intervention via an 
automated Internet-based system, such as SBIR.  
The investigator may contact a GSK Helpdesk (refer to the Table 8) if he/she needs help 
to perform the unblinding process (i.e., if the investigator is unable to access the 
automated Internet-based system). 
A physician other than the investigator (e.g. an emergency room physician) or 
participant/care giver/family member may also request emergency unblinding either via 
the investigator (preferred option) or via the GSK Helpdesk (back up option). The 
participant card provides contact information for the investigator, his/her back up and 
GSK Helpdesk. 
Table 8 
Contact information for emergency unblinding 
GSK Helpdesk 
Available 24/24 hours and 7/7 days 
The Helpdesk is available by phone, fax and email 
Toll-free number:  
South Africa: 0800 984 003 
Phone:  
New Zealand, Panama: +32 2 656 68 04  
Fax: +32 2 401 25 75 
Email: rix.ugrdehelpdesk@gsk.com 
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6.4. 
Study intervention compliance 
The study intervention will be administered at the site, and participants will receive it 
directly from the investigator or designee, under medical supervision. The date of 
administration of each study intervention dose will be recorded in the source documents.  
6.5. 
Dose modification 
Not applicable for this study. 
6.6. 
Continued access to study intervention after the end of the 
study 
During the study conclusion contact, the investigator will ask each participant if they are 
interested in participating in a booster study/long-term study. If a participant is not 
interested in joining the booster study/long-term study the reason for refusal will be 
documented, when available, in the participant’s eCRF. 
6.7. 
Treatment of overdose 
Not applicable for this study. 
6.8. 
Concomitant therapy 
At each study visit/contact, the investigator or his/her delegate should question the 
participant about all medications/products taken, and vaccinations received by the 
participant. 
The following concomitant medication(s)/product(s)/vaccine(s) must be recorded in the 
eCRF: 
• 
All concomitant medications and vaccinations, except vitamins and dietary 
supplements, administered during the 30-day period following each dose of study 
intervention. 
• 
All concomitant medication leading to discontinuation of the study intervention or 
elimination from the analysis, including products/vaccines. Please refer to Sections 
5.2.2 and 9.3.1 for further details. 
• 
All concomitant medication which may explain/cause/be used to treat an SAE/pIMD 
including vaccines/products, as defined in Sections 8.3.1 and 10.3.2. These must also 
be recorded in the Expedited Adverse Event report. 
The Local Medical Lead should be contacted if there are any questions regarding 
concomitant or prior therapy. 
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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study interventions 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of study interventions. A participant who discontinued subsequent study 
intervention may continue other study procedures (e.g. safety or immunogenicity), 
planned in the study protocol at the discretion of the investigator.  
The primary reason for premature discontinuation of the study intervention will be 
documented on the eCRF as follows: 
• 
Adverse event requiring expedited reporting to GSK 
• 
Unsolicited non-serious adverse event  
• 
Solicited adverse event 
• 
Not willing to be vaccinated 
• 
Other (specify). 
7.1.1. 
Contraindications to subsequent study intervention 
administration 
The eligibility of participants in the Control group for subsequent study intervention 
administration must be confirmed before administering the RSV investigational vaccine 
at Visit 2.  
Participants who meet any of the criteria listed below or criteria listed in Sections 5.2.1 
and 5.2.2 should not receive the RSV investigational vaccine at Visit 2. Such participants 
should be encouraged to continue other study procedures, at the investigators’ discretion 
(Section 10.3.7.2). All relevant criteria for discontinuation of study intervention 
administration must be recorded in the eCRF.  
• 
Participants who experience any SAE judged to be possibly or probably related to 
the first study intervention (FLU vaccine administered at Visit 1) and that, in the 
opinion of the investigator, may pose additional risk to the participant if he/she 
receives the second study intervention (RSV investigational vaccine).  
• 
Participants who develop any new condition which, in the opinion of the 
investigator, may pose additional risk to the participant if he/she continues to 
participate in the study. 
• 
Anaphylaxis following the administration of study intervention(s) from Visit 1 
onwards. 
• 
Any condition that in the judgment of the investigator would make intramuscular 
injection unsafe. 
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7.2. 
Participant discontinuation/withdrawal from the study 
A participant is considered to have withdrawn from the study if no new study procedure 
has been performed or no new information has been collected for him/her since the date 
of withdrawal/last contact. 
From an analysis perspective, a study ‘withdrawal’ refers to any participant who was not 
available for the concluding contact planned in the protocol.  
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 
The primary reason for study withdrawal will be documented in the eCRF, based on the 
list below: 
• 
Adverse events requiring expedited reporting to GSK. Please refer to Section 
10.3.9.1 for details. 
• 
Unsolicited non-serious adverse events 
• 
Solicited adverse event 
• 
Withdrawal by participant, not due to an adverse event* 
• 
Migrated/Moved from the study area 
• 
Lost to follow-up 
• 
Sponsor study termination 
• 
Other (specify) 
*If a participant is withdrawn from the study because he/she has withdrawn consent and 
the reason for withdrawal was provided, the investigator must document this reason in the 
eCRF. 
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.7.2). 
7.3. 
Lost to follow-up 
A participant will be considered ‘lost to follow-up’ if he/she fails to return for scheduled 
visits and cannot be contacted by the study site.  
Please refer to the SPM for a description of actions to be taken before considering the 
participant lost to follow-up. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are only permitted when necessary for the management 
of immediate safety concerns for the participant.  
Immediate safety concerns should be discussed with the sponsor as soon as they occur or 
when the study team becomes aware of them. The purpose of this communication is to 
determine if the participant(s) should discontinue the study intervention. 
Study procedures and their timing are summarized in the SoA (Section 1.3).  
The SPM provides the investigator and site personnel with detailed administrative and 
technical information that does not impact participant safety. 
During special circumstances (e.g., COVID-19 pandemic), the specific guidance from 
local public health and other competent authorities regarding the protection of 
individuals’ welfare must be applied. For the duration of such special circumstances, the 
following measures may be implemented for enrolled participants:  
• 
Safety follow-up may be made by a telephone call, other means of virtual contact or 
home visit (from the site staff or from the home care service system), if appropriate. 
• 
Diary cards may be transmitted from and to the site by electronic means and or 
conventional mail or collected at home. 
• 
Biological samples may be collected at a different location* other than the study site 
or at participant’s home. Biological samples should not be collected if they cannot be 
processed in a timely manner or appropriately stored until the intended use.  
• 
If despite best efforts it is not possible to administer the dose of study intervention as 
defined in the protocol (see Table 3, additional 30 days may be added to the Visit 2 
interval (only for RSV investigational vaccine administration in the Control group).  
*It is the investigator’s responsibility to identify an alternate location. The investigator 
should ensure that this alternate location meets ICH GCP requirements, such as adequate 
facilities to perform study procedures, appropriate training of the staff and documented 
delegation of responsibilities in this location. This alternate location should be covered by 
proper insurance for the conduct of study on participants by investigator and staff at a site 
other than the designated study site. Refer to European Medicines Agency (EMA) 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
pandemic (version 2, 27 March, 2020) for more details. 
Impact on the per-protocol set for immunogenicity will be determined on a case by case 
basis. 
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8.1. 
Immunogenicity assessments 
Biological samples will be used for research planned in the protocol and for purposes 
related to the improvement, development and quality assurance of the laboratory tests 
described in this protocol.  
Findings in this or future studies may make it desirable to use samples acquired in this 
study for research not planned in this protocol. In this case, all participants in countries 
where this is allowed will be asked to give consent to allow GSK or a contracted partner, 
to use the samples for further research. The further research will be subject to prior 
IEC/IRB approval, if required by local legislation. 
Information on further research and its rationale can be obtained from GSK.  
Sample testing will be done in accordance with the recorded consent of the individual 
participant.  
By default, collected samples will be stored for a maximum of 20 years. This storage 
period begins when the last participant performs the last study visit. This timeline can be 
adapted based on local laws, regulations or guidelines requiring different timeframes or 
procedures. In all cases, the storage period should be aligned with participant’s consent. 
These additional requirements must be formally communicated to, discussed and agreed 
with GSK. 
8.1.1. 
Biological samples 
Table 9 
Biological samples 
Sample type 
Quantity 
Unit 
Timepoint 
Group 
Blood for humoral response 
~10 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
All participants in the  
Co-Ad group  
Blood for humoral response 
~10 
mL 
Visit 1 (Day 1) 
Visit 2 (Day 31) 
Visit 3 (Day 61) 
All participants in the 
Control  group 
The approximate volume of blood that will be collected per participant during the entire 
study period is as follows: 
• 
Co-Ad group: 2 x ~10 mL = ~20 mL 
• 
Control group: 3 x ~10 mL = ~30 mL 
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8.1.2. 
Laboratory assays 
Table 10 
Laboratory assays  
Assay type 
System 
Component 
Method 
Laboratory 
Humoral 
Immunity 
(Antibody 
determination): 
RSV 
Serum 
Respiratory Syncytial Virus A antibody 
Neutralization 
GSK * 
Respiratory Syncytial Virus B 
Antibody 
Neutralization 
RSVPreF3-specific IgG antibody 
ELISA 
Humoral 
Immunity 
(Antibody 
determination): 
FLU-QIV 
Serum 
H1N1 strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
Hemagglutination 
Inhibition 
H3N2 strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
B/Yamagata strain equivalent to 
vaccine strain (Hemagglutinin Ab) 
B/Victoria strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
ELISA: Enzyme-linked immunosorbent assay.  
*GSK laboratory refers to the Clinical Laboratory Sciences (CLS) in Rixensart, Belgium; Wavre, Belgium. CLS may 
delegate testing to GSK Research laboratories in Rixensart, Belgium; Rockville, USA; Sienna, Italy or to a contracted 
Contract Research Organization. 
Please refer to the Section 10.2 for a brief description of the assays performed in the 
study. 
The addresses of clinical laboratories used for sample analysis are provided in a separate 
document accompanying this study protocol. 
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. 
8.1.3. 
Immunological read-outs  
Table 11 
Immunological read-outs  
Blood sampling timepoint 
Subset tested 
No. 
participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Co-Ad group 
 
 
 
 
Visit 1 (Day 1) 
Pre-dose 1 
All participants  
440 
RSV-A neutralizing antibody 
Immunogenicity 
Subset 
220 
RSV-B neutralizing antibody  
Immunogenicity 
Subset 
220 
RSVPreF3-specific IgG antibody  
 
 
All participants  
440 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
 
 
All participants  
440 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
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Blood sampling timepoint 
Subset tested 
No. 
participants 
Component 
Type of contact 
and timepoint 
Sampling 
timepoint 
Visit 2 (Day 31) 
Post-dose 1  
All participants  
440 
RSV-A neutralizing antibody 
 
 
Immunogenicity 
Subset 
220 
RSV-B neutralizing antibody  
 
 
Immunogenicity 
Subset 
220 
RSVPreF3-specific IgG antibody  
 
 
All participants  
440 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
 
 
All participants  
440 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
Control group 
 
 
 
 
Visit 1 (Day 1) 
Pre-FLU dose 
All participants  
440 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
 
 
All participants  
440 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
Visit 2 (Day 31) 
Post-FLU dose 
All participants  
440 
H1N1 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
H3N2 strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
 
All participants  
440 
B/Yamagata strain equivalent to vaccine 
strain (Hemagglutinin Ab) 
 
 
All participants  
440 
B/Victoria strain equivalent to vaccine strain 
(Hemagglutinin Ab) 
 
Pre-RSV dose 
All participants  
440 
RSV-A neutralizing antibody 
 
 
Immunogenicity 
Subset 
220 
RSV-B neutralizing antibody  
 
 
Immunogenicity 
Subset 
220 
RSVPreF3-specific IgG antibody  
Visit 3 (Day 61) 
Post-RSV dose 
All participants  
440 
RSV-A neutralizing antibody 
 
 
Immunogenicity 
Subset 
220 
RSV-B neutralizing antibody  
 
 
Immunogenicity 
Subset 
220 
RSVPreF3-specific IgG antibody  
8.1.4. 
Immunological correlates of protection 
No generally accepted immunological correlate of protection has been demonstrated so 
far for the antigens used in the RSVPreF3 OA investigational vaccine or the FLU 
vaccine. 
Although there is no accepted correlate of protection against influenza, either seasonal or 
pandemic, the protective role of antibodies against hemagglutinin (HA) and, to a lesser 
extent, neuraminidase, is well established and has been demonstrated both in 
experimentally infected animals and humans [Rimmelzwaan, 2008]. For this reason, the 
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induction of HA-specific antibodies is used as a marker of potential vaccine efficacy and 
the serum HI assay is used to demonstrate this humoral response. HI antibody titers of 
1:40 or greater have been associated with protection from influenza illness in at least 50% 
of participants in challenge studies [Hannoun, 2004] as well as to correlate with vaccine 
effectiveness [Beyer, 1989]. 
8.2. 
Safety assessments 
The investigator and his/her designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE. The investigator and designees 
are responsible for following up AEs that are serious, considered related to the study 
intervention or the study, or that caused the participant’s withdrawal from the study 
interventions. 
8.2.1. 
Pre-vaccination procedures 
8.2.1.1. 
Collection of demographic data 
Record demographic data such as year of birth, sex, race and ethnicity in the participant’s 
eCRF. 
8.2.1.2. 
Medical history 
Obtain the participant’s medical history by interviewing the participant and/or review of 
the participant’s medical records. Record any relevant pre-existing conditions, signs 
and/or symptoms present prior to the study intervention in the eCRF. 
8.2.1.3. 
Vaccination history 
Obtain the participant’s vaccination history by interviewing the participant and/or review 
of the participant’s vaccination records. 
Any vaccine administered up to 1 year before study vaccine administration should be 
recorded in the eCRF with date of vaccination. Any FLU vaccine administered up to 3 
years before study intervention should be recorded with the date of vaccination and 
information about the vaccine formulation (e.g., adjuvanted or non-adjuvanted or high-
dose). 
8.2.1.4. 
History directed physical examination 
• 
History directed physical examination will be performed for each participant. 
• 
If the investigator determines that the participant’s health on the day of study 
intervention administration temporarily precludes dosing, the visit will be 
rescheduled. Refer to Section 5.5 for the list of criteria for temporary delay of study 
intervention administration. 
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• 
Treatment of any abnormality observed during this examination has to be performed 
according to local medical practice outside this study or by referral to an appropriate 
health care provider. 
8.2.1.5. 
Warnings and precautions to vaccination 
Warnings and precautions to administration of study intervention must be checked at 
each visit with planned administration of study intervention. 
8.2.1.6. 
Pre-vaccination body temperature 
The body temperature of each participant needs to be measured prior to any study 
intervention administration and recorded in the eCRF. The route for measuring 
temperature can be oral, axillary or tympanic. If the participant 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, refer to Table 3. 
8.2.2. 
Post-vaccination procedures 
8.2.2.1. 
Safety contact at 6 months post-last vaccination 
Six months after the last dose of study vaccine (i.e. Month 6 for participants in the Co-Ad 
group and Month 7 for participants of the Control group), each participant should be 
contacted to check if he/she has experienced any SAEs or any pIMDs since last study 
intervention administration, and to collect information on concomitant 
medications/vaccinations. 
Multiple formats can be proposed by the site staff to organize these contacts. This contact 
may be done via email, text message, fax or phone call for example. The most 
appropriate format should be agreed between site staff and the study participant. 
Text messages, email and fax may be used as a screening to check if the participant has 
anything to report. If the participant answers "Yes" for at least one of the items of 
interest, a phone call must be done to get the details on the event(s).  
Data collected via phone calls and text messages will have to be recorded in source 
documents. E-mails and faxes can be archived in source documents. Receipt of the 
message must be confirmed by the participant or caregiver, as applicable. 
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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
other safety reporting 
8.3.1. 
Time period and frequency for collecting AE, SAE and other 
safety information  
Table 12 
Timeframes for collecting and reporting of safety information 
Co-Ad group 
 
 
 
 
 
 
 
 
 
Event 
Pre- 
Dose* 
Vacc 
Co-Ad 
 
 
D1 
D4 
D31 
 
 
 
 
6-months 
post-last 
dose ** 
Study 
conclusion 
Administration site and 
systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Control group 
 
 
 
 
 
 
 
 
 
 
Pre- 
Dose 
Vacc 
FLU 
 
 
D1 
D4 
D31 
 
Vacc  
RSV 
 
 
D31 
D34 
D61 
6-months 
post last 
dose** 
Study 
conclusion 
Administration site and 
systemic solicited events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited AEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All participants 
 
 
 
 
 
 
 
 
 
All SAEs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All pIMDs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs related to study 
participation or concurrent 
GSK medication/ vaccine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs leading to 
withdrawal from the study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intercurrent medical 
conditions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D: day; AE: adverse event; SAE: serious adverse event; pIMD: potential immune-mediated disease; Vacc: Vaccination. 
* i.e. consent obtained on Day 1 (prior to intervention administration). 
** post-last dose =  6 months after Co-Ad vaccine administration (Co-Ad group) or 6 months after RSV investigational 
vaccine administration (Control group). 
Note: COVID-19 cases will be collected during the same timeframes as those used for collecting and reporting the 
other safety information (unsolicited AEs/SAEs, etc.)  
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The investigator or designee will record and immediately report all SAEs to the sponsor 
or designee via the Expedited AE Reporting Form. Reporting should, under no 
circumstances, occur later than 24 hours after the investigator becomes aware of an SAE, 
as indicated in Section 10.3.9. 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 periods defined in Table 12. Investigators are not obligated to actively seek AEs 
or SAEs from former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event to be reasonably related to the study intervention, the 
investigator will promptly notify the study contact for reporting SAEs mentioned in the 
Table 14. 
8.3.2. 
Method of detecting AEs, SAEs, and other events  
Detection and recording of AE/SAE/pIMDs are detailed in Section 10.3.7.  
Assessment of AE/SAE intensity, causality and outcome are described in Section 10.3.8.  
Open-ended and non-leading verbal questioning of participants is the preferred method of 
acquiring information related to an AE/SAE/pIMD. 
8.3.3. 
Regulatory reporting requirements for SAEs and other events  
Once an investigator (or designee) becomes aware that a study participant has 
experienced an SAE/pIMD, it must be reported to GSK using the required documentation 
and within the timeframes mentioned in Table 13. This is essential for meeting GSK legal 
obligations and ethical responsibilities for participant safety and the safety of a study 
intervention under clinical investigation. 
For SAEs/pIMDs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.8.2. 
Local regulatory requirements and sponsor policy for preparation of an investigator 
safety report of Suspected Unexpected Serious Adverse Reactions (SUSAR) must be 
followed. These reports will be forwarded to investigators as necessary. 
The sponsor has the legal responsibility to notify local authorities/regulatory agencies 
about the safety of an investigational study intervention. The sponsor will comply with 
country-specific regulatory requirements related to safety reporting to the regulatory 
authority, IRB/IEC and investigators. 
Please refer to the Section 10.3.9 for further details regarding the reporting of 
SAEs/pIMDs. 
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Table 13 
Timeframes for submitting SAE 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 by the investigator/site staff. 
**Timeframe allowed once the investigator determines that the event meets the protocol definition of a pIMD. 
‡‡ The investigator will be required to confirm review of the SAE/pIMD causality by ticking the ‘reviewed’ box in the 
electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/pIMD. 
8.3.3.1. 
Contact information for reporting SAEs and pIMDs 
Table 14 
Contact information for reporting SAEs and pIMDs 
Study contact for questions regarding SAEs and pIMDs 
Refer to the local study contact information document 
Back up study contact for reporting SAEs and pIMDs 
Available 24/24 hours and 7/7 days: 
 
GSK Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
8.3.4. 
Treatment of adverse events 
Any medication, vaccine or products which may explain/cause/be used to treat an 
SAE/pIMD should be recorded in the Expedited Adverse Event Report of the 
participant’s eCRF screen (refer to the Section 10.3.9.1). 
8.3.5. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in his/her/their possession for the duration of the study. 
In an emergency, this card serves to inform the responsible attending 
physician/caregiver/family member that the participant is in a clinical study and that 
relevant information may be obtained by contacting the investigator or his/her back up. 
8.4. 
Pharmacokinetics 
Pharmacokinetics are not evaluated in this study. 
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8.5. 
Genetics  
Genetics are not evaluated in the current study.  
8.6. 
Biomarkers 
Not applicable for this study. 
8.7. 
Immunogenicity 
Immunogenicity is described in Section 8.1. 
8.8. 
Health outcomes 
Not applicable for this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical hypotheses (Amended 24 November 2020) 
The study includes 2 confirmatory co-primary objectives. The non-inferiority margins 
associated to each objective are provided in Table 15. 
Table 15 
Study objectives and null hypothesis (Amended 24 November 2020) 
Objectives 
Null hypothesis 
Co-Primary 
• 
To demonstrate the non-inferiority of RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine compared to RSVPreF3 OA 
investigational vaccine administered alone. 
• 
True Group GMT ratio between RSVPreF3 OA 
investigational vaccine (Control group) divided by 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine (Co-Ad group) in 
RSV-A neutralization antibody titers 1 month after 
the RSVPreF3 OA investigational vaccine dose is 
above 1.5. 
• 
To demonstrate the non-inferiority of FLU vaccine 
when co-administered with the RSVPreF3 OA 
investigational vaccine compared to FLU vaccine 
administered alone. 
• 
True Group GMT ratio between FLU vaccine 
(Control group) divided by RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine (Co-Ad group) in HI antibody titers 
for each of the FLU vaccine strains 1 month after the 
FLU vaccine is above 1.5. 
FLU vaccine is referring to FLU-QIV; HI: Hemagglutinin Inhibition; GMT: Geometric Mean Titer.  
The success of the study depends on the success of all co-primary objectives. Using a 
nominal alpha of 2.5% for each of them will ensure the global type I error for the co-
primary objectives is controlled below 2.5%. 
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9.2. 
Sample size determination (Amended 24 November 2020) 
The target enrolment will be 880 participants (440 in the group receiving the RSVPreF3 
OA investigational vaccine co-administered with the FLU vaccine (Co-Ad group) and 
440 in the Control group where RSVPreF3 OA investigational vaccine and FLU vaccine 
are administered staggered) to obtain at least 786 evaluable participants (393 in the Co-
Ad group and 393 in Control group) for the evaluation of the primary objectives, 
assuming that approximately 10% of the enrolled participants will not be evaluable. 
Each objective will be evaluated with a nominal type I error of 2.5%. 
Table 16 
Overall power to demonstrate co-primary objectives: non-inferiority 
of the immunogenicity of RSVPreF3 OA investigational vaccine 
when co-administered with FLU vaccine as compared to when 
administered alone- assuming 393 participants are available in each 
group (Amended 24 November 2020) 
RSV Non-inferiority* (1-sided test with alpha = 2.5%)  
Endpoint 
Standard deviation 
of log10 
concentration 
Non-
inferiority 
margin 
Type II error 
Power 
GMTs RSV-A neutralization antibody 
0.45 
1.5 
0.02% 
99.98% 
FLU Non-inferiority* (1-sided test with alpha = 2.5%)  
Endpoint 
Standard deviation 
of log10 
concentration 
Non-
inferiority 
margin 
Type II error 
Power 
GMTs HI H1N1 strain 
0.6 
1.5 
1.58% 
98.42% 
GMTs HI H3N2 strain 
0.6 
1.5 
1.58% 
98.42% 
GMTs HI B/Washington strain 
0.6 
1.5 
1.58% 
98.42% 
GMTs HI B/Phuket strain 
0.6 
1.5 
1.58% 
98.42% 
Global Type II error to show non-inferiority 
~6.3% 
 
Global power 
~93.7% 
*Pass 2019 alpha = 2.5%, Two-Sample T-Tests for Non-Inferiority Assuming Equal Variance and Equal mean. 
Considering identical true GMTs in both groups with a common population standard 
error of 0.45 for the RSV-A neutralization antigen and 0.6 for each of the FLU strains in 
log10 transformed concentration, the study has at least 93.7% power to meet the co-
primary objectives. 
Nominal powers to evaluate secondary objective 
The nominal power to evaluate the non-inferiority on seroconversion rate for each of the 
FLU strains is above 79%, depending on the plausible rates. 
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Table 17 
Evaluation of non-inferiority in terms of HI antibody SCR when the 
FLU vaccine is co-administered with the RSVPreF3 OA 
investigational vaccine as compared to FLU when administered 
alone assuming 393 participants are available in each group for a 
range of plausible SCRs  
N evaluable 
participants per 
group 
Threshold  
Plausible 
rates in 
Control 
group** 
Type II error# 
Nominal Power 
 
FLU vaccine: Non-inferiority* in terms of SCR 
393 
10% 
70% 
13.4% 
86.6% 
393 
10% 
50% 
20.4% 
79.6% 
393 
10% 
35% 
16.1% 
83.9% 
393 
10% 
25% 
10.1% 
89.9% 
SCR: Seroconversion Rate. 
*Pass 2019 alpha = 2.5%, for SCR – Non-inferiority: Proportions – Two independent Proportions – Non-Inferiority Tests 
for the Difference Between Two Proportions.  
** SCR observed in the Control group in Zoster-004 study range from 35.3% to 60.9%. 
#The overall power for this secondary objective will be 100-sum of the type II error for each of the 4 strains. 
9.3. 
Analysis sets 
Table 18 
Analysis sets 
Analysis set 
Description 
Enrolled set 
Participants who agreed to participate in a clinical study after completion of the 
informed consent process. 
Exposed set (ES) 
All participants who received a study intervention. Analysis per group is based on 
the study intervention administered. 
Per Protocol set (PPS) 
All eligible participants who received all study interventions as per protocol, had 
immunogenicity results pre- and post-dose, complied with blood draw intervals 
(refer to Table 3) and contribution of participants to PPS at specific timepoint will 
be defined by timepoint, without intercurrent medical conditions that may interfere 
with immunogenicity and without prohibited concomitant medication/vaccination. 
9.3.1. 
Criteria for elimination from analysis 
If the participant meets one of the criteria mentioned in the Sections 7.1.1 
(contraindication to subsequent vaccination) or 5.2.1 (medical conditions) or 5.2.2 
(concomitant therapy), he/she may be eliminated from per-protocol analysis.  
Participants may be eliminated from the PPS for immunogenicity if, during the study, 
they incur a condition that has the capability of altering their immune response 
(intercurrent medical condition) or are confirmed to have an alteration of their initial 
immune status. Refer to Glossary of terms for the definition of intercurrent medical 
conditions. 
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9.4. 
Statistical analyses (Amended 24 November 2020) 
The Statistical Analysis Plan (SAP) will be developed and finalized before first subject 
first visit (FSFV). This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. Supportive analyses, safety and demography 
summaries will be described in the SAP. 
9.4.1. 
Co-primary endpoints (Amended 24 November 2020) 
The co-primary endpoints are described in Section 3. The confirmatory analyses of non-
inferiority will be based on the per-protocol (PP) set. 
• 
Method for non-inferiority of RSV investigational vaccine in terms of RSV-A 
neutralization antibody GMT ratio at 1 month after the RSVPreF3 OA 
investigational vaccine dose (i.e. at Day 31 for the Co-Ad group and at Day 61 for 
the Control group): 
The 2-sided 95% confidence interval (CI) for group GMT ratio between RSVPreF3 
OA investigational vaccine administered alone (Control group) over RSVPreF3 OA 
investigational vaccine when co-administered with the FLU vaccine (Co-Ad group) 
will be derived from an ANCOVA model* on log10 transformed titer.  
• 
Method for non-inferiority of FLU vaccine in terms of HI GMT ratio for each of the 
FLU vaccine strains at 1 month after the FLU vaccine (i.e. at Day 31 for both 
groups): 
The 2-sided 95% CI for group GMT ratio between FLU vaccine administered alone 
(Control group) over RSVPreF3 OA investigational vaccine when co-administered 
with the FLU vaccine (Co-Ad group) will be derived from an ANCOVA model* on 
log10 transformed titer.  
*The model will include the treatment group, the age category (age at vaccination: 60-69, 
70-79 or ≥80 years), country and sex as fixed effects, and the pre-dose log10-transformed 
titer as covariate. Missing data will not be replaced. Titers below the assay cut-off will be 
replaced by half the assay cut-off, titers above the upper-limit of quantification (ULOQ) 
will be replaced by the ULOQ. 
Success criteria for non-inferiority: 
1. The upper limit of the 2-sided 95% CI on the group GMT ratio (Control group 
divided by Co-Ad group) for RSV investigational vaccine is ≤1.5. 
AND 
2. The upper limit of the 2-sided 95% CI on the group GMT ratio (Control group 
divided by Co-Ad group) for each of the FLU vaccine strains are ≤1.5. 
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9.4.2. 
Secondary endpoints 
• 
Method for evaluation of non-inferiority of FLU vaccine in terms of HI 
seroconversion rate for each of the FLU vaccine strains at 1 month after the FLU 
vaccine (i.e. at Day 31 for both groups): 
− 
The 2-sided 95% CI on group difference in seroconversion rate (Control group 
minus Co-Ad group) will be computed based on the method of Miettinen and 
Nurminen [Miettinen, 1985].  
− 
Reference criteria for evaluation of non-inferiority: 
The upper limit of the 2-sided 95% CI on the group difference (Control group minus 
Co-Ad group) in seroconversion rate is ≤10% for anti-HI antibodies. 
• 
The other secondary endpoints are described in Section 3. Descriptive analyses of 
demography, immunogenicity and safety will be detailed in the SAP. 
Table 19 
Definitions of seroconversion rate, seroprotection rate and mean 
geometric increase 
Abbreviation/term 
Definition 
HI SCR/ seroconversion rate 
The percentage of vaccinees who have either a HI pre-dose titer < 1:10 and 
a post-dose titer ≥ 1:40 or a pre-dose titer ≥1:10 and at least a four-fold 
increase in post-dose titer. 
HI SPR/ seroprotection rate 
The percentage of vaccinees with a serum HI titer ≥1:40 that usually is 
accepted as indicating protection. 
MGI/ mean geometric increase 
The geometric mean of the within participant ratios of the post-dose titer over 
the pre-dose titer. 
• 
Additionally, the CBER and CHMP criteria for HI SPR and SCR will be assessed as 
follows: 
CBER’s criteria: 
• 
The lower limit (LL) of the 95% CI for SCR should be ≥40% in participants aged 
18-64* YOA or ≥30% in participants ≥65 YOA. 
• 
The LL of the 95% CI for SPR should be ≥70% in participants aged 18-64* YOA or 
≥60% in participants ≥65 YOA. 
*In this study, only participants from 60 YOA and higher are included, hence we can 
expect only a small proportion of participants in this category of 60 to 64 years. Although 
the SCR will be estimated the criteria cannot be evaluated for this category. 
CPMP / CHMP criteria (EMEA): 
At least one of the 3 following criteria should be met:  
• 
the point estimates of SPR >60%, SCR >30%, and MGI >2.0 for elderly > 60 years 
for each of the antigen strains. 
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9.5. 
Interim analyses  
9.5.1. 
Sequence of analyses 
A final analysis will be conducted once all the immunogenicity data are available for 
primary and secondary endpoints. This final analysis will include immunogenicity and 
safety data up to Visit 2 (Co-Ad group) or Visit 3 (Control group). 
An EoS analysis with all data including the data obtained until 6 months post-last dose 
will be performed.  
9.5.2. 
Statistical consideration for interim analysis 
Not applicable. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
− 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences International Ethical Guidelines 
− 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, 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 protocol amendments 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 participants.  
• 
GSK will provide full details of the above procedures to the investigator, either 
verbally, in writing, or both. 
• 
The investigator will be responsible for the following: 
− 
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. 
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− 
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. 
10.1.2. 
Financial disclosure 
Investigators and sub-investigators must provide the sponsor with full and accurate 
financial disclosure, as requested, to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators must provide their financial interest information before initiation of the 
study center and again at the end of the study. Investigators are responsible for providing 
a financial disclosure update if their financial interests change at any point during study 
participation and for 1 year after completion of the study. 
10.1.3. 
Informed consent process 
The investigator or his/her representative must fully explain the nature of the study to the 
participant and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary.  
Freely given and written/witnessed informed consent must be obtained from each 
participant and/or each participant’s witness, as appropriate, prior to participation in the 
study.  
The content of the informed consent form must meet the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written or witnessed informed consent 
was obtained before the participant was enrolled in the study and the date the consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.  
Participants must be re-consented to the most current version of the ICF(s) or an ICF 
addendum during their participation in the study.  
A copy of the ICF(s) must be provided to the participants.  
10.1.4. 
Data protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets transferred to the sponsor will contain only the identifier. Name and any other 
information which would identify the participant will not be transferred.  
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The participants must be informed that: 
• 
His/her personal study-related data will be used by the sponsor in accordance with 
local data protection law.  
• 
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 ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study, in 
accordance with the Data Privacy Notice that will be sent to the site staff.  
The participants must be notified about their rights regarding the use of their personal 
data in accordance with the data privacy section of the ICF. 
10.1.5. 
Committees structure 
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable regulatory requirements, prior to a site 
initiating the study in that country. This includes IRBs/IECs for review and approval of 
the protocol and subsequent amendments, ICF and any other documentation. 
10.1.6. 
Dissemination of clinical study data 
The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries prior to 
study start and target results summaries submission within 12 months of primary/ study 
completion date. Where external regulations require earlier disclosure, GSK will follow 
those timelines.  
Where required by regulation, summaries will also be posted on applicable national or 
regional clinical trial registers. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the study report, and 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 participants, as appropriate. 
GSK intends to make anonymized patient-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by trial 
participants are used to maximum effect in the creation of knowledge and understanding. 
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10.1.7. 
Data quality assurance 
The investigator should maintain a record of the location(s) of their respective essential 
documents, including source documents (see Glossary of terms for the exact definition of 
essential and source documents). The document 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 trial documents may be added or removed where justified (in advance of trial 
initiation) based on their importance and relevance to the trial. When a copy is used to 
replace an original document (e.g. source documents, eCRF), the copy should fulfill the 
requirements for certified copies (see Glossary of terms for the exact definition of 
certified copies).  
All participant data related to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the 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 participants (see Glossary 
of terms for the exact definition of source documents) that supports information entered 
in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents or certified 
copies for such review and inspection.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the source data (see Glossary of terms for the exact definition of 
source data).  
Study monitors will perform ongoing source data verification to confirm that data entered 
in the eCRF by authorized site personnel are attributable, legible, contemporaneous, 
original, accurate, and complete. Changes to source data must be traceable, not obscure 
the original entry, and be fully explained if necessary (e.g. via an audit trail). The safety 
and rights of participants must be protected, and the study conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
Quality tolerance limits (QTLs) will be pre-defined in the state location(s) to identify 
systematic issues that can impact participant safety and/or the reliability of study results. 
These pre-defined parameters will be monitored during the study. Important deviations 
from the QTLs and remedial actions taken will be summarized in the Clinical Study 
Report (CSR). 
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Trial records and source documents pertaining to the conduct of this study, including 
signed ICFs, must be retained by the investigator for 25 years from issuance of the final 
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.  
10.1.8. 
Source documents 
Source documents provide evidence to establish the existence of the participant and 
substantiate the integrity of collected data. The investigator should maintain a record of 
the location(s) of their source documents.  
Data transcribed into the eCRF from source documents must be consistent with those 
source documents; any 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. 
Definitions of what constitutes source data and documents can be found in the Glossary 
of terms. 
10.1.9. 
Study and site start and closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion, provided there is sufficient notice given to 
account for all participants safe exit from study.  
Regular closure of study sites will occur 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 enough notice in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
10.1.10. 
Publication policy 
GSK aims to submit the results of the study for publication in searchable, peer reviewed 
scientific literature within 18 months from the LSLV for interventional studies and 
follows the guidance from the International Committee of Medical Journal Editors. 
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10.2. 
Appendix 2: Clinical laboratory tests 
RSV-A and RSV-B neutralization assays 
The serum neutralization assay is a functional assay that measures the ability of serum 
antibodies to neutralize RSV entry and replication in a host cell line.  
Virus neutralization is performed by incubating a fixed amount of RSV-A strain (Long, 
ATCC No. VR-26) or RSV-B strain (18537, ATCC No. VR-1580) with serial dilutions of 
the test serum. The serum-virus mixture is then 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 the Vero cells by non-neutralized virus and the 
formation of plaques in the cell monolayer. Following a fixation step, RSV-infected cells 
are detected using a primary antibody directed against RSV (Polyclonal anti-RSV-A/B 
IgG) and a secondary antibody conjugated to 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 a Reading software or equivalent). For each serum dilution, a ratio, 
expressed as a percentage, is calculated between the number of plaques at each serum 
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]. For the testing of phase 3 studies, secondary standards 
calibrated against the international reference (NIBSC 16/284) will be included in every 
run to allow conversion into international units.  
RSVPreF3 protein IgG ELISA 
Responses to the RSVPreF3 antigen will be evaluated by an indirect ELISA allowing the 
detection and the quantification of antigen-specific IgG antibodies in human serum 
samples. 
The principle of these assays is as follows: RSVPreF3 protein antigen will be adsorbed 
onto a 96-well polystyrene microplate. After washing and blocking steps, 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 (total IgG specific), conjugated to HRP. Bound 
antibodies are quantified by the addition of the HRP substrate, tetramethylbenzidine 
(TMB) and hydrogen peroxide, whereby a colored product develops proportionally to the 
amount of anti-RSVPreF3 protein total 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). 
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Hemagglutination-inhibition assay 
HI antibody titers are determined using the method derived from the World Health 
Organization (WHO) Manual on Animal Influenza Diagnosis and Surveillance, 
WHO/CDS/CSR/NCS/2002.5.  
Measurements are conducted on thawed frozen serum samples with a standardized and 
comprehensively validated micro method using 2 hemagglutinating units (2 HAU) of the 
appropriate antigens and a 0.50% fowl erythrocyte suspension. Non-specific serum 
inhibitors are removed by heat treatment and receptor-destroying enzymes.  
Starting with an initial dilution of 1:10, a dilution series (by a factor of 2) is prepared up 
to an end dilution of 1:10240. The titration end-point is taken as the highest dilution step 
that shows complete inhibition of hemagglutination. All assays are performed in 
duplicate. The usual cut-off value is = 10 1/DIL. 
10.3. 
Appendix 3: Adverse Events: definitions and procedures for 
recording, evaluating, follow-up, and reporting Definition of 
AE 
10.3.1. 
Definition of an Adverse Event (AE)  
An AE is any untoward medical occurrence (an unfavorable/unintended sign - including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) in a clinical 
study participant that is temporally associated with the study intervention. The AE may or 
may not be considered related to the study intervention. 
10.3.1.1. 
Events Meeting the AE Definition  
• 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after administration of the study 
intervention even though they may have been present before study start. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug, disease or other 
interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
study intervention or a concurrent medication. 
• 
Signs or symptoms temporally associated with administration of the study 
intervention. 
• 
Signs, symptoms that require medical attention (e.g. hospital stays, physician visits 
and emergency room visits). 
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• 
Pre- or post- intervention events that occur as a result of protocol-mandated 
procedures (i.e. invasive procedures, modification of participant’s previous 
therapeutic regimen). 
• 
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. 
• 
AEs to be recorded as solicited AEs are described in the Section 10.3.3. All other 
AEs will be recorded as UNSOLICITED AEs. 
10.3.1.2. 
Events NOT Meeting the AE Definition 
• 
Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.  
• 
Pre-existing conditions or signs and/or symptoms present in a participant before 
the study intervention. These events will be recorded in the medical history section 
of the eCRF.  
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
10.3.2. 
Definition of an 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 participant 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 participant 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. The 
event will also be considered serious if a complication prolongs hospitalization or 
fulfills any other serious criteria. When in doubt as to whether ‘hospitalization’ 
occurred or was necessary, the AE should be considered serious. 
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d. Results in disability/incapacity  
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, 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 participant 
f. 
Other situations 
Medical or scientific judgment must be exercised in deciding whether reporting is 
appropriate in other situations. Important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition should 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; and 
convulsions that do not result in hospitalization. 
10.3.3. 
Solicited events 
a. Solicited administration site events 
The following administration site events will be solicited: 
Table 20 
Solicited administration site events 
Pain  
Erythema/redness  
Swelling  
b. Solicited systemic events 
The following systemic events will be solicited: 
Table 21 
Solicited systemic events 
Fever  
Headache 
Fatigue 
Myalgia 
Arthralgia 
Note: participants will be instructed to measure and record the temperature in the 
evening. The route for temperature measurement can be oral, axillary or tympanic. If 
additional temperature measurements are taken at other times of the day, participants will 
be instructed to record the highest temperature in the diary card. 
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10.3.4. 
Unsolicited adverse events 
An unsolicited AEs is an AE that was not included in a list of solicited events using a 
Participant Diary. Unsolicited events must have been spontaneously communicated by a 
participant who has signed the informed consent. Unsolicited AEs include both serious 
and non-serious AEs. 
Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalization, or an emergency room visit, or visit to/by a health care 
provider). The participants will be instructed to contact the site as soon as possible to 
report medically attended event(s), as well as any events that, though not medically 
attended, are of participant’s concern. Detailed information about reported unsolicited 
AEs will be collected by qualified site personnel and documented in the participant’s 
records. 
Unsolicited AEs that are not medically attended or perceived as a concern by the 
participant will be collected during an interview with the participants and by review of 
available medical records at the next visit. 
10.3.5. 
Adverse events of special interest (AESIs) 
pIMDs are the only AESIs collected during this study. 
10.3.5.1. 
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 22. Please refer to the Section 10.3.7.1 for reporting details. 
The investigator must exercise his/her medical/scientific judgment to determine 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 22 
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),  
• 
Necrotizing vasculitis (cutaneous or systemic),  
• 
Anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), 
• 
Henoch-Schonlein purpura (IgA vasculitis),  
• 
Behcet's syndrome, 
• 
Leukocytoclastic vasculitis. 
• 
Autoimmune hemolytic anemia. 
• 
Autoimmune thrombocytopenia. 
• 
Antiphospholipid syndrome. 
• 
Pernicious anemia. 
• 
Autoimmune aplastic anemia. 
• 
Autoimmune neutropenia. 
• 
Autoimmune pancytopenia. 
• 
Autoimmune glomerulonephritis including: 
• 
IgA nephropathy,  
• 
Glomerulonephritis rapidly progressive,  
• 
Membranous glomerulonephritis,  
• 
Membranoproliferative glomerulonephritis,  
• 
Mesangioproliferative glomerulonephritis.  
• 
Tubulointerstitial nephritis and uveitis 
syndrome. 
• 
Ocular autoimmune diseases including: 
• 
Autoimmune uveitis  
• 
Autoimmune retinitis. 
• 
Autoimmune myocarditis. 
• 
Sarcoidosis. 
• 
Stevens-Johnson syndrome. 
• 
Sjögren’s syndrome. 
• 
Alopecia areata. 
• 
Idiopathic pulmonary fibrosis. 
• 
Goodpasture syndrome. 
• 
Raynaud’s phenomenon. 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis. 
• 
Primary biliary cirrhosis. 
• 
Primary sclerosing cholangitis. 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel disease, including: 
• 
Crohn’s disease,  
• 
Ulcerative colitis,  
• 
Microscopic colitis,  
• 
Ulcerative proctitis. 
• 
Celiac disease. 
• 
Autoimmune pancreatitis. 
• 
Autoimmune thyroiditis (Hashimoto thyroiditis). 
• 
Grave's or Basedow’s disease. 
• 
Diabetes mellitus type I. 
• 
Addison’s disease. 
• 
Polyglandular autoimmune syndrome. 
• 
Autoimmune hypophysitis. 
 
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10.3.6. 
Clinical laboratory parameters and other abnormal assessments 
qualifying as AEs or SAEs  
In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded as an 
AE or SAE, if they meet the definition of an AE or SAE (refer to the Sections 10.3.1 and 
10.3.2).  
The investigator must exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding, or other abnormal assessment is clinically 
significant. 
10.3.7. 
Recording and follow-up of AEs, SAEs, and pIMDs 
The participants will be instructed to contact the investigator immediately should they 
experience any signs or symptoms they perceive as serious.  
When an AE/SAE occurs, it is the investigator’s responsibility to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to 
the event. The investigator will then record all relevant information regarding an AE/SAE 
on the eCRF. The investigator may not send photocopies of the participant’s medical 
records to GSK instead of appropriately completing the eCRF.  
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers will be blinded on 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 instead of individual signs/symptoms. 
A Paper Diary, hereafter referred to as Participant Diary, will be used in this study to 
capture solicited administration site or systemic events. The Participant Diary will be 
distributed to all participants at Visit 1, and additionally to participants in the Control 
group at Visit 2. The participant should be trained on how and when to complete the 
Participant Diary. 
Anyone who measures administration site or systemic events and who will record the 
event in the Participant Diary should be trained on using the Diary. This training must be 
documented in the participant’s source record. If any individual other than the participant 
is making entries in the Participant Diary, their identity must be documented in the 
Participant Diary. 
• 
Collect and verify completed diary cards during discussions with the participant on 
Visit 2 (from all participants) and Visit 3 (only from participants in the Control 
group). 
• 
Any unreturned diary cards will be sought from the participant through telephone 
call(s) or any other convenient procedure. 
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The investigator or delegate will transcribe the required information into the eCRF in 
English.  
10.3.7.1. 
Time period for collecting and recording AEs, SAEs, and pIMDs 
All solicited administration site and systemic events with onset during the 4 days 
following administration of the study interventions, and all unsolicited AEs that occur 
during the 30 days following administration of the study interventions must be recorded 
into the appropriate section of the eCRF, irrespective of their intensity. 
The time period for collecting and recording SAEs and pIMDs will begin at the first 
receipt of study interventions and will end 6 months after the last administration of the 
study interventions. 
All AEs/SAEs leading to withdrawal from the study will be collected and recorded from 
the time of the first receipt of study intervention until the participant is discharged from 
the study. SAEs related to study participation or to a concurrent GSK medication/vaccine 
will be collected from the time consent is obtained until the participant is discharged from 
the study. 
10.3.7.2. 
Follow-up of AEs, SAEs, and pIMDs 
After the initial AE/SAE/pIMDs or any other event of interest, the investigator is required 
to proactively follow each participant at subsequent visits/contacts. All SAEs and pIMDs 
(as defined in Section 10.3.5.1), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up. 
10.3.7.2.1. Follow-up during the study 
AEs (serious or non-serious) or pIMDs documented at a previous visit/contact and 
defined as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until the end of the study or the participant is lost to follow-up. 
If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available post-mortem findings, including 
histopathology. 
10.3.7.2.2. Follow-up after the participant is discharged from the study 
The investigator will provide any new or updated relevant information to GSK on a 
previously reported SAE/pIMD using a paper/electronic Expedited Adverse Events 
Report and/or pregnancy report as applicable. The investigator is obliged to perform or 
arrange for the conduct of supplemental clinical examinations/tests and/or evaluations to 
elucidate the nature and/or causality of the SAE/pIMD as fully as possible. 
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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.
CCI

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Causality should be assessed by the investigator using the following question: 
Is there a reasonable possibility that the unsolicited AE may have been caused by the 
study intervention? 
YES 
: 
There is a reasonable possibility that the study intervention contributed 
to the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study intervention. There are other, more likely 
causes and administration of the study intervention is not suspected to 
have contributed to the AE. 
If an event meets the criteria to be determined ‘serious’ (see Section 10.3.2), additional 
examinations/tests will be performed by the investigator 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 study intervention, if applicable. 
• 
An error in study intervention administration. 
• 
Other cause (specify).  
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 to 
record an assessment of causality for every event before submitting the Expedited 
Adverse Events Report to GSK.  
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality after 
receiving additional information and update the SAE information accordingly. 
10.3.8.3. 
Medically attended visits 
For each solicited and unsolicited AE the participant experiences, the participant 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). This information will be recorded in the eCRF.  
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10.3.8.4. 
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). 
10.3.9. 
Reporting of SAEs and pIMDs  
10.3.9.1. 
Events requiring expedited reporting to GSK 
Once an investigator becomes aware that an SAE has occurred, the investigator (or 
designee) must complete the information in the electronic Expedited Adverse Events 
Report WITHIN 24 HOURS, even if the investigator does not have complete information 
on the SAE. It must be completed as thoroughly as possible, with all available details of 
the event.  
The SAE report must be updated WITHIN 24 HOURS of the receipt of updated 
information on the SAE. The investigator will always provide an assessment of causality 
at the time of the initial report. 
Refer to the Table 13 for the details on timeframes for reporting of SAEs/pIMDs.  
The investigator will be required to confirm the review of SAE causality by ticking the 
‘reviewed’ box in the electronic Expedited Adverse Events Report within 72 hours of 
submission of the SAE. 
Refer to the Section 10.3.9.2 for information on backup systems in case the electronic 
reporting system does not work. 
10.3.9.2. 
Backup system in case the electronic reporting system does not work 
If the electronic reporting system does not work, the investigator (or designee) must fax a 
completed, dated and signed paper Expedited Adverse Events Report to the study contact 
for reporting SAEs (refer to the Sponsor Information) or to GSK VCSP department 
within 24 hours of becoming aware of the SAE.  
Investigator (or designee) must complete the electronic Expedited Adverse Events Report 
within 24 hours after the electronic reporting system is working again. The information 
reported through the electronic SAE reporting system will be considered valid for 
regulatory reporting purposes. 
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10.4. 
Appendix 4: Abbreviations and glossary of terms 
10.4.1. 
List of abbreviations  
AE: 
Adverse Event 
AS01E: 
Adjuvant System containing MPL, QS-21 and liposome 
(25 µg MPL and 25 µg QS-21) 
CI: 
Confidence Interval 
CLS: 
Clinical Laboratory Sciences 
COVID-19: 
Coronavirus Disease 2019 
CSR: 
Clinical Study Report 
eCRF: 
electronic Case Report Form 
ELISA: 
Enzyme-Linked Immunosorbent Assay 
EoS: 
End of Study 
ES: 
Exposed Set 
FDA: 
Food and Drug Administration, United States of 
America 
FLU: 
Influenza 
FSFV: 
First Subject First Visit 
GCP: 
Good Clinical Practice 
GMC: 
Geometric Mean Concentration 
GMT: 
Geometric Mean Titer 
GSK: 
GlaxoSmithKline 
HA: 
Hemagglutinin 
HI: 
Hemagglutinin inhibition 
HRP: 
Horse-Radish Peroxidase 
IB: 
Investigator Brochure 
ICF: 
Informed Consent Form 
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ICH: 
International Council on Harmonisation 
IEC: 
Independent Ethics Committee 
IgG: 
Immunoglobulin G 
IRB: 
Institutional Review Board 
LSLV: 
Last Subject Last Visit 
MGI: 
Mean Geometric Increase 
OA: 
Older Adults 
pIMD: 
Potential Immune-Mediated Disease 
PP: 
Per-Protocol 
PPS: 
Per-Protocol Set 
QS-21: 
Quillaja saponaria Molina, fraction 21 (Licensed by 
GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation) 
QTL: 
Quality Tolerance Limit 
RSV: 
Respiratory Syncytial Virus 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan 
SBIR: 
Source data Base for Internet Randomization  
SCR: 
Seroconversion Rate 
SDV: 
Source Document Verification 
SmPC: 
Summary of Product Characteristics 
SPM: 
Study Procedures Manual 
SPR: 
Seroprotection Rate 
SUSAR: 
Suspected Unexpected Serious Adverse Reactions 
ULOQ: 
Upper-Limit of Quantification 
US: 
United States 
YOA: 
Years of Age 
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10.4.2. 
Glossary of terms 
Adverse event: 
Any untoward medical occurrence in a patient or clinical 
investigation participant, temporally associated with the 
use of a medicinal product, whether or not considered 
related to the medicinal product.  
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 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 intervention 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 AEs  
In an open-label study, no blind is used. Both the 
investigator and the participant know the identity of the 
intervention assigned.  
Caregiver: 
A ‘caregiver’ is a person who has a continuous caring 
role for a participant or may be a person having 
substantial periods of contact with a participant and/or is 
engaged in his/her daily health care (e.g. a relative of the 
participant including family members or friends).  
In the context of this study, a caregiver can be appointed 
by the participant to oversee and support the 
participant’s compliance with protocol-specific 
procedures (such as transcribing responses to diaries, 
receiving phone calls, planning study visits, etc.). 
However, at no time, the caregiver should evaluate the 
participant’s health status while answering diaries or 
make decisions on behalf of the participant. 
Certified copy: 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e. by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 
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Eligible: 
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Enrolled participant: 
‘Enrolled’ means a participant’s agreement to participate 
in a clinical study following completion of the informed 
consent process. Potential participants who are screened 
for determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, 
unless otherwise specified by the protocol.  
Refer to the Section 9.3 of the protocol for the definition 
of ‘enrolled set’ applicable to the study.  
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. 
Immunological correlate 
of protection: 
A correlate of risk that has been validated to predict a 
certain level of protection from the targeted endpoint. 
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 participant’s initial immune 
status. 
Intervention number: 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Intervention: 
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 participant. 
Investigational vaccine: 
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.  
Synonym: Investigational Medicinal Product. 
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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. 
Participant number: 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Participant: 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject. 
Primary completion date: 
The date that the final participant 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. 
Protocol administrative 
change: 
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.  
Protocol amendment: 
The International Council on Harmonisation (ICH) 
defines a protocol amendment as: ‘A written description 
of a change(s) to or formal clarification of a protocol.’ 
GSK further details this to include a change to an 
approved protocol that affects the safety of participants, 
scope of the investigation, study design, or scientific 
integrity of the study. 
Randomization: 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Self-contained study: 
Study with objectives not linked to the data of another 
study. 
Site Monitor: 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
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Solicited event: 
Events to be recorded as endpoints in the clinical study. 
The presence/occurrence/intensity of these events is 
actively solicited from the participant or an observer 
during a specified follow-up period following study 
intervention administration. 
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 legible documents, data, and records (e.g. 
hospital records, clinical and office charts, laboratory 
notes, memoranda, participants' 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, participant files, and records 
kept at the pharmacy, laboratories and at medico-
technical departments involved in the clinical trial). 
Study intervention: 
Any investigational or marketed product(s) or placebo 
intended to be administered to a participant during the 
study. 
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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10.5. 
Appendix 5: Protocol Amendment history 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date of Issue 
Original Protocol 
19 October 2020 
Overall Rationale for the Amendment 
The protocol is amended to address the comments from CBER, US FDA. Specifically, 
the NI margins have been updated, and accordingly the power calculations associated 
with the co-primary objectives have been updated while the sample size remains the 
same. The formulation of the FLU vaccine has also been added based on WHO 
recommendations for the 2021 influenza season in the Southern Hemisphere, and a 
typographical error has been corrected, in Table 7 (Study interventions administered).  
Detailed description of Protocol Amendment: 
Sponsor Approval: The name of the Sponsor Signatory has been updated. 
Narcisa Mesaros Marie Van Der Wielen, MD. 
Clinical and Epidemiology R&D Project Lead, Older Adults project 
Section 6.1: Study interventions administered: The formulation of the FLU vaccine 
has been added in the footnote for Table 7 based on WHO recommendations. A 
typographical error in the Vaccine Presentation has been corrected. 
Table 7: Study interventions administered  
Study intervention name: 
RSVPreF3 OA investigational vaccine 
FLU-QIV 
Study intervention 
formulation: 
RSVPreF3 (120 µg) 
AS01E: QS-21* (25 µg), MPL (25 
µg), liposomes; Water for injection 
q.s. 0.5 mL 
FLU Quadrivalent Influenza vaccine, 15µg 
hemagglutinin (HA) per strain/dose** 
Presentation: 
RSVPreF3 (120 µg): Vial; Powder for 
suspension for injection 
AS01E: Vial; Suspension for 
suspension for injection 
Syringe, suspension for injection 
Type: 
Biologic 
Biologic 
Route of administration:  
Intramuscular (IM) injection 
IM injection 
Location 
Deltoid 
Deltoid 
Directionality 
Upper 
Upper 
Laterality  
Non-Dominant 
Co-Ad group: Dominant 
Control group: Non-Dominant 
Number of doses to be 
administered: 
1 
1 
Volume to be 
administered***: 
0.5 mL 
0.5 mL 
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Packaging, labeling and 
TM: 
(when applicable) 
Refer to the SPM for more details 
Refer to the SPM for more details 
Manufacturer: 
GSK Biologicals 
GSK Biologicals 
* QS-21: Quillaja saponaria Molina, fraction 21 (Licensed by GSK from Antigenics Inc, a wholly owned subsidiary of 
Agenus Inc., a Delaware, USA corporation)  
**The strains will depend on the World Health Organization recommendation for the 2021 FLU season used in the 
FLU Quadrivalent Influenza vaccine are A/Victoria/2570/2019 (H1N1), IVR-215 (15 µg HA); A/Hong 
Kong/2671/2019 (H3N2), NIB-121 (15 µg HA); B/Washington/02/2019, wild type (15 µg HA); B/Phuket/3073/2013, 
wild type (15 µg HA) 
*** Refer to the SPM for the volume after reconstitution  
Section 9.1 Statistical hypothesis: NI margins in Table 15 have been updated. 
Table 15: Study objectives and null hypothesis  
Objectives 
Null hypothesis 
Co-Primary 
• 
To demonstrate the non-inferiority of RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine compared to RSVPreF3 OA 
investigational vaccine administered alone. 
• 
True Group GMT ratio between RSVPreF3 OA 
investigational vaccine (Control group) divided by 
RSVPreF3 OA investigational vaccine when co-
administered with the FLU vaccine (Co-Ad group) in 
RSV-A neutralization antibody titers 1 month after 
the RSVPreF3 OA investigational vaccine dose is 
above 2.0 1.5. 
• 
To demonstrate the non-inferiority of FLU vaccine 
when co-administered with the RSVPreF3 OA 
investigational vaccine compared to FLU vaccine 
administered alone. 
• 
True Group GMT ratio between FLU vaccine 
(Control group) divided by RSVPreF3 OA 
investigational vaccine when co-administered with 
the FLU vaccine (Co-Ad group) in HI antibody titers 
for each of the FLU vaccine strains 1 month after the 
FLU vaccine is above 2.0 1.5. 
FLU vaccine is referring to FLU-QIV; HI: Hemagglutinin Inhibition; GMT: Geometric Mean Titer.  
Section 9.2 Sample size determination: The sample size consideration in Table 16 have 
been updated based on the NI margin of 1.5. The FLU strains have also been updated. 
Table 16: Overall power to demonstrate co-primary objectives: non-inferiority of 
the immunogenicity of RSVPreF3 OA investigational vaccine when co-administered 
with FLU vaccine as compared to when administered alone- assuming 393 
participants are available in each group 
RSV Non-inferiority* (1-sided test with alpha = 2.5%)  
Endpoint 
Standard deviation 
of log10 
concentration 
Non-
inferiority 
margin 
Type II error 
Power 
GMTs RSV-A neutralization antibody 
0.45 
2.0 1.5 
0.02% <0.1% 
99.98% 
>99.9% 
FLU Non-inferiority* (1-sided test with alpha = 2.5%)  
Endpoint 
Standard deviation 
of log10 
concentration 
Non-
inferiority 
margin 
Type II error 
Power 
GMTs HI H1N1 strain 
0.6 
2.0 1.5 
<0.1% 1.58% 
>99.9% 
98.42% 
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GMTs HI H3N2 strain 
0.6 
2.0 1.5 
<0.1% 1.58% 
>99.9% 
98.42% 
GMTs HI B/Washington Yamagata 
strain 
0.6 
2.0 1.5 
<0.1% 1.58% 
>99.9% 
98.42% 
GMTs HI B/Phuket Victoria strain 
0.6 
2.0 1.5 
<0.1% 1.58% 
>99.9% 
98.42% 
Global Type II error to show non-inferiority 
~6.3% ~0.1% 
 
Global power 
~93.7% 
~99.9% 
*Pass 2019 alpha = 2.5%, Two-Sample T-Tests for Non-Inferiority Assuming Equal Variance and Equal mean. 
Considering identical true GMTs in both groups with a common population standard 
error of 0.45 for the RSV-A neutralization antigen and 0.6 for each of the FLU strains in 
log10 transformed concentration, the study has at least 99.9% 93.7% power to meet the 
co-primary objectives. 
Section 9.4: Statistical analyses 
The Statistical Analysis Plan (SAP) will be developed and finalized before first subject 
first visit (FSFV). This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. Supportive analyses, safety and demography 
summaries will be described in the SAP. 
Section 9.4.1 Co-primary endpoints: The NI criteria have been updated. 
Success criteria for non-inferiority: 
1. The upper limit of the 2-sided 95% CI on the group GMT ratio (Control group 
divided by Co-Ad group) for RSV investigational vaccine is ≤1.5 2.0. 
AND 
2. The upper limit of the 2-sided 95% CI on the group GMT ratio (Control group 
divided by Co-Ad group) for each of the FLU vaccine strains are ≤1.5 2.0. 
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11. 
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Signature Page for  214488 TMF-6055060 v1.0
Signature Page for TMF-6055060 v1.0
Reason for signing: Approved
Name: Marie Van Der Wielen
Role: Approver
Date of signature: 27-Nov-2020 15:59:12 GMT+0000
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