A Single-arm, Open-label, Multi-center, Phase IV Trial to Evaluate the Reactogenicity, Safety, and Immunogenicity of Quadrivalent Seasonal Influenza Vaccine (Fluarix Tetra) in Participants Aged 65 Years and Older in India
Phase: PHASE4
Conditions: Influenza, Human
Sponsor: GlaxoSmithKline

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 1 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
 Phase IV Clinical Trial 
STUDY PROTOCOL 
 
TITLE 
A single-arm, open-label, multi-center, phase IV trial to evaluate 
the reactogenicity, safety, and immunogenicity of quadrivalent 
seasonal influenza vaccine (Fluarix Tetra) in participants aged 
65 years and older in India 
STUDY DRUG(S) 
Fluarix Tetra  
PHASE OF 
DEVELOPMENT 
Phase IV 
VERSION  
 
2.0 
Draft: 10-APR-2023 
Final: 05-May-2023 
Amendment: 01 
SPONSOR 
GlaxoSmithKline Biologicals SA, Rixensart, Belgium  
CONDUCTED BY 
 
IQVIA Consulting and Information Services India Private 
Limited, 902, 9th floor, B-Wing, Supreme Business Park, 
Hiranandani Gardens, Powai, Mumbai – 400076  
 
This protocol contains confidential information that should only be disclosed to those persons 
responsible for execution and organization of the study and on condition that all such persons 
agree not to further disseminate it.  
Anonymized Page 1

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 2 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
TABLE OF CONTENTS 
List of Tables .................................................................................................................................. 8 
List of Figures ................................................................................................................................. 8 
Investigator Signature Page ............................................................................................................ 9 
Informational Contacts .................................................................................................................. 10 
List of Abbreviations .................................................................................................................... 11 
Study Synopsis .............................................................................................................................. 13 
Documentation of Protocol Amendments ..................................................................................... 18 
1. 
BACKGROUND .................................................................................................................. 24 
2. 
RATIONALE ........................................................................................................................ 25 
3. 
BENEFIT/ RISK AND ETHICAL ASSESSMENT............................................................. 26 
4. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 26 
5. 
STUDY DESIGN.................................................................................................................. 27 
5.1 
Study Description............................................................................................ 27 
 
Scientific Rationale for the Study Design ....................................................... 30 
 
Justification of the Dose.................................................................................. 30 
 
End of Study Definition .................................................................................. 31 
5.2 
Study Population ............................................................................................. 31 
 
Inclusion Criteria ............................................................................................ 31 
 
Exclusion Criteria ........................................................................................... 31 
Anonymized Page 2

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 3 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Study Enrollment ............................................................................................ 32 
 
Lifestyle Considerations ................................................................................. 33 
 
Participant Withdrawal and Discontinuation of Study Treatment .................. 33 
5.3 
Exposure Definition and Measures ................................................................. 34 
 
Provision of Study Treatment ......................................................................... 35 
 
Preparation/ Handling/ Storage/ Accountability of Study Treatment ............. 35 
 
Measures to Minimize Bias: Randomization and Blinding ............................ 36 
 
Compliance with Study Treatment ................................................................. 36 
 
Concomitant Therapy...................................................................................... 36 
 
Dose Modification .......................................................................................... 37 
 
Treatment After the End of the Study ............................................................. 37 
5.4 
Outcome Definitions and Measures ................................................................ 37 
 
Immunogenicity Measures .............................................................................. 37 
 
Safety Measures .............................................................................................. 38 
 
Physical Examinations .................................................................................... 38 
 
Vital Signs ....................................................................................................... 38 
 
Electrocardiograms ......................................................................................... 38 
 
Clinical Safety Laboratory Assessments ........................................................ 38 
 
Suicidal Risk Monitoring ................................................................................ 39 
5.5 
Adverse Events ............................................................................................... 39 
Anonymized Page 3

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 4 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Time Period and Frequency for Collecting AE and SAE Information ........... 40 
 
Method of Detecting AEs and SAEs .............................................................. 41 
 
Follow-up of AEs and SAEs ........................................................................... 46 
 
Regulatory Reporting Requirements for SAEs ............................................... 46 
 
Pregnancy ........................................................................................................ 47 
 
Solicited Adverse Events ................................................................................ 47 
 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events .......................................................................... 48 
5.6 
Treatment of Overdose ................................................................................... 48 
 
Other Measures (If Applicable) ...................................................................... 48 
5.7 
Data Sources and Collection ........................................................................... 49 
 
Baseline/ Enrollment ....................................................................................... 50 
 
Follow-up ........................................................................................................ 50 
 
Participant Discontinuation/Withdrawal ......................................................... 51 
6. 
STATISTICAL METHODS ................................................................................................. 51 
6.1 
Statistical Hypotheses ..................................................................................... 51 
6.2 
Sample Size ..................................................................................................... 51 
6.3 
Populations for Analyses ................................................................................ 53 
6.4 
Data Analyses ................................................................................................. 54 
 
General Considerations ................................................................................... 54 
Anonymized Page 4

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 5 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Planned Analyses ............................................................................................ 55 
 
Exploratory Analyses ...................................................................................... 56 
 
Safety Analyses ............................................................................................... 56 
 
Handling of Missing Data ............................................................................... 57 
 
Limitations of Research Methods ................................................................... 57 
6.5 
Data Reporting ................................................................................................ 58 
 
Progress Reports (if applicable) ...................................................................... 58 
 
Annual/ Interim Analyses and Reporting (if applicable) ................................ 58 
 
Final Analyses and Reporting ......................................................................... 58 
7. 
STUDY MANAGEMENT ................................................................................................... 58 
7.1 
Data Entry/ Electronic Data Capture .............................................................. 58 
7.2 
Compensation ................................................................................................. 58 
7.3 
Source Documents .......................................................................................... 59 
7.4 
File Retention and Archiving .......................................................................... 59 
7.5 
Quality Assurance and Monitoring ................................................................. 59 
7.6 
Data Management ........................................................................................... 61 
7.7 
Changes to the Protocol .................................................................................. 61 
7.8 
Study Governance ........................................................................................... 62 
7.9 
Publication Policy ........................................................................................... 62 
8. 
SAFETY REPORTING ........................................................................................................ 62 
Anonymized Page 5

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 6 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
8.1 
Definitions....................................................................................................... 62 
8.2 
Procedures for Reporting Adverse Events in the CRF ................................... 63 
8.3 
Procedures for Reporting Adverse Events to GSK Drug Safety .................... 64 
8.4 
Procedures for Reporting Pregnancies (If Applicable) ................................... 65 
8.5 
Procedures for Reporting Product Complaints and Medication Errors (If 
Applicable) ...................................................................................................... 65 
9. 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 65 
9.1 
Guiding Principles .......................................................................................... 65 
9.2 
Required Documents ....................................................................................... 66 
9.3 
Participant Information and Informed Consent .............................................. 66 
9.4 
Participant Confidentiality .............................................................................. 66 
9.5 
Independent Ethics Committee/ Institutional Review Board .......................... 67 
10. REFERENCES ..................................................................................................................... 68 
11. APPENDICES ...................................................................................................................... 69 
Annex 1 
Regulatory, Ethical, and Study Oversight Considerations .............................. 69 
Regulatory and Ethical Considerations ............................................................................ 69 
Financial Disclosure ............................................................................................................ 69 
Insurance ............................................................................................................................. 70 
Informed Consent Process ................................................................................................. 70 
Administrative Structure ................................................................................................... 70 
Anonymized Page 6

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 7 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Medical Monitor .................................................................................................................. 70 
Dissemination of Clinical Study Data ............................................................................... 71 
Data Quality Assurance ...................................................................................................... 71 
Source Documents ............................................................................................................... 72 
Study and Study Center Closure ....................................................................................... 73 
Publication Policy................................................................................................................ 74 
Anonymized Page 7

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 8 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
List of Tables 
Table 1. 
Study Objectives and Endpoints ......................................................................26 
Table 2. 
Schedule of Activities ......................................................................................29 
Table 3. 
Intensity Scales for Solicited Events in Adults 18 years of Age or 
More .................................................................................................................41 
Table 4. 
Timeframes For Submitting SAEs ...................................................................47 
Table 5. 
List of Pre-Specified Solicited AEs .................................................................48 
Table 6. 
Data Collection Schedule .................................................................................49 
Table 7. 
95% Clopper-Pearson (exact) Confidence Intervals and Probabilities 
to Observe at least One Participant with AE for N=250 Participants, 
with Varying Percentages of Participants with AEs. .......................................51 
Table 8. 
95% Clopper-Pearson Exact Confidence Intervals and Probabilities to 
Observe at least One Participant with SAE for N=250 Participants, 
with Cumulative Incidence up to 1% Over a 6-month Period. ........................53 
Table 9. 
Analysis Sets ....................................................................................................54 
 
List of Figures 
   
Figure 1. 
Schematic Design, Visit schedule ....................................................................30 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 9 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Investigator Signature Page 
Study Title:  A single-arm, open-label, multi-center, phase IV trial to evaluate the reactogenicity, 
safety, and immunogenicity of quadrivalent seasonal influenza vaccine (Fluarix Tetra) 
in participants aged 65 years and older in India. 
Protocol version 2.0, dated 05 May 2023 
I have read and understand the protocol and agree that it contains the ethical, legal, and scientific 
information necessary to participate in this trial. My signature confirms the agreement of both 
parties that the trial will be conducted in accordance with the protocol and all applicable laws and 
regulations including, but not limited to Good Clinical Practice (GCP), and the ethical principles 
that have their origins in the Declaration of Helsinki and applicable privacy laws. 
I will provide copies of this protocol as needed to all physicians, nurses, and other professional 
personnel responsible to me who will participate in the Trial. I will discuss the protocol with them 
to assure myself that they are sufficiently informed regarding the conduct of the Trial. I am aware 
that this protocol will need to be approved by an appropriate reviewing Ethics Committee prior to 
any participants being enrolled and that I am responsible for verifying whether that requirement is 
met. I agree to adhere to the attached protocol and if requested to provide copies of medical 
information for the purpose of verification of submitted information, I will comply. 
Since the information in this protocol is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the trial is prohibited. I 
will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure, or access by third parties. 
Investigator:( Local investigator from the trial site, each site has one signature) 
Name 
 
         
 
Signature 
 
Date 
 
                                                              
 
Name of Institution  
RETURN ORIGINAL TO IQVIA 
Anonymized Page 9

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 10 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Sponsor Signature Page 
 
Reviewed and approved by:   
Vishal Jain  
 
 
 
Sr. Clinical Science Lead 
 
 
GSK 
 
 Signature 
 
Title 
 
Date 
Pascal Peeters  
 
 
 
Sr. Dir. Clinical Project Lead  
 
 
GSK 
 
 Signature 
 
Title 
 
Date 
 
Informational Contacts 
Sponsor 
GSK Belgium is the Sponsor of the trial. It is the responsibility of the sponsor and its local affiliate 
in India (GSK India) who is the Marketing Authorization Holder (MAH) to ensure proper 
monitoring of the trial and compliance with all applicable regulatory guidelines and laws. 
Sponsor Contact: 
Pascal Peeters 
Sr. Dir. Clinical Project Lead 
GlaxoSmithKline Biologicals SA 
Rue de l’Institut 89, 1330 Rixensart, Belgium  
 
Clinical Research Organization (CRO) responsible for the management of the trial  
IQVIA, 3 Forbury Place, 23 Forbury Road, Reading, RG1 3JH, UK  
 
 
Anonymized Page 10

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 11 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
List of Abbreviations 
AE 
Adverse event 
CBER 
Center for Biologics Evaluation and Research  
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case report form 
CRO 
Contract research organization 
DMP 
Data management plan 
DOH 
Declaration of Helsinki 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EHR 
Electronic Health Record 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GMT 
Geometric mean titers 
GPP 
Good Pharmacoepidemiology Practice 
HA 
Hemagglutinin 
HI 
Hemagglutination inhibition 
IB 
Investigator brochure 
I/M 
Intramuscularly 
IP 
Investigational Process 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
Anonymized Page 11

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 12 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
IEC 
Independent ethics committee 
IRB 
Institutional review board 
ISPE 
International Society for Pharmacoepidemiology 
MAE 
Medically attended event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGI 
Mean geometric increase 
NH 
Northern Hemisphere 
PT 
Preferred term 
QA 
Quality assurance 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCR 
Seroconversion rate 
SoA 
Schedule of Activities 
SOC 
System organ class  
SPR 
Seroprotection rate 
TIVs 
Trivalent influenza vaccines 
WHO 
World Health Organization 
WHO DD 
WHO Drug Dictionary 
 
 
 
 
 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 13 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Study Synopsis 
Full Study Title: A single-arm, open-label, multi-center, phase IV trial to evaluate the 
reactogenicity, safety, and immunogenicity of quadrivalent seasonal influenza vaccine (Fluarix 
Tetra) in participants aged 65 years and older in India. 
Phase: Phase IV 
Number of Participants: 250 
Duration of Participant Participation: 22 Days 
Background: 
Influenza (flu) can cause mild to severe illness, ranging from mild fatigue to respiratory failure 
and death. Annual influenza vaccination is the most effective measure to reduce the risk of 
influenza infection and its complications. Globally, GlaxoSmithKline (GSK) Biologicals has 
been marketing an inactivated trivalent influenza split vaccine (Fluarix) since 1992. GSK 
received its first approval of Fluarix Tetra (a quadrivalent influenza split vaccine) on 14 
December 2012 in the United States (US) for active immunization for the prevention of 
influenza disease caused by influenza virus types A and B contained in the vaccine at a dose of 
0.5 mL. Fluarix Tetra is currently approved in the US, in 28 countries of European Economic 
Area (Germany as Reference Member State) as well as over 30 countries outside the European 
Union (EU) including United Kingdom (Great Britain) and India. 
The present study is designed to evaluate the safety and immunogenicity of a Fluarix 
Tetra influenza vaccine (Northern Hemisphere [NH] 2023-2024) in adults aged 65 years of age 
and above in India. 
Rationale: The National Centre for Disease Control (Ministry of Health and Family Welfare, 
Government of India) has recommended influenza vaccination for different groups considered 
to be at risk, across various age groups, including health care workers, pregnant women, persons 
with chronic illnesses, those who are immunocompromised and elderly individuals (≥65 years 
of age). GSK Vaccines’ quadrivalent seasonal influenza vaccine D-QIV, Fluarix Tetra, has 
been approved for the immunization of adults and children ≥6 months of age in India. In order 
to fulfill a post-approval commitment imposed by the Indian regulatory agency, the present 
study is to generate additional evidence of safety and immunogenicity of 1 dose of Fluarix 
Tetra (NH 2023-2024), (0.5 mL) in participants aged 65 years and above in India. 
Anonymized Page 13

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 14 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Objectives and endpoints: 
Primary Objective: To evaluate reactogenicity and safety of Fluarix Tetra single dose 0.5 
mL intramuscularly (I/M) in participants aged 65 years and above in India. 
Endpoints: 
• Number and percentage of subjects with solicited adverse events (AEs) (local as well 
as general) for 7 days from the date of vaccination (Day 1).  
• Number and percentage of subjects with unsolicited AEs starting from the date of 
vaccination for 21 days. 
• Number and percentage of subjects with serious adverse events (SAEs) from the date 
of vaccination for 21 days. 
Secondary Objective: To evaluate immunogenicity of Fluarix Tetra single dose 0.5 mL 
(I/M) in participants aged 65 years and above in India. 
Endpoints: 
• Geometric mean titers (GMT) of serum hemagglutination inhibition (HI) titers against 
the 4 influenza vaccine (or vaccine-like) strains at baseline (Day 1) and on Day 22. 
• Mean geometric increase (MGI) at Day 22. MGI is defined as the fold increase in 
post-vaccination serum HI GMTs (Day 22) compared to Day 1. 
• Seroconversion rate (SCR) at Day 22. SCR is defined as the percentage of subjects who 
have either a pre-vaccination titer < 1:10 and a post-vaccination titer ≥ 1:40 or a pre-
vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer.  
• Seroprotection rate (SPR) at Day 1 and Day 22. SPR is defined as the percentage of 
subjects with a serum HI titer ≥ 1:40. 
 
Anonymized Page 14

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 15 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Study design: 
Overview of study design: A prospective, single-arm, open-label, multi-center, Phase IV trial. 
Study sites: This trial will be conducted in multiple sites during NH influenza season in India. 
Vaccination schedule: A single 0.5 mL intramuscular dose of Fluarix Tetra (NH 2023-2024), 
will be administered. 
Safety and reactogenicity monitoring:  
• Recording of solicited AEs for 7 days after vaccination  
• Recording of unsolicited AEs for 21 days after Fluarix Tetra is administered 
• Recording of SAEs for 21 days after vaccination 
Immunogenicity assessment: 
• Blood Samples: Two 5 mL blood samples will be collected, one before administration 
of a single dose of study vaccine at Day 1 and one at Day 22. 
• Laboratory testing:  Serum HI titers will be measured against the 4 influenza strains 
that the Fluarix Tetra are designed to protect against. GMT, MGI, SCR and SPR shall 
be evaluated to assess immunogenicity. 
Type of study vaccine intervention: Open-label. 
Data collection:  
• Safety data - A diary card will be provided to study participants. Data will be collected 
from completed diary card daily by the participant and a telephone call follow-up by 
Investigator team will be performed to assess participant’s health status. SAEs, if any, 
will be reported using the SAE Reporting Form. 
• Sample collection data for Immunogenicity assessments- Blood samples will be 
collected on pre-vaccination at Day 1 and post-vaccination at Day 22. Samples will be 
tested using HI assay at GSK or GSK designated laboratory. 
Anonymized Page 15

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 16 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Data collection/ Data Sources: 
A Diary card will be provided to trial participants to complete on a daily basis. The completed 
diary card will be collected from the participant on Day 22, and data will be captured in the 
electronic case report form (eCRF). The investigator team will follow-up via a telephone call 
between Day 8-10 to assess the participant’s health status. 
For safety assessment, vital signs and physical examination data on Day 1 will be assessed and 
recorded in the eCRF. Solicitated AEs up to Day 7 and unsolicited AEs and SAEs up to Day 21 
will be recorded and transcribed into the eCRF.  
Data Management and Quality Assurance:  
A data management plan (DMP) will be created before data collection begins and will describe 
all functions, processes, and specifications for data collection, cleaning, and validation. The 
Investigator will maintain a record of the location(s) of their respective essential documents, 
including source documents. The storage system used during the trial and for archiving 
(irrespective of the type of media used) will provide document identification, version history, 
search, and retrieval. Representatives of the Sponsor’s quality assurance (QA) unit/ monitoring 
team and competent regulatory authorities must be permitted to inspect all trial-related 
documents and other materials at the site, including the Investigator Site File, the completed 
eCRFs and the participants’ original medical records. Audits may be conducted at any time 
during or after the study to ensure the validity and integrity of the study data. 
Anonymized Page 16

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 17 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Safety: 
All the AEs, SAEs and other safety reporting data will be collected as per GSK standard 
procedures: 
• Recording of solicited AEs for 7 days after vaccination  
• Recording of unsolicited AEs for 21 days after vaccination 
• Recording of SAEs for 21 days after vaccination 
• AEs leading to discontinuation 
Trial participants will be provided with a diary card at the time of vaccination to record the 
occurrence and intensity of solicited local and general AEs during the first 7 days after 
vaccination and of unsolicited AEs within 21 days after vaccination. These diary cards will be 
reviewed at the trial visit following the vaccination visit. All solicited local AEs will be 
considered to be causally related to vaccination. Causality of all other AEs will be assessed by 
the Investigator. Any AEs and SAEs reported after 21 days will be reported by the Investigator 
as per Indian regulatory requirement. 
Statistical Considerations:  
Sample size: Approximately 250 participants will be enrolled in this trial to achieve 
200 evaluable participants considering 20% (N=50) of participants for possible drop-outs or 
invalid data.  
With N=250, the width of the 95% CIs for the incidences correspond to the very common 
(≥1/10) AEs will always be <13%, and for uncommon and common AEs it will be ≤3%. The 
probability of observing at least 1 participant with an AE will be above 91% for common and 
very common AEs. 
Interim and Final Analyses: There will be no interim analysis. The final analysis will be 
performed when all data, up to the end of the trial, are available and completely cleaned. 
Anonymized Page 17

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 18 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Ethical and Regulatory Considerations:  
This Phase IV clinical trial will be conducted in accordance with the protocol and all applicable 
laws and regulations including, but not limited to Good Clinical Practice (GCP), Good 
Pharmacoepidemiology Practice (GPP), the ethical principles that have their origins in the 
Declaration of Helsinki (DOH) and applicable privacy laws. Data protection and privacy 
regulations will be strictly observed in capturing, forwarding, processing, and storing 
participant data.  Every effort will be made to protect participant confidentiality according to 
the DOH, international ethical guidance and country regulatory requirements on the protection 
of individuals. An institutional review board (IRB)/ independent ethics committee (IEC) must 
review and approve the protocol and informed consent form (ICF) before any participants are 
enrolled. Before any protocol-directed data collection is performed, the participant must sign 
and date the IRB/ IEC-approved ICF. 
 
 
Documentation of Protocol Amendments 
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
List of Abbreviations, 
p.11, p.12 
Added the following abbreviations: 
Hemagglutinin (HA)  
Northern Hemisphere (NH)  
World Health Organization (WHO)  
To maintain consistency in the 
study document 
Study Synopsis,  
p.15, p.16 
Section 5, Study Design,  
Section 5.1 , Study Description, 
Schedule of Activities,  
p.28, p.29, p.30, 
Section 5.3.4,  
Abbreviation - DC was expanded to Diary card across the 
document 
To maintain consistency in the 
study document 
Anonymized Page 18

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 19 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
Compliance 
with 
Study 
Treatment, p.36, 
Section 5.5.1, Time Period and 
Frequency for Collecting AE and 
SAE Information, 
p.40, 
Section 
5.5.2, 
Method 
of 
Detecting AEs and SAEs, 
p.41, 
Section 5.7, Data Sources and 
Collection, 
p.49, p.50, 
Section 6.4.6, Limitations of 
Research Methods, 
p.57, 
Section 7.3, Source Documents, 
p.59 
Study Synopsis 
p.15, p.17 
Section 5, Study Design,  
Section 5.1, Study Description 
p.28 
 
Study design section  
Safety and reactogenicity monitoring 
Safety - Removed following brackets (Day 1 to Day 7 ) and 
(Day 1 to Day 21) 
 
Removed 
additional 
information in the bracket for 
better clarity  
Anonymized Page 19

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 20 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
Section 1, Background,  p.24 
Recently, US Centers for Disease Control and Prevention 
(CDC) estimated 26 000 000 to 51 00 000 cases of seasonal 
influenza with the mortality of 19 000 to 56 000, from  01 
October 2022, through 8 April 2023 (preliminary data). 
Updated 
information 
from 
CDC for the year 2022-2023 
Section 1, Background,  p.25 
This trial will use the updated formulation for the Fluarix 
Tetra (NH 2023-2024) as per the WHO recommendation 
[WHO 2023].  
Added information as per  
WHO 
recommendations 
issued in February 2023 for 
use of updated formulation of 
the Fluarix Tetra vaccine (NH 
2023-2024). 
Section 2,  
Rationale,  
p.25 
Added Fluarix Tetra (NH 2023-2024) 
Updated as above  
Section 5, Study Design,   
p.27, p.28 
Vaccination schedule: A single 0.5 mL IM dose of Fluarix 
Tetra (NH 2023-2024) will be administered. 
Added information on the composition of the Fluarix Tetra 
(NH 2023-2024) vaccine  
Laboratory testing: Serum HI titers will be measured 
against the 4 influenza strains Fluarix Tetra (NH 2023-2024) 
is designed to protect against (vaccine or vaccine-like 
strains). GMT, SCR, MGI, and SPR will be evaluated to 
assess immunogenicity 
Updated information on the 
formulation of Fluarix Tetra 
vaccine that will be used was 
added. 
 
 
 
 
 
 
Section 4 Objectives p.27 and 
Section 5.4.1 Immunogenicity 
measures p.37 
 
 
 
 
Secondary endpoint:  
Geometric mean titers (GMT) of serum hemagglutination 
inhibition (HI) titers against the 4 influenza vaccine strains at 
baseline (Day 1) and on Day 22. 
• 
Mean geometric increase (MGI) at Day 22. MGI is 
defined as the fold increase in post-vaccination serum HI 
GMTs (Day 22) compared to Day 1. 
 
Day 21 has been changed to 
Day 22 to align with previous 
GSK studies/trials 
 
 
To align with language in the 
synopsis  
 
 
Anonymized Page 20

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 21 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
 
 
 
 
 
 
 
Section 5, Study Design,   
 p.30 
• 
Seroconversion rate (SCR) at Day 22. SCR is 
defined as the percentage of subjects who have either a pre-
vaccination titer < 1:10 and a post-vaccination titer ≥ 1:40 or 
a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase 
in post-vaccination titer.  
• 
Seroprotection rate (SPR) at Day 1 and Day 22. 
SPR is defined as the percentage of subjects with a serum 
HI titer ≥ 1:40. 
Figure 1. Study design, Visit schedule updated 
Updated to show that blood collection on Day 1 prior to 
vaccination. 
 
Updated to reflect the exact dates Day 8 +2 for contact and 
Day 22+3 for final blood draw. 
 
 
 
 
 
 
 
 
 
 
To provide more clarity  
 
 
To align with previous GSK 
studies/trial 
Section 5.2.1, Inclusion Criteria,  
p.31 
Updated  
• 
Male or female participants aged ≥65 years of age 
• 
Participants and/or legally acceptable representative 
(s) (LAR) who in the opinion of the Investigator, can and 
will comply with the requirements of the protocol (e.g. 
completion of the diary cards, return for follow-up visits 
• 
Written or witnessed/thumb printed informed consent 
obtained from the participant and/or participant’s 
LAR(s) after the study has been explained according to 
the local authority requirements and prior to 
performance of any study-specific procedure 
To align with the approved 
indication of Fluarix Tetra, 
which does not have any 
reference to current Indian 
national CDC guideline for flu 
vaccination 
To align the language with 
standard text used in GSK 
studies/trials  
To align the language with 
standard text used in GSK 
studies/trials and to include 
the role of LAR. Also, to clarify 
that thumb printed informed 
consent is acceptable for 
illiterate trial subjects 
Section 5.3.2,  
 
Preparation/ 
Handling/ 
Instructions for administration of the vaccine are presented 
in the Pharmacy Manual. 
Updated as per the Pharmacy 
manual  
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 22 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
Storage/ 
Accountability of Study 
Treatment, 
p.35 
 
Section 5.4.3, 
 
Physical Examinations, 
p.38 
A physical examination of each participant will be 
performed before vaccination. The collected information 
will be recorded in the medical history section of the eCRF. 
Updated  
“medical history section of 
the” eCRF to provide more 
clarity in the data capture 
Section 5.5, 
Adverse Events 
p.39 
Pre-existing conditions or signs and/or symptoms present in 
a participant before the administration of the study vaccine. 
Removed first dose from the 
sentence as only single dose 
will be administered. 
Section 6.3, 
Populations for Analyses, 
Table 9. Analysis Set 
p.54 
The Exposed Set will include all participants from the 
Enrolled Set who received the study  vaccine. 
The Per Protocol Set will include all participants from the 
Enrolled Set who received the study intervention as per 
protocol, 
Updated and removed “a 
single dose”, 
 
Updated and removed “even 
single dose”  
 
As only single dose will be 
administered. 
Section 8.1 Definitions, 
p.62 
Detailed SAE definitions have been added 
As per the GSK guidelines 
Section 8.2, 
Procedures 
for 
Reporting 
Adverse Events in the CRF 
p.63 
Each suspected AE occurring during the study must be 
recorded in the eCRF and/or specific AE forms as 
designated by the GSK, including the description, 
seriousness criteria, severity, duration onset and resolution 
date, causal relationship with the study treatment, actions 
taken with the study treatment (withdrawal), any other 
required treatment, and outcome. 
Removed “dose reduction” as 
not applicable in the study 
Section 
9.4, 
Participant 
Confidentiality,  p.66 
However, race and ethnicity information will be collected as 
a part of demographics to determine the diversity in the 
clinical study participation. 
Information on data collection 
for 
ethnic 
and 
racial 
background 
added 
with 
justification. 
Anonymized Page 22

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 23 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Section Number 
Section Title 
Protocol page 
Change made 
 
Rationale 
Section 10, References,  
p.68 
CDC, 2023. 2022-2023 U.S. Flu Season: Preliminary In-
Season Burden Estimates. centers for disease control and 
prevention. 
Available 
at 
https://www.cdc.gov/flu/about/burden/preliminary-in-
season-estimates.htm 
 
WHO 2023. Recommendations announced for influenza 
vaccine composition for the 2023-2024 northern hemisphere 
influenza 
season. 
Available 
at 
https://www.who.int/news/item/24-02-2023-
recommendations-announced-for-influenza-vaccine-
composition-for-the-2023-2024-northern-hemisphere-
influenza-season 
Added reference to CDC 
website 
with 
updated 
information for 2023.  
 
 
 
 
Added reference to   recent 
WHO recommendations for 
use of influenza vaccine 
composition for the 2023-2024 
NH influenza season. 
 
 
 
 
 
Anonymized Page 23

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 24 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
1. 
BACKGROUND 
Influenza is a common respiratory infection caused by influenza virus and transmitted through 
respiratory droplets [Wright, 2007]. Influenza occurs in seasonal epidemics and manifests as an 
acute febrile illness with variable degrees of systemic symptoms, ranging from mild fatigue to 
respiratory failure and death [Dangi, 2012].  
Globally, it is estimated that 291 243 to 645 832 seasonal influenza-associated respiratory deaths 
(4.0 to 8.8 per 100 000 individuals) occur annually [Iuliano, 2018], 36% of which occur in low 
and middle-income countries like India [Narayan, 2020]. Recently, US (United States) Centers for 
Disease Control and Prevention (CDC) estimated 26 000 000 to 51 00 000 cases of seasonal 
influenza with the mortality of 19 000 to 56 000, from 01 October 2022, through 8 April 2023 
(preliminary data). Mortality was the highest in infants and elderly persons [CDC, 2023]. An 
Indian study reported high burden of influenza-associated mortality among adults ≥65 years (51.1, 
(95% confidence interval (CI) = 9.2 - 93.0) deaths per 100 000 population). Influenza-associated 
cardiovascular death rates were also higher for the ≥65-year age group (71.8, 
95% CI = 7.9 - 135.8 per 100 000) as compared to those aged <65 years (1.9, 95% CI = 0 - 4.6 per 
100 000) [Narayan, 2020]. These estimates may inform strategies for influenza prevention and 
control in India, including the use of vaccines. 
Annual influenza vaccination is the most effective measure to reduce the risk of influenza infection 
and its complications. Globally, GlaxoSmithKline (GSK) Biologicals has been marketing an 
inactivated trivalent influenza split vaccine (Fluarix) since 1992. Fluarix contains 15 mcg 
hemagglutinin (HA) of each of the recommended 3 inactivated split virion antigens. More than 
434 million doses have been distributed worldwide, and the vaccine is registered in more than 100 
countries. After the introduction of the quadrivalent inactivated split virion influenza vaccine 
(Fluarix Tetra), trivalent Fluarix license cancellation activities were initiated and are still ongoing 
in 2 international countries. Fluarix Tetra has been administered to millions of recipients without 
particular safety issues and has proven to be highly immunogenic. Fluarix Tetra is manufactured 
in the Dresden (Germany) plant by the same method as the commercial trivalent Fluarix vaccine 
except that it contains a second B-strain as a fourth inactivated split virion antigen. Fluarix Tetra 
was first approved on 14 December 2012 in the US for active immunization of adults and children 
3 years and older for the prevention of disease caused by the influenza A subtype viruses and type 
B viruses contained in the vaccine. Fluarix Tetra is currently approved for active immunization of 
population from 6 months of age and older in the US, in 28 countries of European Economic Area 
(Germany as Reference Member State) as well as over 30 countries outside the European Union 
Anonymized Page 24

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 25 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
(EU) including United Kingdom (Great Britain) and India. The brand name of Fluarix Tetra is 
Fluarix Quadrivalent in the US, Fluarix Tetra in the UK, Fluarix Tetra in France, Alpharix-Tetra 
in Belgium, and Influsplit Tetra in Germany.  
The present trial is designed to evaluate the safety and immunogenicity of Fluarix Tetra influenza 
vaccine in adults aged 65 years of age and above in India. This trial will use the updated 
formulation for the Fluarix Tetra (Northern Hemisphere [NH] 2023-2024) as per the World Health 
Organization (WHO) recommendation [WHO 2023].  
2. 
RATIONALE 
Influenza causes substantial morbidity and mortality worldwide. In the Indian context, estimated 
influenza-associated mortality rates are the highest for those aged ≥65 years. These estimates may 
inform strategies for influenza prevention and control in India, such as possible vaccine 
introduction [Narayan, 2020]. The National Centre for Disease Control (Ministry of Health and 
Family Welfare, Government of India) has recommended influenza vaccination in the following 
categories of persons across various age groups such as health care workers, pregnant women, 
persons with chronic illnesses, those who are immunocompromised and elderly individuals 
(≥65 years of age). GSK Vaccines’ quadrivalent seasonal influenza vaccine D-QIV, Fluarix Tetra, 
has been approved for the immunization of adults and children ≥6 months of age in India. GSK 
has committed to gather additional evidence of the safety and immunogenicity of 1 dose of Fluarix 
Tetra (0.5 mL) in individuals aged 65 years and above to fulfill a post-approval condition imposed 
by the Indian regulatory authorities (CDSCO) for this age group in India.   
Clinical benefit of the vaccine has been demonstrated in a large, appropriately designed 
immunogenicity trial [Kieninger, 2013; US PI]. The most frequently reported local solicited 
adverse events (AEs) in participants aged 65 years and above were pain at injection site, fatigue, 
muscle ache and headache. Allergic reaction is a risk observed with multiple vaccines, including 
the influenza vaccines already licensed in the US. Therefore, the risk of allergic reaction to Fluarix 
Tetra has not affected the favorable benefit risk profile of Fluarix Tetra [Clinical Review, Fluarix 
Quadrivalent]. 
This study is designed to assess the frequency and severity of solicited AEs experienced within 
7 days and unsolicited AEs experienced within 21 days post-vaccination with Fluarix Tetra (NH 
2023-2024). Serious Adverse Events (SAEs) will also be recorded within 21 days 
post-vaccination.  
Anonymized Page 25

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 26 of 74     
 
 
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                                                ©2022 GSK group of companies or its licensor.                                                        
3. 
BENEFIT/ RISK AND ETHICAL ASSESSMENT 
The influenza virus is an important respiratory pathogen that causes annual epidemics and 
occasional pandemics. Virtually every year, epidemic influenza has a significant impact in terms 
of morbidity, mortality, and economic burden. Vaccination is presently the most effective way of 
controlling influenza and preventing its complications and mortality in persons at risk. Annual 
trivalent influenza vaccines (TIV) containing 2 A strains (H1N1 and H3N2) and 1 B-strain, which 
are intended to provide protection against influenza viruses that are expected to circulate in the 
upcoming season, have been used against seasonal influenza. However, since 1983, 2 antigenically 
and genetically distinct lineages of influenza B have co-circulated worldwide. As a consequence 
of the co-circulation of these 2 lineages, there is a certain degree of mismatch each season between 
the B-strain contained in the trivalent vaccine and the circulating B-strains. Since the 
2 evolutionarily distinct lineages of influenza B virus continue to co-circulate, an additional 
B-strain antigen in the seasonal vaccine is expected to offer greater efficacy and broader protection. 
Fluarix Tetra is a quadrivalent influenza vaccine, comprising 2 A and 2 B-strains. 
By participating in this study, the participant may benefit from being vaccinated with an 
inactivated quadrivalent influenza vaccine.  
4. 
OBJECTIVES AND ENDPOINTS  
Table 1. 
Study Objectives and Endpoints 
Objective(s)  
Endpoint(s)/Estimand(s)  
Primary  
• 
To evaluate reactogenicity and safety of Fluarix Tetra 
single dose 0.5 mL intramuscularly (I/M) in participants 
aged 65 years and above in India. 
• 
Number and percentage of subjects with solicited AEs (local as
well as general) for 7 days from the date of vaccination (Day 1). 
• 
Number and percentage of subjects with unsolicited AEs starting
from the date of vaccination for 21 days.  
• 
Number and percentage of subjects with SAEs from the date of
vaccination for 21 days. 
Secondary 
Anonymized Page 26

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 27 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Objective(s)  
Endpoint(s)/Estimand(s)  
• 
To evaluate immunogenicity of Fluarix Tetra single 
dose 0.5 mL I/M in Participants aged 65 years and 
above in India. 
• 
Geometric mean titers (GMT) of serum hemagglutination 
inhibition (HI) titers against the 4 influenza vaccine strains at 
baseline (Day 1) and on Day 22. 
• 
Mean geometric increase (MGI) at Day 22. MGI is defined as 
the fold increase in post-vaccination serum HI GMTs (Day 22) 
compared to Day 1. 
• 
Seroconversion rate (SCR) at Day 22. SCR is defined as the 
percentage of subjects who have either a pre-vaccination titer 
<1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination 
titer ≥1:10 and at least a 4-fold increase in post-vaccination 
titer.  
• 
Seroprotection rate (SPR) at Day 1 and Day 22. SPR is 
defined as the percentage of subjects with a serum HI titer 
≥1:40. 
 
5. 
STUDY DESIGN 
5.1 
 Study Description 
Overview of study design: This trial is a prospective, multi-center, single-arm, open-label, 
Phase IV trial. 
Study sites: This trial will be conducted in multiple sites during NH influenza season in India. 
Study population: 250 participants aged 65 years and above in India will be enrolled. 
Vaccination schedule: A single 0.5 mL I/M dose of Fluarix Tetra (NH 2023-2024) will be 
administered. The composition of the Fluarix Tetra (NH 2023-2024) vaccine is as follows: 
A/Victoria/4897/2022 (H1N1) pdm09 - like strain* 
(A/Victoria/4897/2022, IVR-238) 
15 micrograms HA** 
A/Darwin/9/2021 (H3N2) - like strain* 
(A/Darwin/6/2021, IVR-227) 
15 micrograms HA** 
B/Austria/1359417/2021 – like strain* 
(B/Austria/1359417/2021, BVR-26) 
15 micrograms HA** 
Anonymized Page 27

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 28 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
B/Phuket/3073/2013 - like strain* (B/Phuket/3073/2013, 
wild type) 
15 micrograms HA** 
per 0.5 mL dose 
* propagated in fertilized hens’ eggs from healthy chicken flocks 
** HA - hemagglutinin 
 
Safety and reactogenicity monitoring through the daily diary card: 
• 
Recording of solicited AEs for 7 days after vaccination 
• 
Recording of unsolicited AEs for 21 days after vaccination 
• 
Recording of SAEs for 21 days after vaccination 
Immunogenicity assessment: 
• 
Blood Samples: Two 5 mL blood samples will be collected, one before 
administration of a single dose of trial vaccine at Day 1 and one at Day 22 
• 
Laboratory testing: Serum HI titers will be measured against the 4 influenza 
strains Fluarix Tetra (NH 2023-2024) is designed to protect against (vaccine or 
vaccine-like strains). Geometric mean titers (GMT), seroconversion rate (SCR), MGI, 
and SPR will be evaluated to assess immunogenicity. 
Duration of the trial: 22 days per participant. 
Type of study vaccine intervention: Open-label. 
Data collection: 
Safety data - Trial participants will receive a diary card. The Investigator team will follow-up via 
a telephone call on Day 8 to assess participant’s health status. The completed diary card will be 
collected on Day 22. The Investigator team will capture the data in an electronic case report form 
(eCRF). SAEs will be reported using the SAE Reporting Form. 
Sample collection for immunogenicity data - Blood samples will be collected pre-vaccination at 
Day 1 and post-vaccination at Day 22. Samples will be tested at GSK or GSK designated 
laboratory.  
Anonymized Page 28

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 29 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
SCHEDULE OF ACTIVITIES (SoA) 
Table 2. 
Schedule of Activities 
Data capture 
Baseline 
Follow-up 
(Telephonic) 
End of trial 
Time points 
Day 1 
Day 8 (+2) 
Day 22 (+3)  
Trial clinic visit 
1 
2 
Informed consent 
✓ 
 
 
Inclusion and exclusion criteria 
✓ 
 
 
Enrollment 
✓ 
 
 
Questionnaire survey  
✓ 
 
 
Physical exam and vital signs 
✓ 
 
 
Blood sample collection for serum immunogenicity 
assessmentsa 
✓ 
 
✓ 
Administration of Fluarix Tetra vaccine 
✓ 
 
 
Provide diary card for reporting daily health status 
✓ 
 
 
Phone contact for safety follow-up and diary card 
assessmentb 
 
✓ 
 
Recording solicited AEsc 
✓ 
✓ 
 
Recording unsolicited AEs, SAEsd and AEs leading to 
withdrawal from the study 
✓ 
✓ 
✓ 
Return of paper diary card 
(Review for completeness of diary cards) 
 
 
✓ 
Trial conclusion 
 
 
✓ 
AE: adverse event; SAE: serious adverse event.  
a) Sample to be collected pre-vaccination at Day 1 and post-vaccination at Day 22 (+3) 
b) The telephonic follow-up with participant will be conducted on Day 8 (+2). 
c) 
Recording solicited AEs on a daily basis for 7 days 
d) Recording unsolicited AEs and SAEs for 21 days 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 30 of 74     
 
 
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Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Figure 1. 
Schematic Design, Visit schedule 
 
 
 
 
 
 
 
 
 
 
Scientific Rationale for the Study Design  
The prospective, multi-center, single-arm, open-label, Phase IV trial can accomplish the study 
objectives: 
• 
To evaluate the safety and reactogenicity of Fluarix Tetra 
• 
To evaluate the humoral immunogenicity in terms of GMTs, MGI, SCR, and SPR with 
respect to the viral strains included in Fluarix Tetra 
 
Justification of the Dose 
As per [Kieninger, 2013]; US PI, post-vaccination, 0.5 mL dose of Fluarix Tetra achieved the 
lower geometric mean antibody titers GMTs and SCR among ≥65 years of age vaccinees 
compared to younger participants (aged 18 through 64 years). The HI antibody responses against 
all 4 strains fulfilled the Center for Biologics Evaluation and Research (CBER) immunogenicity 
acceptance criteria in trial participants ≥65 years of age. The reactogenicity and safety profiles of 
Study Participants 
Study time point 
Day 1
- 
Day 1
Day 8 +2
Day 22 +3 
Influenza vaccine 
= Blood sample
= Contact 
Pre- 
Vaccination 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 31 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Fluarix Tetra were comparable in this age group (≥65 years) to that in a younger population. Thus, 
a single dose of 0.5 mL IM will be used in this trial. 
 
End of Study Definition  
The end of the trial is defined as the date of the last visit of the last participant in the trial or last 
scheduled procedure shown in the Schedule of Activities (SoA) for the last participant in the trial. 
A participant is considered to have completed the trial if he/she has completed all scheduled visits 
of the trial and data are available for protocol analysis.  
5.2 
Study Population 
The trial will aim to enroll approximately 250 participants from multiple centers in India. 
 
Inclusion Criteria 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the trial. Therefore, adherence to the criteria as specified in the protocol is 
essential. 
The following criteria must be met in order to be enrolled in the trial: 
• Male or female participants aged ≥65 years of age. 
• Participants and/or legally acceptable representative(s) (LAR) who in the opinion of the 
Investigator, can and will comply with the requirements of the protocol (e.g. completion of the 
diary cards, return for follow-up visits). 
• Written or witnessed/thumb printed informed consent obtained from the participant and/or 
participant’s LAR(s) after the study has been explained according to the local authority 
requirements and prior to performance of any study-specific procedure. 
 
Exclusion Criteria 
Deviations from the exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the trial. Therefore, adherence to the criteria as specified in the protocol is 
essential. 
Participants meeting ANY of the following criteria are not eligible for participation: 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 32 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
• History of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine, 
including egg protein, or following a previous dose of any influenza vaccine.  
• Receipt of licensed vaccine, immune sera and/or any blood products, or an investigational trial 
agent within previous 30 days or planned during their participation in the trial. 
• Receipt of any flu vaccine within 6 months before trial start or any other vaccine within 30 days 
before the trial.  
• Receipt of any dose of a COVID-19 vaccine within 15 days of trial start. 
• History of Guillain-Barré Syndrome. 
• Altered immune status or chronic administration (defined as more than 14 days) of 
immunosuppressants or other immune-modifying agents within 6 months prior to 
administration of trial vaccine. 
• History of acute infectious disease or acute respiratory illness needing antibiotics or antivirals 
in the previous 7 days, based on Investigator’s judgment. 
• If a participant candidate has fever, the trial vaccination should be postponed to when the fever 
has resolved for at least 2 days (temporary exclusion criterion). Fever is defined as temperature 
≥38.0°C (100.4°F) by any route. The preferred location for measuring temperature will be oral 
route. 
• Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, or renal functional 
abnormality, as determined by medical history, physical examination, or laboratory screening 
tests.  
• Any other clinical condition that, in the opinion of the Investigator, might pose additional risk 
to the participant due to participation in the trial. 
 
Study Enrollment 
All participants presenting during the enrolment period will be assessed for eligibility according 
to the defined selection criteria and all eligible participants will be consecutively proposed to be 
enrolled in the trial. A screening log will be maintained by each site to record the disposition of 
consecutive participants potentially eligible for trial participation, in order to better assess the 
representativeness of the sampled population. 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 33 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
5.2.3.1 
Screen Failures  
Screen failures are defined as participants who consent to participate in the trial but are not 
subsequently enrolled in the trial. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any AE/SAE prior to vaccine administration. 
5.2.3.2 
Procedures for Handling Incorrectly Enrolled or Randomized Participants  
Before data are locked for statistical analysis, a review of all data will occur. Any decision to 
exclude either a participant or single assessment from the statistical analysis will be justified and 
documented. Normally no data should be excluded from the exposed set. The participants or 
observations to be excluded and the reasons for their exclusion will be documented and signed by 
those responsible before the database lock. The participants and observations excluded from 
analysis sets, and the reason for this, will be described in the trial report. 
 
Lifestyle Considerations  
Not applicable 
 
Participant Withdrawal and Discontinuation of Study Treatment 
All data collected until the date of withdrawal of the participant will be used for the analysis. 
Information related to the withdrawal of the participant will be documented. The Investigator will 
document whether the decision to withdraw a participant from the trial was made by the participant 
himself/herself, or by the Investigator, as well as which of the following possible reasons was 
responsible for the withdrawal: 
• 
Protocol deviation, especially for inclusion/exclusion criteria 
• 
SAE 
• 
Solicited AE 
• 
Unsolicited non-serious AE 
Anonymized Page 33

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 34 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
• 
Consent withdrawal, not due to an AE 
• 
Investigator discretion to discontinue the participants with appropriate reason 
• 
Migrated/moved from the trial center 
• 
Lost to follow-up 
• 
Sponsor trial termination 
• 
Other (please specify) 
Participants who are withdrawn from the trial because of SAEs must be clearly distinguished from 
participants who are withdrawn for other reasons. 
Withdrawn participants will not be replaced. 
Discontinuation of Study Treatment: Not applicable. 
Lost to Follow-up:  
A Participant will be considered lost to follow-up if he or she fails to attend 2nd scheduled visit 
(Day 22) within the window of 3 days and is unable to be contacted by the trial center. 
The following actions must be taken if a participant fails to return to the clinic for a required trial 
visit: 
• The trial center must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the trial. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant. These contact attempts should be 
documented in the participant’s medical record. 
5.3 
Exposure Definition and Measures 
The exposure under trial is administration of Fluarix Tetra vaccine. As this is a single-arm trial 
with no comparison group, there will be no exposure variable per se in the analyses of the primary 
and secondary endpoints. The associations between the exposure and the clinical parameters 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 35 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
investigated in the trial will be evaluated at baseline and at the end of the follow-up for the same 
participant. 
 
Provision of Study Treatment 
The Sponsor shall supply adequate doses of Fluarix Tetra to the Investigator site. The received 
vaccine doses will be verified for the sealed condition of packs and adequacy of label such as 
Project Number, Product Name, Strength, Number of Dosage, Manufacturer, Lot Number or Batch 
Number, Expiry Date and Storage Condition mentioned clearly (store at 2°C to 8°C) and with 
statement as ‘Clinical Trial Use Only’. 
The Investigator site pharmacy custodian or his/her designated trial personnel will receive the 
vaccine doses. 
 
Preparation/ Handling/ Storage/ Accountability of Study Treatment 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all trial treatment received and that any discrepancies are reported 
and resolved before use of the trial treatment. Only participants enrolled in the trial may receive 
trial treatment, and only authorized trial center staff may supply or administer trial treatment. All 
trial treatments must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to the 
Investigator and authorized trial center staff. 
Handling: 
• The vaccine should be allowed to reach room temperature before use. 
• Shake well before use. Inspect visually prior to administration. 
• Instructions for administration of the vaccine are presented in the Pharmacy Manual. 
Storage: 
• Store in a refrigerator (2°C to 8°C). 
• Do not freeze. 
• Store in the original package in order to protect from light. 
• Keep out of reach of children. 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 36 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Accountability: 
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for trial treatment accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records). The Investigator, a member of the trial center staff, 
or a hospital pharmacist must maintain an adequate record of the receipt and distribution of all trial 
medication using the Drug Accountability Form. These forms must be available for inspection at 
any time. Further guidance and information for the final disposition of unused trial treatment are 
provided in the Pharmacy Manual. 
 
Measures to Minimize Bias: Randomization and Blinding 
Since this trial is single arm, randomization and blinding do not apply. 
 
Compliance with Study Treatment 
Compliance with trial treatment will be assessed among a number of participants for receiving flu 
vaccination at Day 1, missing visits and returning diary card. 
 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrollment (within 2 days before the 
time of enrollment) or receives during the trial must be recorded on the eCRF along with: 
• Reason for use. 
• Dates of administration, including start and end dates. 
• Dosage information, including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Rescue Medication 
As with all injectable vaccines, appropriate medical treatment and supervision should always be 
readily available in case of an anaphylactic event following the administration of the vaccine. It is 
good clinical practice to precede vaccination by a review of the medical history (especially with 
regards to previous vaccination and possible occurrence of undesirable events) and a clinical 
Anonymized Page 36

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 37 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
examination. The Investigator will manage untoward events of vaccine administration as per their 
clinical judgment. 
 
Dose Modification 
Not applicable. 
 
Treatment After the End of the Study 
The Sponsor will not provide any additional care to participants after they complete the trial. 
5.4 
Outcome Definitions and Measures 
 
Immunogenicity Measures 
• GMT of serum HI titers against the 4 influenza vaccine (or vaccine-like) strains at baseline 
(Day 1) and on Day 22. 
• MGI, defined as the fold increase, in post-vaccination serum HI GMTs (Day 22) compared 
to Day 1. 
• SCR, defined as the percentage of participants who have either a pre-vaccination titer <1:10 
and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and at least a 4-fold 
increase in post-vaccination titer. 
• SPR, defined as the percentage of participants with a serum HI titer ≥1:40. 
Biological samples will be used for research planned in the protocol and for purposes related 
to the improvement, development and quality assurance (QA) of the laboratory tests described 
in this protocol. Additional exploratory testing to characterize the immune response of the 
vaccine/vaccine components or to characterize the disease may be performed on the serum 
samples if deemed necessary for accurate interpretation of the data and/or should such test(s) 
become available in the GSK Biologicals’ laboratory, or a laboratory designated by GSK 
Biologicals. These additional assays may not be represented in the objectives/endpoints of the 
study protocol. Serum might also be used for assay development/validation purpose outside of 
this protocol. 
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 
Anonymized Page 37

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 38 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
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 
Please refer to the Laboratory Manual for details on biospecimen management (handling, 
storage and shipment). Tests will be conducted at the Sponsor’s laboratory, or laboratories 
designated by the Sponsor. 
 
Safety Measures  
All the AEs, SAEs and other safety reporting will be captured as per GSK standard procedures. 
• Solicited local symptoms during the 7-day post-vaccination follow-up  
• Solicited general symptoms during the 7-day post-vaccination follow-up  
• Unsolicited symptoms during the 21-day post-vaccination follow-up period  
• SAEs during the 21-day post-vaccination follow-up period  
 
Physical Examinations 
A physical examination of each participant will be performed before vaccination. The collected 
information will be recorded in the medical history section of the eCRF. Treatment of any 
abnormality observed during the physical examination will be performed outside this trial 
according to local medical practice guidelines or by referral to an appropriate health care provider. 
 
Vital Signs 
Vital signs (blood pressure, pulse rate, respiratory rate, and body temperature) will be assessed 
pre-vaccination at Day 1. 
 
Electrocardiograms 
Not applicable. 
 
Clinical Safety Laboratory Assessments 
Not applicable. 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 39 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Suicidal Risk Monitoring 
Not applicable. 
5.5 
Adverse Events 
Definition of 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 
trial participant that is temporally associated with the administration of a marketed vaccine. The 
AE may or may not be considered related to the marketed vaccine. 
 
Events Meeting the AE Definition: 
• 
Significant or unexpected worsening or exacerbation of the condition/indication under trial. 
• 
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 following the performance of the administration of 
marketed vaccine even though they may have been present before trial start. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug, disease, or other interaction. 
• 
Signs, symptoms, or the clinical sequelae of administration error of either the marketed 
vaccine or a concurrent medication. 
• 
Signs or symptoms temporally associated with the marketed vaccine. 
• 
Signs, symptoms that require medical attention (e.g., hospital stays, physician visits and 
emergency room visits). 
• 
Significant failure of an expected pharmacologic or biological action. 
• 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
present at baseline and significantly worsen following the start of the trial will also be reported 
as AEs or SAEs. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfill the definition of an AE or SAE. 
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 trial that do not worsen. 
Anonymized Page 39

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 40 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
• 
Pre-existing conditions or signs and/or symptoms present in a participant before the 
administration of the trial vaccine. 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. 
Definition of SAE: A SAE is any untoward medical occurrence that: 
a. 
Results in death. 
b. 
Is life-threatening. 
c. 
Requires hospitalization or prolongation of existing hospitalization. 
d. 
Results in disability/incapacity. 
e. 
Is a congenital anomaly/birth defect in the offspring of a trial participant. 
Other adverse events (AEs): Other AEs not included in the list of solicitated AEs that are 
experienced by the participants within 21 days post-vaccination (i.e., the day of vaccination and 
the following 6 days) will be collected in the free-text field of the diary card. Other AEs include 
both serious and non-serious AEs. 
Participants will be instructed to contact the Investigator immediately should they/the participant 
manifest any signs or symptoms perceived as serious/of concern or indicating a change in their 
health status. 
 
Time Period and Frequency for Collecting AE and SAE Information 
All solicited AEs that occur within 7 days and unsolicited AEs for 21 days following the 
administration of Fluarix Tetra must be recorded into the appropriate section of the eCRF, 
irrespective of intensity, as reported by the participant in the completed diary card. 
All SAEs regardless of possible relation to vaccination should be reported in an expedited way 
throughout the study. 
The Investigator or designee will record and immediately report to the Sponsor or designee all 
SAEs in enrolled participants occurring within 21 days post-vaccination via the eCRF. Reporting 
should, under no circumstances, occur later than 24 hours after the Investigator becomes aware of 
Anonymized Page 40

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 41 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
the SAE. The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it 
being available. 
Medical occurrences that begin before the start of receipt of trial vaccine but after obtaining 
informed consent will be recorded on the Medical History/ Current Medical Conditions section of 
the eCRF, not the AE section. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the trial 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the trial, and he/she considers the event to be reasonably 
related to the trial treatment or trial participation, the Investigator must promptly notify the 
Sponsor.  
 
Method of Detecting AEs and SAEs 
A diary card will be used in this trial to capture solicited and other AEs. In addition to the 
participant completing and returning the diary card, the Investigator will record any occurrence of 
SAEs into the participant’s eCRF to minimize potential missing data (e.g., when a participant’s 
hospitalization prevents the completion of the diary). An AE that is assessed as severe should not 
be confused with a SAE. Severity is a categorization used for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets 1 of 
the pre-defined outcomes as described above (Section 5.5). 
Assessment of Intensity 
The intensity of the following solicited AEs will be assessed as described: 
Table 3. 
Intensity Scales for Solicited Events in Adults 18 years of Age or More 
Event 
Intensity 
Grade 
Parameter 
Pain at administration-site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing normal 
everyday activities 
2 
Moderate: Painful when limb is moved and interferes with everyday 
activities 
3 
Severe: Significant pain at rest. Prevents normal everyday activities 
Headache 
0 
Normal 
1 
Mild: Headache that is easily tolerated 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 42 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Event 
Intensity 
Grade 
Parameter 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
Normal 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Muscle ache all over body 
0 
Normal 
1 
Mild: Muscle aches that are easily tolerated 
2 
Moderate: Muscle aches that interfere with normal activity 
3 
Severe: Muscle aches that prevent normal activity 
Joint pain 
0 
Normal 
1 
Mild: Joint pain that is easily tolerated 
2 
Moderate: Joint pain that interferes with normal activity 
3 
Severe: Joint pain that prevents normal activity 
Shivering (chills) 
0 
Normal 
1 
Mild: Shivering (chills) that is easily tolerated 
2 
Moderate: Shivering (chills) that interferes with normal activity 
3 
Severe: Shivering (chills) that prevents normal activity 
Sweating 
0 
Normal 
1 
Mild: Sweating that is easily tolerated 
2 
Moderate: Sweating that interferes with normal activity 
3 
Severe: Sweating that prevents normal activity 
Gastrointestinal symptoms: nausea, 
vomiting, diarrhea and/or abdominal 
pain 
0 
Normal 
1 
Mild: Gastrointestinal symptoms that are easily tolerated 
2 
Moderate: Gastrointestinal symptoms that interfere with normal 
activity 
3 
Severe: Gastrointestinal symptoms that prevent normal activity 
Redness at administration-site 
Record greatest surface diameter in mm 
Swelling at administration-site 
Record greatest surface diameter in mm 
Temperature* 
Record temperature in °C/°F 
* Fever is defined as temperature ≥38.0°C (100.4°F) by any route. The preferred location for measuring temperature will be the 
oral route. 
The maximum intensity of local injection site redness/swelling will be scored at GSK as follows: 
0: 
≤20 mm 
1: 
>20 to 50 mm 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 43 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
2: 
>50 to 100 mm 
3: 
>100 mm 
The maximum intensity of fever will be scored at GSK as follows: 
0: 
<38.0°C (<100.4°F) 
1: 
≥38.0–38.4°C (≥100.4–101.2°F) 
2: 
≥38.5–38.9°C (≥101.3–102.1°F) 
3: 
≥39.0–40.0°C (≥102.2–104.0°F) 
4: 
>40.0°C (>104.0°F) 
The Investigator will assess the maximum intensity that occurred over the duration of the event 
for all unsolicited AEs (including SAEs) recorded during the study. The assessment will be based 
on the Investigator’s clinical judgment. 
The intensity should be assigned to one of the following categories: 
1 (mild) 
= 
An AE which is easily tolerated by the participant, causing minimal 
discomfort, and not interfering with everyday activities. 
2 (moderate) 
= 
An AE which is sufficiently discomforting to interfere with normal 
everyday activities. 
3 (severe) 
= 
An AE which prevents normal, everyday activities  
In adults, such an AE would, for example, prevent attendance at 
work/school and would necessitate the administration of corrective 
therapy. 
An AE that is assessed as Grade 3 (severe) should not be confused with an SAE. Grade 3 is a 
category used for rating the intensity of an event; and both AEs and SAEs can be assessed as 
Grade 3. An event is defined as ‘serious’ when it meets 1 of the pre-defined outcomes as described 
in the Section 5.5. 
 
 
Anonymized Page 43

 
CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 44 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Assessment of causality 
All solicited administration-site and systemic events will be considered causally related to 
vaccination. The complete list of these events is provided in the Table 5. 
The Investigator must assess the relationship between study vaccine/product and the occurrence 
of each unsolicited AE/SAE using clinical judgment. Where several different vaccines/products 
were administered, the Investigator should specify, when possible, if the unsolicited AE/SAE 
could be causally related to a specific vaccine/product (i.e., investigational, control/placebo or co-
administered vaccine). When causal relationship to a specific vaccine/product cannot be 
determined, the Investigator should indicate the unsolicited AE/SAE to be related to all products. 
Alternative plausible causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study vaccine/product 
will be considered and investigated. The investigator will also consult the investigator brochure 
(IB) to determine his/her assessment. 
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 
vaccine/product? 
YES 
: 
There is a reasonable possibility that the study vaccine/product contributed to 
the AE.  
NO 
: 
There is no reasonable possibility that the AE is causally related to the 
administration of the study vaccine/product. There are other, more likely 
causes and administration of the study vaccine/product is not suspected to have 
contributed to the AE. 
If an event meets the criteria to be determined as ‘serious’ (see Section 5.5), 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. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 45 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
• 
Protocol required procedure. 
• 
Other procedure not required by the protocol. 
• 
Lack of efficacy of the vaccine/product, if applicable. 
• 
Erroneous administration. 
• 
Other causes: 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. 
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. 
(1) 
Medically attended visits 
For each solicited and unsolicited symptom 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.  
(2) 
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). 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 46 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator will proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up, or until the trial is concluded. 
 
Regulatory Reporting Requirements for SAEs 
It will be clearly communicated to participating investigators that the trial does not replace the 
reporting of AEs/SAEs that should occur as part of routine practice as specified by local 
regulations. It is not the intention of the trial to influence or change the usual local reporting 
processes. Investigators should continue to report any AEs/SAEs they would typically report using 
the mechanisms routinely used in their healthcare practice. Therefore, although the data collected 
for this trial are primarily safety-related data, reporting mechanisms of AEs to regulatory 
authorities should not be altered and are to continue according to local standards. 
If an investigator (or designee) becomes aware that a trial participant has experienced a SAE within 
21 days post-vaccination, it must be reported to Sponsor using the eCRF and within the timeframes 
mentioned in below Table 4. This is essential for meeting Sponsor legal obligations and ethical 
responsibilities for participant safety and the safety of a marketed vaccine. The report must be 
completed as thoroughly as possible, with all available details of the event. The SAE will be linked 
to the central safety database with a trial ID link mechanism and reporting to Indian regulatory 
authority will be performed as per their requirement.  
For SAEs related to the marketed vaccine, the investigator must always provide an assessment of 
causality at the time of the initial report. 
The Sponsor will comply with country-specific regulatory requirements related to safety reporting 
to the regulatory authority, institutional review board/independent ethics committee (IRB/IEC), 
and investigators. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 47 of 74     
 
 
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Reference:  RWI_WI_EPI0005 
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                                                ©2022 GSK group of companies or its licensor.                                                        
Table 4. 
Timeframes For Submitting SAEs 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours 
eCRF 
14 Calendar days  
eCRF, SAE Form, 
Table 5 as per NDCT 
Rule 2019 and 
relevant medical 
records 
eCRF: electronic Case Report Form; SAE: serious adverse event, NDCT: New Drug and Clinical Trials 
Backup System in Case the Electronic Reporting System Does Not Work 
If the electronic reporting system does not work, the Investigator (or designee) must report the 
SAE directly to Sponsor central safety within the required timeframe. 
Contact information for reporting SAEs to Sponsor in case the electronic reporting system does 
not work 
Study contact for reporting SAEs in case the eCRF reporting system does not work 
24/24 hour and 7/7 day availability: 
GSK Clinical Safety & Pharmacovigilance 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: PV.ICSRManagement@gsk.com 
 
 
Pregnancy 
Not applicable. 
 
Solicited Adverse Events  
AEs that comprise the primary interest of the study are designated as solicited AEs. The list of 
pre-specified solicited AEs is listed below: 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 48 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Table 5. 
List of Pre-Specified Solicited AEs 
Solicited Administration-site Events 
Pain 
Redness 
Swelling 
Solicited Systemic Events 
Fever 
Headache 
Myalgia (Muscle pain) 
Arthralgia (Joint pain) 
Fatigue 
Gastrointestinal symptoms (including nausea, vomiting, diarrhea and/or abdominal pain) 
Sweating 
Shivering 
 
Body temperature will be recorded preferably in the evening and in case temperature was measured 
more than once per day, the highest temperature will be recorded in the eCRF. 
 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Not applicable. 
5.6 
Treatment of Overdose 
Not applicable. 
 
Other Measures (If Applicable) 
Not applicable. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 49 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
5.7 
Data Sources and Collection  
A diary card will be provided to trial participants to fill it on a daily basis. The completed diary 
card will be collected from the participant on Day-22 and data will be captured in the eCRF. A 
telephone follow-up call will be performed by the Investigator team to assess the participant’s 
health status. 
Blood sample collection for immunogenicity data will be collected pre-vaccination at Day 1 and 
post-vaccination at Day 22. The Investigator team will capture the data in an eCRF. SAEs, if any, 
will be reported using the SAE Reporting Form. 
For safety assessment, vital signs and physical examination data at Day 1 will be assessed and 
recorded in the eCRF. Solicited AEs up to Day 7, unsolicited AEs up to Day 21 and SAEs up to 
Day 21 will be recorded in the paper diary card by participant and transcribed into the eCRF. 
Table 6. 
Data Collection Schedule 
Visit number 
Baseline 
Follow-up 
(Telephonic) 
End of Study 
Time points 
Day 1 
Day 8 (+2) 
Day 22 (+3) 
Informed consent 
  
 
 
Inclusion and exclusion criteria 
  
 
 
Physical examination 
  
 
 
Demographic data 
  
 
 
Medical history 
  
 
 
History of Flu vaccination  
  
 
 
Current medical condition 
  
  
  
Concomitant medication 
  
  
  
Vital signs 
  
 
 
Data related to sample collection  
  
 
  
Telephonic data collection 
 
  
 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 50 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Visit number 
Baseline 
Follow-up 
(Telephonic) 
End of Study 
Time points 
Day 1 
Day 8 (+2) 
Day 22 (+3) 
Diary card data collection 
 
 
  
Trial conclusion 
 
 
  
 
 
Baseline/ Enrollment 
The following data will be collected at baseline for all enrolled participants: 
• Demographics (age, year of birth, ethnicity, race, and sex) 
• Medical history 
• History of flu vaccination for last 3 years 
• Current medical condition 
• Vitals 
• Physical examination 
• Immunogenicity assessment parameters: GMT, MGI, SCR and SPR 
 
Follow-up  
The following data will be collected for all enrolled participants at the telephonic follow-up 
timepoint: 
• Current medical condition 
• Any AEs 
• Assessment of patient diary card  
The following data will be collected in eCRF for all enrolled participants at Day 22 which is end 
of trial for the participant: 
• Current medical condition 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 51 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
• Immunogenicity assessment parameters: GMT, MGI, SCR and SPR 
• SAEs 
• Solicited and unsolicited AEs 
• Study conclusion data 
 
Participant Discontinuation/Withdrawal 
Refer to section 5.2.5. 
6. 
STATISTICAL METHODS 
6.1 
Statistical Hypotheses  
All analyses will be descriptive. No hypothesis will be tested. 
6.2 
Sample Size 
Approximately 250 participants will be enrolled in this trial to achieve 200 evaluable participants 
considering that some participants may drop out of the study or some may not be included in data 
analysis due to missing or invalid data. 
Table 7. 
95% Clopper-Pearson (exact) Confidence Intervals and Probabilities to 
Observe at least One Participant with AE for N=250 Participants, with Varying 
Percentages of Participants with AEs. 
  
  
95% CI1 
  
 
Category 
Lower Limit 
Upper Limit 
Width 
Probability to Observe ≥1 
Participant with AE (%)2 
0.1% 
Uncommon 
0.00 
1.67 
1.67 
22.1 
1% 
Common 
0.17 
3.17 
3.00 
91.9 
10% 
Very common 
6.58 
14.41 
7.83 
>99.9 
50% 
43.63 
56.37 
12.73 
>99.9 
1. 
Calculations done using SAS version 9.4 and validated using PASS (19) software. 
2. 
Calculated using the binomial distribution.   
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 52 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Table 7 shows 95% Clopper-Pearson CIs for the proposed N=250 and varying incidence of 
solicited/ unsolicited AEs. The AE incidences shown correspond to the categories uncommon 
(≥1/1 000 to <1/100), common (≥1/100 to <1/10) and very common (≥1/10).  
With N=250, the width observed for the 95% CIs is always <13%, and for uncommon and common 
AEs it is ≤3%. 
Table 7 also shows, in the last column, the probability of observing at least 1 participant with AE. 
This probability is at least 91.9% for common and very common AEs. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 53 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Table 8. 
95% Clopper-Pearson Exact Confidence Intervals and Probabilities to 
Observe at least One Participant with SAE for N=250 Participants, with Cumulative 
Incidence up to 1% Over a 6-month Period. 
  
  
Clopper-Pearson 95% CI1 
  
Months after 
Vaccination 
Cumulative Incidence 
of SAE (%)2 
Lower 
Limit 
(%) 
Upper 
Limit (%) 
Width 
Probability to Observe 
≥1 participant with SAE (%)3 
1 
0.17 
0.00 
1.79 
1.79 
34.1 
2 
0.33 
0.00 
2.09 
2.09 
56.6 
3 
0.50 
0.02 
2.38 
2.35 
71.4 
4 
0.67 
0.06 
2.65 
2.59 
81.2 
5 
0.83 
0.11 
2.91 
2.80 
87.7 
6 
1.00 
0.17 
3.17 
3.00 
91.9 
1. 
SAS version 9.4 and validated using PASS (19) software. 
2. 
Assuming linear increase in incidence from date of vaccination to 1% at 6 months. 
3. 
Calculated using binomial distribution. 
Table 8 shows 95% Clopper-Pearson CIs for 250 participants by cumulative incidence of SAE. 
The width of the 95% CIs is ≤ 3% throughout. The probability of observing at least 1 participant 
with SAE is >56% for cumulative incidence from Month 2 onward [Clopper_1934]. 
Further details about the actual implementation of the Clopper-Pearson CIs will be provided in the 
Statistical Analysis Plan (SAP).   
6.3 
Populations for Analyses 
Analyses will be performed as per protocol and will be fully described in the SAP. For purposes 
of analysis, the analysis sets in Table 9 are defined.
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 54 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Table 9. 
Analysis Sets 
Analysis Set 
Description 
Enrolled Set 
The Enrolled Set will include all eligible participants with informed consent signed. 
Exposed Set 
The Exposed Set will include all participants from the Enrolled Set who received the trial 
vaccine. 
Per Protocol Set (PPS) 
The Per Protocol Set will include all participants from the Enrolled Set who received the 
trial intervention as per protocol, had immunogenicity results pre- and post-dose, 
complied with the allowed dosing/blood draw intervals, without intercurrent conditions 
that may interfere with immunogenicity and without prohibited concomitant 
medication/vaccination. 
Solicited Safety Set 
Solicited Safety Set will include all participants who returned the daily diary. 
6.4 
Data Analyses 
 
General Considerations 
All AE verbatim terms will be recorded and coded using the current version of Medical Dictionary 
for Regulatory Activities (MedDRA), 25.0 or latest. The concomitant medication will be coded 
using WHO Drug Dictionary (WHO DD) (last updated on 1 Sep 2020) or latest. 
All computations and generation of tables, listings and data for figures will be performed using 
SAS® version 9.4 or higher (SAS Institute, Cary, NC, USA). The following descriptive statistics 
will be used as applicable to summarize the trial data: 
• Continuous variables: number of non-missing values (n), mean, standard deviation (SD), 
median, minimum (min) and maximum (max). 95% CI of the mean may be provided as 
well. The number of missing values will also be provided. 
• Categorical variables: frequencies, percentages and associated 95% Clopper-Pearson (exact) 
CIs, as applicable. 
 
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CONFIDENTIAL 
 
Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 55 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Planned Analyses 
Analysis of primary endpoints:  
The primary endpoint analysis will be performed on the Exposed Set. 
The number and percentage of participants reporting solicited local (any, Grade 3, medically 
attended) and general (any, Grade 3, related, Grade 3 related, medical attended) AE during the 
follow-up period will be tabulated with exact Clopper-Pearson 95% CI. 
The duration (in terms of number of days) of each solicited local and general AE during the 7-day 
follow-up period (Day 1 - Day 7) will be tabulated. 
The number and percentage of participants reporting ongoing solicited (local and general) AEs at 
the end of the 7-day follow-up period will be tabulated with exact 95% CI. 
Occurrence of fever will also be reported per 0.5°C cumulative increments. 
The number and percentage of participants reporting at least 1 unsolicited AE (any, Grade 3, 
related, Grade 3 related, medically attanded) classified by the MedDRA during the 21-day 
follow-up period (Day 1 - Day 21) will be tabulated with exact 95% CI, overall, by MedDRA 
system organ class (SOC) and preferred term  (PT).  
The number and percentage of participants reporting at least 1 SAE during the trial period will be 
tabulated with exact 95% CI, overall and by MedDRA SOC and PT. 
SAEs and withdrawals due to AE(s) will be described in detail in listings. 
Analysis of secondary endpoints: 
The secondary endpoint analysis will be performed on the PPS and Exposed Set. 
• GMTs of HI titers on Days 1 and 22, with 95% CI. 
• MGI at Day 22, with 95% CI. 
• SCRs at Day 22, with 95% CI. 
• SPRs on Day 22, with 95% CI. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 56 of 74     
 
 
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Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Exploratory Analyses 
Not applicable. 
 
Safety Analyses  
All safety analyses will be performed on the Exposed Set and Solicited Safety Set. 
For the analysis of vaccine safety, the following parameters and the 95% CI will be calculated: 
• 
The percentage of participants with at least 1 local AE (solicited and/or unsolicited), with at 
least 1 general AE (solicited and/or unsolicited) and with any AE during the solicited 
follow-up period after vaccination will be tabulated with exact 95% CI. 
• 
The percentage of participants reporting each individual solicited local (any, Grade 3) and 
general (any, Grade 3, related, Grade 3 related, medically attended) AE during the solicited 
follow-up period after vaccination will be tabulated with exact 95% CI. 
• 
The duration statistics (in terms of number of days) of each solicited local and general AE 
during the 7 day post-vaccination follow-up period will be tabulated. 
• 
The percentage of participants reporting ongoing solicited (local and general) AEs at the end 
of the solicited follow-up period will be tabulated with exact 95% CI. 
• 
Temperature will be reported per 0.5°C cumulative increments beginning with temperature 
37.5°C/99.5°F. 
• 
The percentage of participants with at least 1 report of an unsolicited AE (any, Grade 3, 
related, Grade 3 related) classified by the MedDRA during the follow-up period will be 
tabulated with exact 95% CI. 
• 
The proportion of participants who started to receive at least 1 concomitant medication during 
the follow-up period will be tabulated with exact 95% CI. 
• 
The percentage of participants with at least 1 report of SAE classified by MedDRA during the 
trial period will be tabulated with exact 95% CI. 
• 
The percentage of participants with at least 1 report of a medically attended event classified 
by MedDRA during the trial period will be tabulated with exact 95% CI. 
• 
SAEs and withdrawals due to AE(s) will be described in detail in Listings. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
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Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
 
Handling of Missing Data 
It is optimal to prevent missing data, to the extent possible, through strategies set forth in the design 
and conduct of a trial. For the current trial, we will aim to minimize missing information; for a 
given participants and a given immunogenicity measurement, missing or non-evaluable 
measurements will not be replaced. 
The data will be analyzed as they are recorded in the trial eCRF. However, the amount of missing 
values for data elements will be reported. Characteristics of participants who returned and who did 
not return the diary card will be described. 
 
Limitations of Research Methods 
Some limitations can be anticipated for this trial. The trial is designed/powered to capture very 
common (≥1 per 10) and common (≥1 per 100 to <1 per 10) AEs. Due to its limited size the trial 
is not well suited to detect uncommon (≥1 per 1000 to <1 per 100), rare (≥1 per 10 000 to 
<1 per 1000) or very rare (<1 per 10 000) AEs.   
Furthermore, as this trial aims to collect data that are self-reported and encoded by the participant, 
it is anticipated that limitations common to non-interventional studies that use participant-reported 
data may also apply to the current trial. As we expect that the majority of participants will not have 
a medical background, it cannot be completely ruled out that, despite instructions, the severity 
grade of any AEs experienced may be inaccurately reported by the vaccinees. This possibility is 
expected, however, to be mitigated/minimized by the straightforward definitions from the US Food 
and Drug Administration (FDA) AE Grading provided in the diary card.  
In addition, it could be possible to face some underreporting of events, as the reporting will be 
solely based on the participants’ willingness to complete the information in the card and return the 
completed card to the Investigator.  
To minimize reporting bias, we will provide a pre-defined list of symptoms commonly experienced 
after the receipt of inactivated influenza vaccines to ease the identification and capture of 
symptoms experienced. In addition, the participants will be provided with the opportunity to report 
any other symptoms that they may experience and explicitly indicate if they have not experienced 
any AE to maximize the accuracy and comprehensiveness of the reporting. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
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Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
6.5 
Data Reporting 
 
Progress Reports (if applicable) 
Not applicable. 
 
Annual/ Interim Analyses and Reporting (if applicable) 
Not applicable. 
 
Final Analyses and Reporting 
A final trial report will be generated after all data collection is complete, including up to 21 days 
of follow-up for all enrolled participants. The final report will encompass all planned analyses, 
including a description of the complete trial population, as described above and in the SAP. 
7. 
STUDY MANAGEMENT 
This trial will be performed by IQVIA with guidance, input, review and approval of GSK, 
including development of materials, recruitment, training and management of sites, electronic data 
capture (EDC) and data management and analysis. 
7.1 
Data Entry/ Electronic Data Capture 
All data will be collected and entered directly into the EDC system. All participating sites will 
have access to the data entered regarding the individual site its own enrolled participants. All sites 
will be fully trained in using the online data capture system, including eCRF completion guidelines 
and help files. Sites will be responsible for entering extracted participant data into a secure internet-
based EDC registry database via the eCRF. Investigators and site personnel will be able to access 
their account with a username and password. All eCRFs should be completed by designated, 
trained personnel or the trial coordinator, as appropriate. All the eCRFs should be reviewed, 
electronically signed, and dated by the Principal Investigator. All changes or corrections to eCRFs 
are documented in an audit trail and an adequate explanation is required. 
7.2 
Compensation 
Not applicable. 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
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7.3 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Investigators should maintain a record of the location(s) of their 
source documents. Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. The source documents will include diary card, 
laboratory reports and any medical records of individual participants. All original source 
documentation is expected to be stored at the site for 15 years as required by applicable local 
regulations. 
7.4 
File Retention and Archiving 
To enable evaluations and/or audits from regulatory authorities or the GSK, the Investigator agrees 
to keep records, including the identity of all participating participants, all original signed informed 
consent forms (ICFs), copies of all case report forms (CRFs), SAEs forms, source documents and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls 
reports).  The records should be retained by the Investigator according to local regulations, or as 
specified in the trial contract, whichever is longer. 
Each site will receive a trial site file at trial initiation which contains all documents necessary for 
the conduct of the trial and is updated throughout the trial.  This file must be available for review 
in the event the site is selected for monitoring, audits, or inspections and must be safely archived 
for at least 15 years after the completion of participation in the trial. Documents to be archived 
include the participant enrollment log and the signed ICF. In the event that archiving of the file is 
no longer possible at the site, the site will be instructed to notify the Sponsor. 
7.5 
Quality Assurance and Monitoring 
The Investigator will maintain a record of the location(s) of their respective essential documents 
including source documents. The storage system used during the trial and for archiving 
(irrespective of the type of media used) will provide for document identification, version history, 
search, and retrieval. 
Essential documents for the trial may be added or reduced where justified (in advance of trial 
initiation) based on the importance and relevance to the trial. When a copy is used to replace an 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 60 of 74     
 
 
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                                                ©2022 GSK group of companies or its licensor.                                                        
original document (e.g., source documents, CRF), the copy will fulfill the requirements for 
certified copies. 
All participant data relating to the trial will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the 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 that support the information 
entered in the eCRF. 
The Investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents or certified copies. 
The Sponsor or designee is responsible for the data management of this trial, including quality 
checking of the source data. 
To ensure compliance with Good Clinical Practice (GCP) or other applicable guidelines and all 
applicable regulatory requirements, GSK may conduct a QA audit. Regulatory agencies may also 
conduct a regulatory inspection of this trial. Such audits/inspections can occur at any time during 
or after completion of the trial. If an audit or inspection occurs, the database owner and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her 
time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant 
issues. 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are attributable, legible, contemporaneous, original, accurate, 
and complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (e.g., via an audit trail). Safety and rights of participants must 
be protected, and the trial should be conducted in accordance with the currently approved protocol 
and any other trial agreements, International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) GCP, and all applicable regulatory 
requirements. 
GSK will inform the Investigator/institution of the time period for retaining these records to 
comply with all applicable regulatory requirements. However, the Investigator/institution should 
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adults aged 65 years and older 
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seek the written approval of the Sponsor before proceeding with the disposal of these records. The 
minimum retention time will meet the strictest standard applicable to a particular site, as dictated 
by ICH GCP or other applicable guidelines, any institutional requirements or applicable laws or 
regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years 
from the date of completion of study report/equivalent summary. 
A trial monitoring plan, including for-cause monitoring, that is appropriate for the trial design will 
be developed and implemented. 
7.6 
Data Management 
A data management plan (DMP) will be created before data collection begins and will describe all 
functions, processes, and specifications for data collection, cleaning, and validation. The eCRFs 
will include programmable edits to obtain immediate feedback if data are missing, out-of-range, 
illogical or potentially erroneous. Concurrent manual data review will be performed based on 
parameters dictated by the plan. Ad hoc queries will be generated within the EDC system and 
followed up for resolution. 
High data quality standards will be maintained, and processes and procedures utilized to repeatedly 
ensure that the data are as clean and accurate as possible when presented for analysis. Data quality 
will be enhanced through a series of programmed data quality checks that automatically detect 
out-of-range or anomalous data. 
7.7 
Changes to the Protocol 
Changes to the protocol will be documented in written protocol amendments. Major (i.e., 
substantial, significant) amendments will usually require submission to the relevant IRB/ IECs for 
approval or favorable opinion. In such cases, the amendment will be implemented only after 
approval or favorable opinion has been obtained. 
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
at each participating site and will be submitted to the relevant IRB/ IEC or regulatory authorities 
where required by pertinent regulations. Any amendment that could have an impact on the 
participant’s agreement to participate in the trial requires the participant’s informed consent prior 
to continued participation in the trial. 
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adults aged 65 years and older 
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7.8 
Study Governance 
Not applicable 
7.9 
Publication Policy 
Trial information from this protocol will be posted on applicable publicly available clinical trial 
registers before enrolment of participants begins. 
Summaries of the results of GSK interventional studies (Phase I-IV) are posted on applicable 
publicly available results registers within 12 months of the primary completion date for studies of 
authorized vaccines  
GSK also aims to publish the results of these studies in searchable, peer reviewed scientific 
literature. Manuscripts are submitted for publication within 24 months of the last participant’s last 
visit. 
8. 
 
SAFETY REPORTING 
The Investigator or site staff is/are responsible for the detection, documentation and reporting of 
events meeting the criteria and definition of an AE or SAE as provided in this protocol.  
Each participant will be instructed to contact the Investigator immediately should he/she 
experience any signs or symptoms he/she perceives as serious. 
8.1 
Definitions 
Adverse events (AEs) 
An AE is any untoward medical occurrence in a clinical investigation participant, temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
A SAE is any untoward medical occurrence that: 
a. Results in death. 
b. Is life-threatening. 
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adults aged 65 years and older 
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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 outpatient setting. Complications that occur during 
hospitalization are also considered as AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event will also be considered serious. When in doubt as 
to whether ‘hospitalization’ occurred, or was necessary, the AE should be considered serious. 
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 trial participant. 
  
f. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy). 
g. Other situations 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These should also be considered serious. Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization. 
 
8.2 
Procedures for Reporting Adverse Events in the CRF 
All AEs (serious and non-serious) reported during the follow-up period will be captured on the 
eCRF. Each suspected AE occurring during the trial must be recorded in the eCRF and/or specific 
AE forms as designated by the GSK, including the description, seriousness criteria, severity, 
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adults aged 65 years and older 
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duration (onset and resolution date), causal relationship with the trial treatment, actions taken with 
the trial treatment (withdrawal), any other required treatment, and outcome. 
The outcome of each AE (serious or non-serious) should be entered with a term such as those 
described below: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
If any of the same AEs occur on several occasions in the same participant, then the AE in question 
must be documented and assessed each time. In cases of surgical or diagnostic procedures, the 
condition/ illness leading to such a procedure is considered as the AE rather than the procedure 
itself. 
8.3 
Procedures for Reporting Adverse Events to GSK Drug Safety 
In addition to recording the event on the eCRF, all SAEs and non-serious AEs considered related 
to Fluarix Tetra reported during follow-up must also be reported to IQVIA and GSK 
Pharmacovigilance for purposes of regulatory reporting. Site personnel must complete and submit 
the appropriate SAE report form (available through the EDC system) and forward it to IQVIA and 
GSK Pharmacovigilance within 24 hours of becoming aware of the event.  To ensure participant 
safety, all SAEs and non-serious AEs considered related to Fluarix Tetra occurring after informed 
consent is signed and until 21days after last exposure to the product, should be reported to IQVIA 
and GSK Pharmacovigilance within 24 hours of learning of its occurrence. 
All completed SAE forms should be sent to: 
IQVIA Drug Safety 
Email: QLS_Fluarix_SO@iqvia.com 
Fax: + 001 919 800-0122 
Telephone: + 0091 80 71311011 
 
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A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
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In order to maintain compliance with the Indian and other regulatory bodies, Investigator may be 
further contacted by GSK Pharmacovigilance in order to collect additional information required 
to evaluate the potential event.  AEs/ SAEs will be reported to local and regional health authorities 
by the Sponsor, when appropriate, in accordance with applicable local and regional regulations. 
The Investigator is responsible for maintaining compliance with any applicable site-specific 
requirements related to the reporting of SAEs or other safety information to the local IRB/ IEC 
that approved the trial. 
Study contact for reporting vaccine related SAEs in case the eCRF reporting system does 
not work 
24/24 hour and 7/7 day availability: 
GSK Clinical Safety & Pharmacovigilance 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: PV.ICSRManagement@gsk.com 
 
8.4 
Procedures for Reporting Pregnancies (If Applicable) 
Not applicable. 
8.5 
Procedures for Reporting Product Complaints and Medication Errors (If Applicable) 
Not applicable. 
9. 
ETHICAL AND REGULATORY CONSIDERATIONS 
9.1 
Guiding Principles 
To ensure the quality and integrity of research, this trial will be conducted under the GCP, the 
GPPs issued by the International Society for Pharmacoepidemiology (ISPE), the Declaration of 
Helsinki (DOH) and its amendments, ICH GCP, New Drugs and Clinical Trial Rules, 2019 and 
applicable national guidelines. 
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A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
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9.2 
Required Documents  
Prior to the enrollment of any participant in the trial, the following documents must be provided 
by the site to the GSK: 
• Copy of the IRB/ IEC approval letter for the protocol and informed consent (all written 
information provided to the participant must be approved by the IRB/IEC) 
• Copy of the IRB/ IEC-approved informed consent document to be used 
• Copy of the protocol signoff page signed by the Investigator 
• Fully executed Clinical Trial Agreement 
9.3 
Participant Information and Informed Consent 
Please refer appendix 1 - ANNEX 1 (Section Informed Consent Process) 
9.4 
Participant Confidentiality 
In order to maintain participant confidentiality, each participant will be assigned a unique 
participant identifier upon trial enrolment. This participant identifier will be used in place of 
participant name for the purpose of data analysis and reporting. Medical record numbers or other 
local reference identifiers are not collected as part of the database. However, race and ethnicity 
information will be collected as a part of demographics to determine the diversity in the clinical 
trial participation. All parties will ensure protection of participant personal data and will not 
include participant names on any trial forms, reports, publications, or in any other disclosures, 
except where required by law. In accordance with local regulations, participants will be informed 
about data handling procedures and asked for their consent. Data protection and privacy 
regulations will be observed in capturing, forwarding, processing, and storing participant data. 
Participant confidentiality will be strictly maintained. 
The database will be housed at the IQVIA in a physically and logically secure computer system 
maintained by the IQVIA in accordance with a written security policy. The system meets approved 
established standards for the security of health information and is validated. The system also meets 
the standards of the ICH guideline E6 R2 regarding electronic trial data handling and is available 
for audit upon request. 
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adults aged 65 years and older 
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9.5 
Independent Ethics Committee/ Institutional Review Board 
Consistent with local regulations and prior to enrollment of participants at a given site, the trial 
protocol will be submitted together with its associated documents (e.g., ICF) to the responsible 
IRB/ IEC for its review. Participant enrollment will not start at any site before the written 
confirmation of a favorable opinion/ approval from the relevant central or local IRB/ IEC. The 
IRB/ IEC will be asked to provide documentation of the date of the meeting at which the favorable 
opinion/ approval was given that clearly identifies the trial, the protocol version, and the ICF 
version reviewed. 
Before implementation of any substantial changes to the protocol, protocol amendments will also 
be submitted to the relevant IRB/ IEC in a manner consistent with local regulations. Pertinent 
safety information will be submitted to the relevant IECs during the course of the trial in 
accordance with local regulations and requirements. It is the responsibility of the Investigator to 
have prospective approval of the trial protocol, protocol amendments, and ICFs, and other relevant 
documents, if applicable, from their local IRB/ IEC and provide documentation of approval to 
IQVIA. All correspondence with the IRB/ IEC should be retained in the Investigator File. 
Should the trial be terminated early for any unanticipated reason, the Investigator will be 
responsible for informing the IRB/ IEC of the early termination. 
 
 
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adults aged 65 years and older 
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10. 
REFERENCES 
• Barr G, Jelley LL. The coming era of quadrivalent human influenza vaccines: who will benefit? 
Drugs. 2012;72(17):2177-85. 
• Clinical Review, Fluarix Quadrivalent, GlaxoSmithKline Biologicals. 
• Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26:404-13. 
• Dangi, T., Jain, A. Influenza Virus: A Brief Overview. Proc. Natl. Acad. Sci. India Sect B. 
Biol. Sci. 2012;82(1):111–121. 
• Fluarix Tetra vaccine US Prescribing information, revised in 2021. 
• Iuliano AD, Roguski KM, Chang HH, et al. Estimates of global seasonal influenza-associated 
respiratory mortality: a modelling study. Lancet. 2018;391:1285-300. 
• Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled 
in 
Preventive 
Vaccine 
Clinical 
Trials. 
Available 
at 
https://www.fda.gov/media/73679/download. Accessed: June 5, 2022. 
• Kieninger D, Sheldon E, Lin WY, et al. Immunogenicity, reactogenicity and safety of an 
inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza 
vaccine: a phase III, randomized trial in adults aged ≥18 years. BMC Infect Dis. 2013;13:343.  
• Narayan VV, Iuliano AD, Roguski K, et al. Burden of influenza-associated respiratory and 
circulatory mortality in India, 2010-2013. J Glob Health. 2020;10(1).  
• Wright PF, Neumann G, Kawaoka Y. Orthomyxoviruses. In: Knipe DM, Howley PM, 
editors. Fields 
Virology. 5th 
Philadelphia, 
PA: 
Lippincott 
Williams 
& 
Wilkins; 
2007:1691-740. 
• CDC, 2023. 2022-2023 U.S. Flu Season: Preliminary In-Season Burden Estimates. centers for 
disease 
control 
and 
prevention. 
Available 
at 
https://www.cdc.gov/flu/about/burden/preliminary-in-season-estimates.htm. Accessed: April 
10, 2023.  
• WHO 2023. Recommendations announced for influenza vaccine composition for the 2023-
2024 northern hemisphere influenza season. Available at https://www.who.int/news/item/24-
02-2023-recommendations-announced-for-influenza-vaccine-composition-for-the-2023-
2024-northern-hemisphere-influenza-season. Accessed: April 10, 2023.  
 
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A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
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11. 
APPENDICES 
ANNEX 1 
REGULATORY, 
ETHICAL, 
AND 
STUDY 
OVERSIGHT 
CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the DOH 
and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines. 
o Applicable ICH GCP Guidelines. 
o Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, and other relevant documents (e.g., advertisements) 
must be submitted to an IRB/ IEC by the Investigator and reviewed and approved by the IRB/ 
IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/ IEC and regulatory authority approval, 
when applicable, before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to participants.  
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/ IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC. 
o Notifying the IRB/ IEC of SAEs or other significant safety findings as required by IRB/ 
IEC procedures. 
o Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC for clinical studies (if 
applicable), and all other applicable local regulations. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Client with sufficient, accurate financial 
information as requested to allow the GSK to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study. 
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adults aged 65 years and older 
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Insurance 
IQVIA/GSK will obtain liability insurance, which covers this study as required by local law and/or 
national regulations and/or ICH guidelines, whichever is applicable. The terms of the insurance 
will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative must fully explain the nature of the trial including 
the risks and benefits, to the participant or their care giver and answer all questions regarding 
the trial. 
• Participants must be informed that their participation is voluntary. 
• Freely given and written informed consent must be obtained from each participant, as 
appropriate, prior to participation in the trial. 
• Participant or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of local regulations, ICH guidelines, privacy, 
and data protection requirements, where applicable, and the IRB/ IEC or study center.  
• The medical records must include a statement that written informed consent was obtained 
before the participant was enrolled in the trial and the date when the consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented if a new version of the ICF(s) or an ICF addendum is released 
during their participation in the trial. 
• A copy of the ICF(s) must be provided to the participants. 
 
Administrative Structure 
Not applicable. 
Medical Monitor 
 
 
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A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
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Dissemination of Clinical Study Data 
• 
The key design elements of this protocol and results summaries will be posted on GSK 
Clinical Study register in compliance with the applicable regulations/GSK policy according 
to the timelines described below. 
• 
Protocol summaries will be registered prior to study start. 
• 
Results summaries will be posted within 12 months of analysis completion date. 
• 
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. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on eCRFs unless transmitted to the 
Client or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/ IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• GSK is responsible for the data management of this study including quality checking of the 
data. 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized study center personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• Details of study monitoring, including action required due to SARS-CoV-2 (COVID-19), will 
be included in a separate Study Monitoring Plan. 
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• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion 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 Client. No records may be transferred to 
another location or party without written notification to the Client. 
Source Documents 
The Investigator should maintain a record of the location(s) of their respective essential documents 
including source documents. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search, and retrieval. 
Essential documents for the study may be added or reduced where justified (in advance of study 
initiation) based on the importance and relevance to the study. When a copy is used to replace an 
original document (e.g., source documents, CRF), the copy should fulfill the requirements for 
certified copies. 
All participant data relating to the study will be recorded on electronic CRF unless transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the electronic case 
report form (eCRF). 
The Investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants that support the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source documents or certified copies. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the source data. 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are attributable, legible, contemporaneous, original, accurate, 
and complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (e.g., via an audit trail). Safety and rights of participants must 
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be protected, and study be conducted in accordance with the currently approved protocol and any 
other study agreements, and all applicable regulatory requirements. 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined parameters will be 
monitored during the study and important deviations from the QTLs and remedial actions taken 
will be summarized in the study report. 
GSK will inform the Investigator/institution of the time period for retaining these records to 
comply with all applicable regulatory requirements. However, the Investigator/ institution should 
seek the written approval of GSK before proceeding with the disposal of these records. The 
minimum retention time will meet the strictest standard applicable to a particular site, as dictated 
by ICH GCP or other applicable guidelines, any institutional requirements, applicable laws or 
regulations, or GSK standards/procedures. Otherwise, the retention period will default to 15 years 
from the date of completion of study report/equivalent summary. 
Study and Study Center Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of GSK, provided there is sufficient notice given to account for 
participant’s safe exit from study. Study sites regular closure 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 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are not 
limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures 
• 
Inadequate recruitment of participants by the Investigator 
• 
Total number of participants included earlier than expected 
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Phase IV Clinical Trial Protocol 
GlaxoSmithKline 
A phase IV trial of Fluarix Tetra in Indian 
adults aged 65 years and older 
Version 2.0, dated: 05 May 2023 
Protocol/ Study No.: 218702 
Page 74 of 74     
 
 
Template No.:  RWI_TP_EPI0022 Revision 2 
Reference:  RWI_WI_EPI0005 
Effective Date:  01Feb2022 
 
                                                ©2022 GSK group of companies or its licensor.                                                        
Publication Policy 
The data generated by this study are confidential information of the GSK. The GSK will make the 
results of the study publicly available. The publication policy with respect to the Investigator and 
study center will be set forth in the Clinical Trial Agreement. 
The following information is required by ICH to be in the protocol if not addressed in another 
document. If not addressed in the Clinical Trial Agreement, use the following example text, and 
modify as needed: 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to GSK before submission. This 
allows the GSK to protect proprietary information and to provide comments.  
• The GSK will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, GSK will generally support publication of 
multi-center studies only in their entirety and not as individual study center data. In this case, 
a Coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors’ authorship requirements. 
Anonymized Page 74

Protocol Amendment (Study Level) - V2.0 - Approval - 05-May-2023
Electronic Signature Manifestation 
This page is a manifestation of the electronic signature(s) used in compliance with the organization's 
electronic signature policies and procedures.
Page 75 - Object 1000551A000000007D826879
Signer Full 
Name
Meaning of Signature
Date and Time
Document Approval (I certify that I have the
education, training and experience to perform this
task)
05 May 2023
16:36:19 UTC
Document Approval (I certify that I have the
education, training and experience to perform this
task)
05 May 2023
16:38:00 UTC
Anonymized Page 75
PPD
PPD