Immunogenicity and Safety of a High-Dose Quadrivalent Influenza Vaccine Administered by the Intramuscular Route in Subjects 60 Years of Age and Older
Phase: PHASE3
Conditions: Influenza Immunization, Healthy Volunteers
Sponsor: Sanofi Pasteur, a Sanofi Company

Sanofi Pasteur 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 1 of 81 
Immunogenicity and Safety of a High-Dose Quadrivalent 
Influenza Vaccine Administered by the Intramuscular Route in 
Subjects 60 Years of Age and Older 
Phase III, randomized, modified double-blind, active-controlled, multi-center study evaluating the 
immunogenicity and safety of high-dose quadrivalent influenza vaccine (QIV-HD) in healthy 
subjects 60 years of age and older in Europe 
Clinical Study Protocol 
Health Authority File Number(s): 
EudraCT #: 
2019-000655-14 
WHO Universal Trial Number 
(UTN): 
U1111-1225-0952 
Study Code: 
QHD00011 
Development Phase: 
Phase III 
Sponsor: 
Sanofi Pasteur 
14 Espace Henry Vallée, 69007 Lyon, France 
Investigational Product: 
High-Dose Influenza Vaccine (split virion, inactivated), Quadrivalent 
(QIV-HD)  
Form / Route: 
Liquid / Intramuscular 
Indication For This Study: 
Single dose for individuals 60 years of age and older 
Manufacturer: 
Same as Sponsor 
Investigators: 
This is a multi-center study with multiple investigators. Investigators and 
study sites are listed in the “List of Investigators and Centers Involved in 
the Trial” document. 
Sponsor’s Responsible Medical 
Officer: 
Clinical Team Leader: 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 1 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 1 of 82
NCT04024228

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 2 of 81 
Global Safety Officer: 
Regional Trial Manager: 
Version and Date of the Protocol: 
Version 2.0 dated 23 August 2019 
 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 2 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 2 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 3 of 81 
History of Protocol Versions 
 
Version 
Date 
Comments 
1.0 
02 April 2019 
IEC/IRB-approved version not used in the study 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 3 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 3 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 4 of 81 
Table of Contents 
History of Protocol Versions........................................................................................................... 3 
List of Tables .................................................................................................................................... 9 
Synopsis .......................................................................................................................................... 10 
Table of Study Procedures ............................................................................................................ 18 
List of Abbreviations ..................................................................................................................... 20 
1 
Introduction ..................................................................................................................... 23 
1.1 
Background ..................................................................................................................... 23 
1.2 
Background of the Investigational Product ..................................................................... 24 
1.3 
Potential Benefits and Risks ........................................................................................... 25 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 25 
1.3.2 
Potential Risks to Subjects ........................................................................................... 25 
1.3.2.1 
Potential Risks and Possible Side Effects of QIV-HD Vaccination .......................... 25 
1.3.2.2 
Potential Risks and Possible Side Effects of QIV-SD Vaccination ........................... 26 
1.3.2.3 
Possible Reactions to Blood Draw ............................................................................. 27 
1.4 
Rationale for the Study ................................................................................................... 27 
2 
Study Objectives .............................................................................................................. 28 
2.1 
Primary Objective ........................................................................................................... 28 
2.2 
Secondary Objectives ...................................................................................................... 28 
2.3 
Observational Objectives ................................................................................................ 28 
3 
Investigators and Study Organization ........................................................................... 29 
4 
Independent Ethics Committee / Institutional Review Board .................................... 29 
5 
Investigational Plan ......................................................................................................... 30 
5.1 
Description of the Overall Study Design and Plan ......................................................... 30 
5.1.1 
Study Design ................................................................................................................ 30 
5.1.2 
Justification of the Study Design .................................................................................. 30 
5.1.3 
Study Plan ..................................................................................................................... 31 
5.1.4 
Visit Procedures ............................................................................................................ 32 
5.1.5 
Planned Study Calendar ............................................................................................... 34 
5.2 
Enrollment and Retention of Study Population .............................................................. 35 
5.2.1 
Recruitment Procedures ................................................................................................ 35 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 4 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 4 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 5 of 81 
5.2.2 
Informed Consent Procedures ...................................................................................... 35 
5.2.3 
Screening Criteria ......................................................................................................... 35 
5.2.4 
Inclusion Criteria .......................................................................................................... 36 
5.2.5 
Exclusion Criteria ......................................................................................................... 36 
5.2.6 
Medical History ............................................................................................................ 37 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 38 
5.2.8 
Conditions for Withdrawal ........................................................................................... 38 
5.2.9 
Lost to Follow-up Procedures....................................................................................... 38 
5.2.10 
Classification of Subjects Who Discontinue the Study ................................................ 38 
5.2.11 
Follow-up of Discontinuations ..................................................................................... 39 
5.2.12 
Follow-up and Reporting of Pregnancies ..................................................................... 39 
5.3 
Safety Emergency Call ................................................................................................... 40 
5.4 
Modification of the Study and Protocol .......................................................................... 40 
5.5 
Interruption of the Study ................................................................................................. 41 
6 
Products Administered ................................................................................................... 41 
6.1 
Identity of the Investigational Product ............................................................................ 41 
6.1.1 
Identity of Study Product (QIV-HD) ............................................................................ 41 
6.1.1.1 
Composition ............................................................................................................... 41 
6.1.1.2 
Preparation and Administration ................................................................................. 42 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 42 
6.1.2 
Identity of Control Product (Licensed QIV-SD) .......................................................... 42 
6.1.2.1 
Composition ............................................................................................................... 43 
6.1.2.2 
Preparation and Administration ................................................................................. 43 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 43 
6.2 
Identity of Other Product ................................................................................................ 43 
6.3 
Product Logistics ............................................................................................................ 43 
6.3.1 
Labeling and Packaging ............................................................................................... 43 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 44 
6.3.2.1 
Product Shipment ....................................................................................................... 44 
6.3.2.2 
Product Storage .......................................................................................................... 44 
6.3.2.3 
Product Accountability ............................................................................................... 44 
6.3.3 
Replacement Doses....................................................................................................... 45 
6.3.4 
Disposal of Unused Products ........................................................................................ 45 
6.3.5 
Recall of Products ......................................................................................................... 45 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 45 
6.5 
Randomization and Allocation Procedures ..................................................................... 46 
6.6 
Treatment Compliance .................................................................................................... 47 
6.7 
Concomitant Medications and Other Therapies ............................................................. 48 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 5 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 5 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 6 of 81 
7 
Management of Samples ................................................................................................. 49 
7.1 
Sample Collection ........................................................................................................... 49 
7.2 
Sample Preparation ......................................................................................................... 49 
7.3 
Sample Storage and Shipment ........................................................................................ 49 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 50 
8 
Clinical Supplies .............................................................................................................. 50 
9 
Endpoints and Assessment Methods ............................................................................. 51 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 51 
9.1.1 
Safety ............................................................................................................................ 51 
9.1.2 
Immunogenicity ............................................................................................................ 51 
9.1.2.1 
Immunogenicity Endpoints ........................................................................................ 51 
9.1.2.2 
Immunogenicity Assessment Methods ...................................................................... 51 
9.1.2.2.1 
Hemagglutination Inhibition .................................................................................... 51 
9.1.3 
Efficacy ......................................................................................................................... 52 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 52 
9.2.1 
Safety ............................................................................................................................ 52 
9.2.1.1 
Safety Definitions ....................................................................................................... 52 
9.2.1.2 
Safety Endpoints ........................................................................................................ 54 
9.2.1.3 
Safety Assessment Methods ....................................................................................... 55 
9.2.1.3.1 
Immediate Post-vaccination Observation Period ..................................................... 55 
9.2.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Vaccination) ...... 55 
9.2.1.3.3 
Unsolicited Adverse Events ..................................................................................... 61 
9.2.1.3.4 
Medically-Attended Adverse Events ....................................................................... 62 
9.2.1.3.5 
Adverse Events of Special Interest .......................................................................... 62 
9.2.1.3.6 
Assessment of Causality .......................................................................................... 62 
9.2.2 
Immunogenicity ............................................................................................................ 63 
9.2.2.1 
Immunogenicity Endpoints ........................................................................................ 63 
9.2.2.2 
Immunogenicity Assessment Methods ...................................................................... 63 
9.2.3 
Efficacy ......................................................................................................................... 63 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 63 
9.3.1 
Safety ............................................................................................................................ 63 
9.3.2 
Immunogenicity ............................................................................................................ 64 
9.3.2.1 
Immunogenicity Endpoints ........................................................................................ 64 
9.3.2.1.1 
Immunogenicity Assessment by Seroneutralization ................................................ 64 
9.3.2.1.2 
Immunogenicity Assessment by ELLA ................................................................... 64 
9.3.2.2 
Immunogenicity Assessment Methods ...................................................................... 64 
9.3.2.2.1 
Seroneutralization .................................................................................................... 64 
9.3.2.2.2 
Enzyme-Linked Lectin Assay for the Measurement of Anti-Neuraminidase ......... 65 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 6 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 6 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 7 of 81 
9.3.3 
Efficacy ......................................................................................................................... 65 
10 
Reporting of Serious Adverse Events ............................................................................ 66 
10.1 
Initial Reporting by the Investigator ............................................................................... 66 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 67 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 67 
10.4 
Assessment of Causality ................................................................................................. 67 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 67 
11 
Data Collection and Management ................................................................................. 68 
11.1 
Data Collection and CRB Completion ............................................................................ 68 
11.2 
Data Management ........................................................................................................... 69 
11.3 
Data Review .................................................................................................................... 69 
12 
Statistical Methods and Determination of Sample Size ............................................... 70 
12.1 
Statistical Methods .......................................................................................................... 70 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective ......................................... 70 
12.1.1.1 
Immunogenicity ......................................................................................................... 70 
12.1.1.1.1 
Hypotheses ............................................................................................................... 70 
12.1.1.1.2 
Statistical Methods ................................................................................................... 71 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 71 
12.1.2.1 
Immunogenicity ......................................................................................................... 71 
12.1.2.1.1 
Hypotheses ............................................................................................................... 71 
12.1.2.1.2 
Statistical Methods ................................................................................................... 71 
12.1.2.2 
Safety .......................................................................................................................... 71 
12.1.2.2.1 
Hypotheses ............................................................................................................... 71 
12.1.2.2.2 
Statistical Methods ................................................................................................... 71 
12.1.3 
Statistical Methods for Observational Objectives ........................................................ 71 
12.2 
Analysis Sets ................................................................................................................... 71 
12.2.1 
Full Analysis Set ........................................................................................................... 72 
12.2.2 
Safety Analysis Set ....................................................................................................... 72 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 72 
12.2.4 
Populations Used in Analyses ...................................................................................... 73 
12.3 
Handling of Missing Data and Outliers .......................................................................... 73 
12.3.1 
Safety ............................................................................................................................ 73 
12.3.2 
Immunogenicity ............................................................................................................ 73 
12.3.3 
Efficacy ......................................................................................................................... 73 
12.4 
Interim / Preliminary Analysis ........................................................................................ 73 
12.5 
Determination of Sample Size and Power Calculation ................................................... 74 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 7 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 7 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 8 of 81 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 74 
13.1 
Ethical Conduct of the Study / Good Clinical Practice ................................................... 74 
13.2 
Source Data and Source Documents ............................................................................... 75 
13.3 
Confidentiality of Data, Data Protection, and Access to Subject Records ..................... 75 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 76 
13.4.1 
Monitoring .................................................................................................................... 76 
13.4.2 
Audits and Inspections ................................................................................................. 77 
13.4.3 
Archiving ...................................................................................................................... 77 
13.5 
Financial Contract and Insurance Coverage ................................................................... 77 
13.6 
Stipends for Participation ................................................................................................ 78 
13.7 
Publication Policy ........................................................................................................... 78 
14 
Reference List .................................................................................................................. 79 
15 
Signature Page ................................................................................................................. 81 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 8 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 8 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 9 of 81 
List of Tables 
Table 6.1: Randomization of subjects by vaccine group (QIV-HD; QIV-SD) ...............................46 
Table 6.2: Randomization to the Observational Subsets .................................................................47 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales ...........57 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales .................59 
Table 12.1: Random assignment of subjects to observational subsets ............................................74 
 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 9 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 9 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 10 of 81 
Synopsis 
Company: 
Sanofi Pasteur 
Investigational Product: 
High-Dose Influenza Vaccine (split virion, inactivated), Quadrivalent 
(QIV-HD) 2019-2020 Northern Hemisphere formulation 
Active Substances: 
A/(H1N1)-like strain, A/(H3N2)-like strain, B (Victoria Lineage)-like strain, 
B (Yamagata Lineage)-like strain 
Title of the Study: 
Immunogenicity and Safety of a High-Dose Quadrivalent Influenza Vaccine 
Administered by the Intramuscular Route in Subjects 60 Years of Age and 
Older 
Development Phase: 
Phase III 
Coordinating Investigator: 
To be determined (TBD) 
Study Sites: 
This will be a multi-center study conducted at approximately 15 to 20 study 
sites in Europe.  
Investigators and sites are listed in the “List of Investigators and Centers 
Involved in the Trial” document. 
Planned Study Period: 
Quarter (Q)3 2019 to Q2 2020 
Study Design, Schedule of Study 
Procedures, and Methodology: 
QHD00011 will be a Phase III, randomized, modified double-blind, active-
controlled, multi-center study to be conducted in approximately 1540 healthy 
adults (770 adults 60 to 64 years of age and 770 adults 65 years of age and 
older) to evaluate the immunogenicity and safety of the high-dose quadrivalent 
influenza vaccine (QIV-HD) administered by intramuscular (IM) route in 
subjects in Europe. A standard-dose quadrivalent influenza vaccine (QIV-SD) 
will serve as a control arm. 
Vaccination 
In each age group, eligible subjects will be randomized in a 1:1 ratio to 
receive a single IM injection of either QIV-HD or QIV-SD at Day (D)0. 
Because the volumes for injection differ between the 2 vaccines (QIV-HD 
[0.7 milliliter (mL)] and QIV-SD [0.5 mL]), an unblinded administrator at 
each site will be in charge of administering the vaccines. This person will not 
be involved in any safety or immunogenicity assessments. Due to the 
different volumes for injection, the syringes will be masked to keep the blind 
of the subjects and other members of the clinical site. Additional details will 
be provided in the Operating Guidelines for the study. 
Blood sampling 
All subjects will provide a pre-vaccination (baseline) blood sample at 
Visit (V)01 (D0) and a post-vaccination blood sample at V02 (D28 [+7 days]) 
for immunogenicity assessment. If the D0 blood sample cannot be obtained, the 
subject should be given the opportunity to return to the study site for another 
attempt, as long as the study is still enrolling subjects and as long as the subject 
continues to remain eligible for the trial and that includes reviewing 
Inclusion/Exclusion criteria, medical history, and informed consent form (ICF) 
process. All attempts should be made to obtain a blood sample; however, if the 
attempts are unsuccessful, the subject should not be vaccinated and should be 
discontinued from the study. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 10 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 10 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 11 of 81 
Study Design, Schedule of Study 
Procedures, and Methodology: 
(continued) 
Collection of safety data 
• 
All subjects will be observed for 30 minutes after vaccination. Any 
unsolicited systemic adverse events (AEs) occurring during that time will 
be recorded as immediate unsolicited systemic AEs in the Case Report 
Book (CRB). 
 
• 
Solicited reactions will be collected up to 7 days after vaccination (D0 to 
D7), and unsolicited AEs will be collected up to 28 days after 
vaccination (D0 to D28 [V02]). Subjects will record this information in a 
diary card (DC).  
• 
Serious adverse events (SAEs) and adverse events of special interest 
(AESIs) will be collected throughout the study (D0 through 
approximately D180 [6 month follow-up period]). Subjects will be asked 
to notify the site immediately about any potential SAEs (including 
AESIs) at any time during the study. 
• 
Staff will review the V01 (D0) to V02 (D28) safety data with subjects at 
V02. 
• 
Subjects will continue to collect information on SAEs and AESIs in a 
memory aid (D28 [V02]-D180). It is to be noted that AESIs will be 
captured as SAEs. These AESIs include new onset of Guillain-Barré 
syndrome (GBS), encephalitis / myelitis (including transverse myelitis), 
Bell’s palsy, optic neuritis, and brachial neuritis. 
• 
Staff will contact subjects by telephone at D180 post-vaccination to 
review the memory aid and to identify the occurrence of any SAEs and 
AESIs that had not yet been reported.  
• 
Interactive response technology (IRT) will be used to randomly assign 
subjects, in each age group, to one of the 2 vaccine groups and to assign 
subject numbers in each of the groups. 
• 
Electronic data capture will be used for the collection of data. 
Interruption of the Study 
The study may be discontinued if new data about the investigational product 
resulting from this study or any other studies become available; or for 
administrative reasons; or on advice of the Sponsor, the Investigators, the 
Independent Ethics Committees (IECs)/ Institutional Review Boards (IRBs), 
or the governing regulatory authorities in the countries where the study is 
taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall 
promptly inform the Investigators, the IECs/IRBs, the regulatory authorities, 
and any contract research organization(s) used in the study of the reason for 
termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the study subjects and 
should assure appropriate subject therapy and/or follow-up. 
Primary Objective: 
Immunogenicity 
To demonstrate that QIV-HD induces an immune response that is superior to 
the responses induced by QIV-SD for all 4 virus strains 28 days post-
vaccination in subjects 60 to 64 years of age and in subjects 65 years of age 
and older. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 11 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 11 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 12 of 81 
Primary Endpoints: 
Immunogenicity  
For subjects in each age group (60 to 64 years of age; 65 years of age and 
older) and for subjects in each vaccine group (QIV-HD; QIV-SD): 
• 
hemagglutination inhibition (HAI) antibody (Ab) titers obtained on D28 
Secondary Objectives: 
Immunogenicity 
To further describe the immune response induced by QIV-HD and QIV-SD 
in all subjects by age group, in pooled age groups, and by vaccine group 
(QIV-HD; QIV-SD) 
Safety 
To describe the safety profile of all subjects by age group, in pooled age 
groups, and by vaccine group (QIV-HD; QIV-SD) 
Secondary Endpoints: 
Immunogenicity 
For subjects in each age group (60 to 64 years of age; 65 years of age and 
older) and for subjects in each vaccine group (QIV-HD; QIV-SD): 
• 
HAI Ab titers obtained on D0 and D28 
• 
Individual HAI titers ratio D28/D0 
• 
Subjects with titers ≥ 40 [1/dilution (dil)] at D28 
• 
Seroconversion (titer < 10 [1/dil] at D0 and post-vaccination titer ≥ 40 
[1/dil] at D28, or titer ≥ 10 [1/dil] at D0 and a ≥ 4-fold increase in titer 
[1/dil] at D28) 
 
Safety 
Safety will be described for all subjects: 
• 
Occurrence, nature (Medical Dictionary for Regulatory Activities 
[MedDRA] preferred term [PT]), intensity, and relationship to 
vaccination of any unsolicited systemic AEs reported in the 30 minutes 
after vaccination. 
• 
Occurrence, time to onset, number of days of occurrence, intensity, and 
action taken of solicited (prelisted in the subject’s DC and CRB) 
injection site reactions and systemic reactions occurring up to 7 days 
after vaccination. 
• 
Occurrence, nature (MedDRA PT), time to onset, duration, intensity, 
and relationship to vaccination (for systemic AEs only) of unsolicited 
AEs up to 28 days after vaccination. 
• 
Occurrence, nature (MedDRA PT), time to onset, seriousness criteria, 
relationship to vaccination, and outcome of SAEs (including AESIs) 
throughout the study. 
Observational Objectives: 
1) 
To describe the immune response 28 days after vaccination by virus 
seroneutralization (SN) measurement method for at least 50% of 
subjects in each age group (60 to 64 years of age; 65 years of age and 
older), and in pooled age group by vaccine group (QIV-HD; QIV-SD) 
2) 
To describe the anti-neuraminidase (NA) immune response in at least 
50 subjects in each age group and in pooled age group by vaccine 
group (QIV-HD; QIV-SD) 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 12 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 12 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 13 of 81 
Observational Endpoints: 
Immunogenicity Assessment by SN for subjects in each age group (60 to 
64 years of age; 65 years of age and older) and for subjects in each 
vaccine group (QIV-HD; QIV-SD). 
Neutralizing Ab titers will be measured for each influenza strain with the SN 
method. The analyses will be performed on blood samples obtained on D0 
and D28.  
• 
Individual neutralization test (NT) Ab titer on D0 and D28  
• 
Individual NT Ab titer ratio (fold-rise in serum NT post-vaccination 
relative to D0) at D28  
• 
Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28  
• 
Fold-rise in NT Ab titer [post/pre] ≥ 2 and ≥ 4 at D28  
• 
Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0 and D28 
 
 
Immunogenicity Assessment by enzyme-linked lectin assay (ELLA) for 
subjects in each age group (60 to 64 years of age; 65 years of age and 
older) and for subjects in each vaccine group (QIV-HD; QIV-SD). 
Anti-N1and -N2 titers will be measured for the 2 influenza A strains using 
ELLA. The analyses will be performed on blood samples obtained on D0 
and D28. 
• 
Individual ELLA Ab titer on D0 and D28  
• 
Individual ELLA Ab titer ratio (fold-rise in serum ELLA post-
vaccination relative to D0) at D28  
• 
Subjects with ELLA Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at 
D28  
• 
Fold-rise in ELLA Ab titer [post/pre] ≥ 2 and ≥ 4 at D28  
• 
Detectable ELLA (ELLA Ab titer ≥ 10 [1/dil]) at D0 and D28 
Planned Sample Size: 
A total of 1540 subjects are planned to be enrolled as follows: 
Vaccine 
Number of 
subjects 60 to 64 
years of age 
Number of subjects 
65 years of age and 
older 
Total 
QIV-HD 
Group 
385 
385 
770 
QIV-SD 
Group 
385 
385 
770 
Total 
770 
770 
1540 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 13 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 13 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 14 of 81 
Planned Sample Size: 
(continued) 
For the assessment of the immune response by virus SN and ELLA methods, 
randomization to the observational subsets (Full Analysis 
Set-Seroneutralization [FAS-SN] subset and Full Analysis 
Set-Neuraminidase [FAS-NA] subset) will be performed with stratification 
on vaccine group, age groups (60 through 64 years of age or ≥65 years of 
age), and site. The FAS-NA subset is a subset of the FAS-SN subset. 
A subset of the 1540 enrolled subjects will be randomly assigned to the 
observational subset to be assessed for neutralizing Ab titers (at least 50% of 
subjects in each age group and each vaccine group) and for Anti-N1and -N2 
titers (at least 50 subjects in each age group and each vaccine group) at D0 
and D28 as shown in the following table. 
 
Vaccine/Assay 
Number of 
subjects 60 to 64 
years of age 
Number of subjects 
65 years of age and 
older 
Total 
QIV-HD 
Group/SN 
≥193 
≥193 
≥386 
QIV-SD 
Group/SN 
≥193 
≥193 
≥386 
QIV-HD 
Group/NA 
≥50 
≥50 
≥100 
QIV-SD 
Group/NA 
≥50 
≥50 
≥100 
Duration of Participation in the 
Study: 
The duration of each subject’s participation will be approximately 6 months 
including the safety follow-up (D0 through D180). 
Investigational Product: 
High-Dose Influenza Vaccine (split virion, inactivated), Quadrivalent 
(QIV-HD) 2019-2020 Northern Hemisphere formulation 
 Form: 
Suspension for injection 
 Presentation: 
Pre-filled syringe 
Composition: 
Each 0.7 mL dose of QIV-HD will contain: 
Strains to be determined based on World Health Organization (WHO) 
recommendations for the 2019-2020 Northern Hemisphere (NH) influenza 
season, as determined by the WHO and European Union (EU) for the 
2019/2020 season. 
Composition: (continued) 
Active Substances: 
• 
A/(H1N1)-like strain  
 
60 microgram (μg) 
 
 
 
 
 
hemagglutinin (HA) 
• 
A/(H3N2)-like strain  
 
60 μg HA 
• 
B/(Victoria Lineage)-like strain 
60 μg HA 
• 
B/(Yamagata Lineage)-like strain 
60 μg HA 
Excipients: 
• 
Octylphenol Ethoxylate  
  
not more than 
(Octoxinol-9/Triton X-100®)  
 
350 μg 
Diluent: 
• 
Buffered saline solution 
 
quantity sufficient (qs) to 
 
 
 
 
 
 
appropriate volume 
 Route: 
IM, injected into the upper arm (deltoid area) 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 14 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 14 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 15 of 81 
 Batch Number: 
TBD 
Control Product: 
Standard-Dose influenza virus surface antigens (haemagglutinin and 
neuraminidase), Inactivated, Influenza Vaccine Quadrivalent, 2019-2020 
Northern Hemisphere Strains (Influvac™ Tetra [QIV-SD]) 
 Form: 
Suspension for injection 
 Presentation: 
Pre-filled syringe 
 Composition: 
Each 0.5 mL dose of QIV-SD will contain: 
Strains to be determined based on WHO recommendations for the 
2019-2020 Northern Hemisphere (NH) influenza season, as determined by 
the WHO and EU for the 2019/2020 season. 
 
Active Substances: 
• 
A/(H1N1)-like strain  
 
15 μg HA 
• 
A/(H3N2)-like strain  
 
15 μg HA 
• 
B/(Victoria Lineage)-like strain 
15 μg HA 
• 
B/(Yamagata Lineage)-like strain 
15 μg HA 
Excipients: 
Potassium chloride, potassium dihydrogen phosphate, disodium phosphate 
dihydrate, sodium chloride, calcium chloride dihydrate, magnesium chloride 
hexahydrate, and water for injection. 
 Route: 
IM, injected into the upper arm (deltoid area) 
 Batch Number: 
TBD 
Inclusion Criteria: 
An individual must fulfill all of the following criteria to be eligible for trial 
enrollment: 
1) Sixty years of age and older on the day of inclusion 
2) Informed consent form has been signed and dated 
3) Able to attend all scheduled visits and to comply with all trial 
procedures 
4) Covered by health insurance if applicable in the country 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from 
trial enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential and not 
using an effective method of contraception or abstinence from at least 4 
weeks prior to vaccination until at least 4 weeks after vaccination. To be 
considered of non-childbearing potential, a female must be post-
menopausal for at least 1 year, or surgically sterile. 
2) Participation at the time of trial enrollment (or in the 4 weeks [28 days] 
preceding the trial vaccination) or planned participation during the 
present trial period in another clinical trial investigating a vaccine, drug, 
medical device, or medical procedure  
3) Receipt of any vaccine in the 4 weeks (28 days) preceding the trial 
vaccination or planned receipt of any vaccine prior to V02 
4) Previous vaccination against influenza (in the previous 6 months) with 
either the trial vaccine or another vaccine 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 15 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 15 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 16 of 81 
Exclusion Criteria: (continued) 
5) Receipt of immune globulins, blood or blood-derived products in the 
past 3 months 
6) Known or suspected congenital or acquired immunodeficiency; or 
receipt of immunosuppressive therapy, such as anti-cancer 
chemotherapy or radiation therapy, within the preceding 6 months; or 
long-term systemic corticosteroid therapy (prednisone or equivalent for 
more than 2 consecutive weeks within the past 3 months) 
7) Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to the vaccines used in the trial or 
to a vaccine containing any of the same substances.  
 
8) Thrombocytopenia or bleeding disorder, contraindicating IM 
vaccination based on Investigator’s judgment 
9) Deprived of freedom by an administrative or court order, or in an 
emergency setting, or hospitalized involuntarily 
10) Alcohol or substance abuse that, in the opinion of the Investigator might 
interfere with the trial conduct or completion 
11) Chronic illness that, in the opinion of the Investigator, is at a stage 
where it might interfere with trial conduct or completion. It is to be 
noted that chronic illness may include, but is not limited to, cardiac 
disorders, renal disorders, autoimmune disorders, diabetes, psychiatric 
disorders, or chronic infection. 
12) Moderate or severe acute illness/infection (according to Investigator 
judgment) or febrile illness (temperature ≥ 38.0°C) on the day of 
vaccination. A prospective subject should not be included in the trial 
until the condition has resolved or the febrile event has subsided. 
13) Identified as an Investigator or employee of the Investigator or trial 
center with direct involvement in the proposed trial, or identified as an 
immediate family member (ie, parent, spouse, natural or adopted child) 
of the Investigator or employee with direct involvement in the proposed 
trial. 
14) Personal or family history of Guillain-Barré syndrome (GBS). 
15) Neoplastic disease or any hematologic malignancy (except localized 
skin or prostate cancer that is stable at the time of vaccination in the 
absence of therapy and subjects who have a history of neoplastic disease 
and have been disease-free for ≥ 5 years). 
Statistical Methods: 
The per-protocol analysis set (PPAS) and full analysis set (FAS) will be 
used for the main immunogenicity analyses. Conclusions will be made based 
on the FAS results. The safety analysis set (SafAS) will be used for all 
safety analyses. 
The statistical analysis will be performed in at least 2 steps: 
• 
First analysis on immunogenicity and safety results obtained on data 
collected within the 28 days following the vaccination (from D0 to 
D28).  The study blind will be broken at that time. 
• 
Second analysis after the 6-month data have been collected.   
 
Primary Objective 
A superiority approach will be used to compare post-vaccination geometric 
mean titers (GMTs) between QIV-HD and QIV-SD groups for each strain 
and in each age group using a 1-sided test with Type I error rate of 0.025 
following the individual hypotheses: 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 16 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 16 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 17 of 81 
Statistical Methods: (continued) 
 
 
where  
s: strain 
 
If superiority is demonstrated for post-vaccination GMTs for the 4 strains 
within a same age group, then the immunogenicity of QIV-HD will be 
considered as superior to QIV-SD in the corresponding age group. 
The statistical methodology will be based on the use of the lower bound of 
the 2 sided 95% confidence intervals (CIs) of the ratio of post-vaccination 
GMTs between the QIV-HD and QIV-SD groups. The CIs will be calculated 
by normal approximation of log-transformed titers for GMTs. 
 
Secondary Objective - Immunogenicity  
Immunogenicity endpoints will be summarized per vaccine group (by age 
group and in pooled age groups) with 95% CIs. CIs of geometric mean 
(GM) of titers and individual titer ratios will be calculated assuming normal 
approximation of log-transformed values. CIs of proportions will be 
calculated using Clopper-Pearson method. Reverse cumulative distribution 
curves against each strain will be performed for each time point additional 
parameters may be displayed as appropriate. 
Secondary Objective - Safety  
Safety endpoints will be summarized per vaccine group (by age group and in 
pooled age groups), with 95% CI for the main endpoints. CIs will be 
calculated using Clopper-Pearson method. 
Calculation of Sample Size:  
A total of approximately 1540 adults 60 years of age and older (770 adults 
60 to 64 years of age and 770 adults 65 years of age and older) will be 
enrolled. This sample size is determined per simulations based on an overall 
power of 90% for demonstrating the primary objective. The thresholds for 
superiority are defined as 1 for GMTs. No alpha adjustment is needed. Other 
assumptions are listed as follows: 
• 
Allocation ratio: 1:1 (QIV-HD versus QIV-SD) 
• 
GMT ratio: 1.5 for all strains 
• 
Standard deviations of log10-transformed titers in QIV-SD group of 
0.6 for 2 strains and 0.5 for the other 2 strains 
• 
Attrition rate: 5% in FAS 
It should be noted that the power per strain is 97.7% when the standard 
deviation is 0.6 and 99.7% when the standard deviation is 0.5. 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 17 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 17 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 18 of 81 
Table of Study Procedures 
Phase III Study, 2 Visits, 1 Telephone Call, 1 Vaccination, 2 Blood Samples, Approximately 
180 Days Duration Per Subject 
Visit (V)/Contact 
V01 
V02 
D180 Safety 
Follow-up 
Call 
Study timelines (day [D]) 
D0 
D28 
D180 
Time windows (days) 
Not 
applicable 
[+7 days] 
[+14 days] 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Collection of demographic data* 
X 
 
 
Urine pregnancy test (if applicable) 
X 
 
 
Medical history 
X 
 
 
History of seasonal influenza vaccination/influenza infection 
(diagnosis laboratory confirmed) in the previous 3 years 
X 
 
 
Collection of reportable concomitant medications 
X 
X 
 
Physical examination† 
X 
X 
 
Contacting interactive response technology (IRT) 
X 
 
 
Randomization/allocation of subject number and unique 
treatment number using IRT 
X 
 
 
Blood sampling (BL), 10 mL‡ 
BL0001§ 
BL0002 
 
Vaccination 
X 
 
 
Immediate surveillance (30 minutes) 
X 
 
 
Diary card (DC) provided** 
X 
 
 
Collection of solicited injection site and systemic reactions 
D0-D7 
 
 
Collection of unsolicited adverse events (AEs) 
D0-V02 
 
DC reviewed and collected 
 
X†† 
 
Memory aid provided‡‡ 
 
X 
 
Study termination record for the active phase of the trial 
 
X 
 
Follow-up telephone call 
 
 
X§§ 
Memory aid reviewed 
 
 
X 
Study termination for the 6-month safety follow-up 
 
 
X 
Collection of serious adverse events (SAEs) and adverse 
events of special interest (AESIs)*** 
To be reported at any time during the study 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 18 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 18 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 19 of 81 
 
*  
To comply with US FDA expectations, Sponsors are to enroll participants who reflect the demographics 
for clinically relevant populations with regard to age, gender, race, and ethnicity as described in 
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126396.pdf. Please note that 
ethnicity will not be collected during this study. 
†  
Targeted physical examination based on medical history will be performed at V01. Targeted physical 
examination may also be performed at V02, as necessary. 
‡  
If the D0 blood sample cannot be obtained, the subject should be given the opportunity to return to the 
study site for another attempt, as long as the study is still enrolling subjects and as long as the subject 
continues to remain eligible for the trial and that includes reviewing Inclusion/Exclusion criteria, medical 
history, and ICF process. All attempts should be made to obtain a blood sample; however, if the attempts 
are unsuccessful, the subject should not be vaccinated and should be discontinued from the study. 
§  
Collection of the first blood sample (BL0001) is to occur before vaccination. 
**  
Subjects will use this diary card to record information about solicited reactions from D0 to D7, as well as 
unsolicited AEs, SAEs, and AESIs from D0 to V02 after vaccination. 
††  
Staff will collect the diary card at V02, and review any solicited reactions ongoing at V02, unsolicited AEs, 
concomitant medications, SAEs, and AESIs. 
‡‡  
Subjects will use this memory aid to collect information on SAEs and AESIs from V02 to the D180 Safety 
Follow-up Call. 
§§  
During the D180 telephone call, staff will review the memory aid to identify the occurrence of any SAEs 
and AESIs that had not yet been reported. 
***  
AESIs will have the same detailed information collected as SAEs. These include new onset of Guillain-
Barré Syndrome (GBS), encephalitis/myelitis (including transverse myelitis), Bell’s Palsy, optic neuritis, 
and brachial neuritis. 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; BL, blood sampling; D, day; DC, diary card; 
FDA, Food and Drug Administration; GBS, Guillain-Barré Syndrome; ICF, informed consent form; SAE, serious adverse 
event; US, United States; V, visit. 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 19 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 19 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 20 of 81 
List of Abbreviations 
μg 
microgram(s) 
Ab 
antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AR 
adverse reaction 
BL 
blood sampling 
CI 
confidence interval 
CDM 
Clinical Data Management 
CQA 
Clinical Quality Assessment 
CRA 
Clinical Research Associate 
CRB 
(electronic) case report book [all the case report forms for a subject] 
CRF 
(electronic) case report form 
CRO 
contract research organization 
CTL 
Clinical Team Leader 
D 
day 
DC 
diary card 
dil 
dilution 
DO 
Doctor of Osteopathic Medicine 
DP 
drug product 
DS 
drug substance 
ELISA 
enzyme-linked immunosorbent assay 
ELLA 
enzyme-linked lectin assay 
EDC 
electronic data capture 
EU 
European Union 
FAS 
full analysis set 
FAS-NA 
full analysis set-neuraminidase subset 
FAS-SN 
full analysis set-seroneutralization subset 
FDA 
Food and Drug Administration 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GBS 
Guillain-Barré syndrome 
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GDPR 
Global Data Protection Regulation 
GM 
geometric mean 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 20 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 20 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 21 of 81 
GMT 
geometric mean titer 
GPV 
Global Pharmacovigilance 
HA 
hemagglutinin 
HAI 
hemagglutination inhibition  
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IM 
intramuscular(ly) 
IME 
important medical event 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LCLS 
last contact, last subject 
LLOQ 
lower limit of quantification 
LLT 
lowest level term 
MD 
Doctor of Medicine 
MDCK 
Madin-Darby canine kidney 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
NA 
neuraminidase 
NH 
Northern Hemisphere 
NSAID 
non-steroidal anti-inflammatory drug 
NT 
neutralization test 
OD 
optical density 
OPD 
o-Phenylenediamine dihydrochloride 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PNA 
peanut-agglutinin 
PPAS 
per-protocol analysis set 
PT 
preferred term 
Q 
quarter 
QIV-HD 
high-dose quadrivalent influenza vaccine 
QIV-SD 
standard-dose quadrivalent influenza vaccine 
qs 
quantity sufficient 
RBC 
red blood cell 
RMO 
Responsible Medical Officer 
RNA 
ribonucleic acid 
RWE 
real world evidence 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 21 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 21 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 22 of 81 
SAE 
serious adverse event 
SafAS 
safety analysis set 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
subcutaneous(ly) 
SD 
standard dose 
SMT 
Safety Management Team 
SN 
seroneutralization 
TBD 
to be determined 
TIV 
trivalent influenza vaccine 
TIV-HD 
high-dose trivalent influenza vaccine 
TIV-SD 
standard-dose trivalent influenza vaccine 
TMF 
trial master file 
UN 
United Nations 
US 
United States 
ULOQ 
upper limit of quantification 
V 
visit 
WHO 
World Health Organization 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 22 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 22 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 23 of 81 
1 
Introduction 
1.1 
Background 
Influenza is a highly contagious, acute viral respiratory disease caused by influenza A subtype  
and type B viruses and is typically characterized by the rapid onset of fever, myalgia, sore throat, 
and nonproductive cough. Influenza can also cause severe malaise lasting for several days. 
Influenza virus types A and B belong to the genus Orthomyxoviridae and are characterized as 
enveloped, negative strand, segmented ribonucleic acid (RNA) viruses. The viral envelope 
contains 2 virus coded glycoproteins, hemagglutinin (HA) and neuraminidase (NA), which form 
spikes on the viral surface and are key antigens in the host response in both natural infection and 
vaccination (1) (2). 
Genetic and antigenic variations are an important feature of the influenza virus. The viral HA and 
NA antigens are subject to continuous, sequential evolution within immune or partially immune 
populations. Genetic and antigenic drift results from single or multiple mutations affecting the 
RNA segment coding for either NA or, more commonly, HA proteins. As a result, there is 
alteration in the receptor binding domain of HA involving one or more amino acids resulting in 
minor changes in antigenicity. Antigenic variants within the A subtype (eg, H1 or H3) that emerge 
through natural selection gradually become the predominant circulating virus strain, while the 
preceding antigenic variant is suppressed by a specific immunity in the population. In contrast to 
antigenic drift, antigenic shift occurs when completely new viral subtypes emerge typically 
through gene reassortment with other circulating strains and acquisition of antigenically different 
gene sequences. Occurring at irregular intervals, antigenic shift may lead to pandemics (3). 
Influenza A viruses (of subtypes H1N1 and H3N2) account for the majority of circulating 
influenza viruses in most countries and seasons, although influenza B is common in all regions of 
the world with approximately 20% of the reported influenza cases (4). Influenza B often co-
circulates with influenza A, although it is rarely dominant, and usually circulates later in the 
season than influenza A viruses. According to data from the European Influenza Network, from 
2001–2002 through 2010–2011 (excluding the 2009–2010 pandemic), on average 23% (range: 
1%–60%) of influenza samples annually were identified as influenza B (5). For several decades, 
2 distinct lineages of influenza B (the Victoria and Yamagata lineages) have circulated worldwide 
with varying intensity. Different B lineages have predominated or co-circulated in different 
regions, making the prediction of the circulating B lineage challenging (5) (6) (7). 
The burden of influenza morbidity and mortality is high with a greater number of infections 
attributable to influenza A than influenza B. In Europe, nearly 40 000 people die prematurely each 
year due to influenza (8). In the United States (US), the burden of influenza in all ages is currently 
estimated to be 25 to 50 million cases per year, leading to 150 000 hospitalizations and 30 000 to 
40 000 deaths. If these figures were extrapolated to the rest of the world, the average global 
burden of seasonal influenza would be in the order of 600 million cases, 3 million cases of severe 
illness and 290 000 to 650 000 deaths per year (9). 
Influenza B outbreaks have been described among older adults, and have led to excess mortality 
in some annual epidemics (10) (11). Among the elderly, influenza B is associated with excess 
pneumonia and influenza hospitalizations, and while excess population-based hospitalization rates 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 23 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 23 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 24 of 81 
associated with influenza B are lower than those associated with A/H3N2, they are twice as high 
as those associated with A/H1N1 (12). During the 2017-2018 season, the dominant circulating 
influenza B virus (B/Yamagata) was of high (11) severity, causing long duration of peak influenza 
activity and all-cause excess mortality in the European Union (EU) (11). Overall, influenza B is a 
significant cause of employee absenteeism, clinic visits, hospitalizations and deaths (13) (14) (15). 
1.2 
Background of the Investigational Product 
The World Health Organization (WHO) recommends annual vaccination against influenza 
because it has been shown to be effective in reducing influenza-associated morbidity and 
mortality (9).  
Traditional trivalent and quadrivalent inactivated influenza vaccines (TIV and QIV) administered 
by the intramuscular (IM) route contain a standard dose (SD) of 15 µg HA of each of the virus 
strains (one A/H1N1 strain, one A/H3N2 strain and one B strain for TIV and 2 B strains [B 
Yamagata lineage and B Victoria lineage for QIV]) with a total of 45 µg and 60 µg of HA antigen 
per dose, respectively. 
However, the effectiveness of the influenza vaccine in preventing or attenuating illness depends in 
part on the age, underlying conditions, and immune competence of the vaccine recipient and on 
the similarity between the virus strains present in the vaccine and the strains circulating in the 
community.  
The immune response to SD influenza vaccines (15 µg HA per strain) is sub-optimal in adults 
65 years of age and older compared to healthy young adults (16). A strategy to improve protection 
against influenza in adults 65 years of age and older is to increase the antigen dose. Therefore, 
Sanofi Pasteur has developed a high-dose quadrivalent influenza vaccine (QIV-HD) containing 
60 µg of HA of each of 4 virus strains (A/H1N1, A/H3N2, and 1 B strain from each of the 
Victoria and the Yamagata lineages). 
The QIV-HD has been developed based on the experience gained with Sanofi Pasteur’s high-dose 
trivalent influenza vaccine (TIV-HD) which contains 60 µg HA of each of 3 virus strains and is 
manufactured in the US. TIV-HD was licensed by Sanofi Pasteur under the name of Fluzone® 
High-Dose for use in adults 65 years of age and older in the US since 2009, Canada since 2015, 
Australia since 2017, Brazil since 2018, and the United Kingdom since 2019. The production of 
QIV-HD uses the same drug substance (DS) and drug product (DP) manufacturing processes 
except for the DP formulation step, which includes the addition of a 2nd influenza B strain at the 
same HA content as the other 3 strains (60 micrograms [μg] HA/strain/dose). This results in a 
slightly higher fill volume of 0.7 mL. 
Results of clinical studies conducted in adults 65 years of age and older have shown that TIV-HD 
resulted in superior immune responses (17) and improved vaccine efficacy (18) compared to a 
standard-dose trivalent influenza vaccine (TIV-SD). The benefit of TIV-HD was further 
confirmed by post-licensure real world evidence (RWE) studies conducted in more than 6 million 
people (19) (20) (21) (22). Approximately 26 546 subjects have been exposed to TIV-HD through 
its clinical development program and after post-marketing surveillance up to 30 September 2018 
(ie, more than 109 million doses distributed), and the safety profile of TIV-HD in humans has 
been shown to be well tolerated with no safety concerns. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 24 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 24 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 25 of 81 
A Phase III clinical study (QHD00013) was conducted in adults 65 years of age and older in the 
US during the 2017-2018 Northern Hemisphere influenza season. QHD00013 demonstrated the 
non-inferior immunogenicity of QIV-HD compared to the TIV-HD controls for all strains. 
QIV-HD was also found to be safe and well tolerated and showed comparable reactogenicity 
(solicited injection site reactions and solicited systemic reactions) to TIV-HD. These results 
support the objective of the clinical development of QIV-HD by demonstrating that QIV-HD is 
able to induce robust immune responses to the 4 influenza strains contained in the vaccine while 
offering the possibility of increased protection by containing both B lineages, without 
compromising vaccine safety. 
In addition, a Phase II descriptive safety and immunogenicity study (QHD00008) has also been 
conducted in adults 65 years of age and older in Japan to describe the safety and immunogenicity 
of QIV-HD in the Japanese population and support further clinical development in Japan.  
1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
All subjects participating in Study QHD00011 will receive influenza vaccination with either the 
investigational QIV-HD or the control, standard-dose quadrivalent influenza vaccine (QIV-SD). 
All subjects will therefore be vaccinated against the influenza viruses recommended by the WHO 
for the 2019-2020 Northern Hemisphere (NH) influenza season. Thus, these older adults may be 
protected against those strains and be less likely to catch influenza or develop complications from 
an influenza infection during the respective influenza season. 
Regarding immunogenicity, QIV-HD has been shown to induce an effective immune response 
against the 4 influenza strains included in the vaccine in adults 65 years of age and older. In adults 
60 to 64 years of age, the immune response of TIV-HD is expected to be similar to the response 
induced in adults 65 years of age and older. The QIV-HD is also expected to induce an effective 
immune response against 4 influenza strains and higher geometric mean titers (GMTs) and 
seroconversion rates than the control QIV-SD. Therefore, the investigational QIV-HD is likely to 
bring an increased benefit versus QIV-SD in terms of immunogenicity against influenza virus 
strains.  
1.3.2 
Potential Risks to Subjects 
1.3.2.1 
Potential Risks and Possible Side Effects of QIV-HD Vaccination 
The QIV-HD is safe and well tolerated in this population. Safety data of QIV-HD observed in 
adults 65 years of age and older can be anticipated to be at least similar in adults 60 to 64 years of 
age. However, as with any vaccine, the QIV-HD vaccine may cause side effects in certain people. 
Expected Adverse Events  
The safety of QIV-HD is based on adverse reactions (ARs) that were recorded following 
vaccination with QIV-HD during study QHD00013 (1,777 adults 65 years of age and older) and 
ARs reported during clinical development and post-marketing experience with TIV-HD. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 25 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 25 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 26 of 81 
The very common reactions (may affect more than 1 in 10 people) occurring after QIV-HD 
administration were injection site pain, myalgia, headache and malaise.  
The following reactions have been also observed: 
• Reactions at the injection site such as erythema, swelling, bruising, and induration. Their 
frequencies have been estimated as common (may affect up to 1 in 10 people) 
• Systemic reactions such as pruritus, fever, nausea, diarrhea, cough, and vertigo.  Their 
frequencies have been estimated as uncommon (may affect up to 1 in 100 people) 
• Fatigue, flushing, arthralgia, dizziness, vomiting pruritus, urticaria and pain in extremities. 
Their frequencies have been estimated as rare (may affect up to 1 in 1000 people) 
• Muscle weakness, dyspepsia, night sweats, lethargy and rash. Their frequencies cannot be 
estimated from available data 
Most of these reactions usually occurred within the 3 days following vaccination, and resolved 
within 3 days of vaccination. The intensity of these reactions was mostly Grade 1 (mild) to Grade 
2 (moderate). 
Other Potential Adverse Events 
In addition to the expected adverse events (AEs), the following additional AEs have been 
spontaneously reported during the post-marketing use of TIV-HD (23) or during clinical trials 
conducted on TIV-HD, and may occur in people receiving QIV-HD: 
These events are reported voluntarily from a population of uncertain size, consequently it is not 
always possible to reliably estimate the frequency of the events or establish a causal relationship 
to vaccine exposure. The AEs were included based on one or more of the following factors: 
severity, frequency of reporting, or strength of evidence for a causal relationship to TIV-SD: 
• Blood and Lymphatic System Disorders: thrombocytopenia, lymphadenopathy  
• Immune System Disorders: anaphylaxis, other allergic/hypersensitivity reactions (including 
urticaria, angioedema)  
• Eye Disorders: ocular hyperemia  
• Nervous System Disorders: Guillain-Barré syndrome (GBS), convulsions, febrile convulsions, 
myelitis (including encephalomyelitis and transverse myelitis), facial palsy (Bell’s palsy), 
optic neuritis/neuropathy, brachial neuritis, syncope (shortly after vaccination), paresthesia  
• Vascular Disorders: vasculitis, vasodilatation  
• Respiratory, Thoracic and Mediastinal Disorders: dyspnea, wheezing, throat tightness, 
oropharyngeal pain, rhinorrhea  
• General Disorders and Administration Site Conditions: chest pain  
1.3.2.2 
Potential Risks and Possible Side Effects of QIV-SD Vaccination 
Refer to the package inserts of the marketed QIV-SD vaccine (Influvac™ Tetra) for information 
regarding potential risks. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 26 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 26 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 27 of 81 
1.3.2.3 
Possible Reactions to Blood Draw 
Venipuncture causes transient discomfort and may cause temporary hypotension from a vasovagal 
response (eg, fainting). If pressure is not applied long enough to the venipuncture site, bruising 
due to bleeding beneath the skin may occur. Infection at the site of needle insertion could 
theoretically occur but is exceedingly rare when the standard sterile technique is utilized. 
1.4 
Rationale for the Study 
While federal health agencies in European countries recommend that elderly persons receive 
influenza vaccination, the results of a European seasonal influenza vaccination survey, reported 
by the European Centre for Disease Prevention and Control, reveal that the recommended ages for 
influenza vaccination of the elderly vary from country to country (24). During the 2014-2015 
influenza season, all 30 participating countries recommended seasonal influenza vaccination for 
people in the “older” age groups, but the actual age specified as “older” differed between 
countries. The recommended age of “older” adults who should be vaccinated against influenza 
was ≥ 65 years of age in 18 countries. A cut-off of ≥ 60 years was reported by 6 countries 
(Germany, Greece, Hungary, Iceland, the Netherlands, and Portugal). Slovakia recommended 
vaccination of persons 59 years of age and older. Malta and Poland recommended vaccination of 
persons 55 years of age and older. Three countries (Austria, Belgium, and Ireland) recommended 
vaccination of those who are 50 years of age and older. 
Clinical data generated with TIV-HD or QIV-HD support an indication in persons starting at 65 
years of age and older. To extend the age indication downwards to 60 to 64 years of age in 
Europe, the QHD00011 study is being proposed to collect and analyse immunogenicity and safety 
data in the 60 to 64 years of age population. In addition, as no data comparing the QIV-HD to the 
QIV-SD standard of care licensed in Europe have been generated to date, a group of subjects 65 
years of age and older is also proposed to be evaluated in QHD00011. 
QHD00011 will be a Phase III, randomized, modified double-blind , active-controlled, 
multi-center trial to assess the immunogenicity and safety of the QIV-HD in approximately 1540 
healthy subjects 60 years of age and older in Europe. The goal of this study is to show that 
vaccination with QIV-HD induces an immune response (as assessed by hemagglutination 
inhibition [HAI] GMTs) that is superior to responses induced by the QIV-SD for the 4 virus 
strains at 28 days post-vaccination in subjects 60 to 64 years of age and in subjects 65 years of age 
and older. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 27 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 27 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 28 of 81 
2 
Study Objectives 
2.1 
Primary Objective 
Immunogenicity 
To demonstrate that QIV-HD induces an immune response that is superior to the responses 
induced by QIV-SD for all 4 virus strains 28 days post-vaccination in subjects 60 to 64 years of 
age and in subjects 65 years of age and older. 
The endpoints for the primary objective are presented in Section 9.1.2.  
2.2 
Secondary Objectives 
Immunogenicity 
To further describe the immune response induced by QIV-HD and QIV-SD in all subjects by age 
group, in pooled age groups, and by vaccine group (QIV-HD; QIV-SD). 
Safety 
To describe the safety profile of all subjects by age group, in pooled age groups, and by vaccine 
group (QIV-HD; QIV-SD). 
The endpoints for the secondary objectives are presented in Section 9.2.1 and Section 9.2.2 for 
safety and immunogenicity, respectively. 
2.3 
Observational Objectives 
Immunogenicity 
• To describe the immune response 28 days after vaccination by virus seroneutralization (SN) 
measurement method for at least 50% of subjects in each age group (60 to 64 years of age; 
65 years of age and older) and in pooled age group by vaccine group (QIV-HD; QIV-SD). 
• To describe the anti-NA immune response in at least 50 subjects in each age group and in 
pooled age group by vaccine group (QIV-HD; QIV-SD). 
Blood samples from at least 50% of subjects in each age group and each vaccine group will be 
analyzed for SN. And among these subjects, blood samples from at least 50 subjects in each age 
group and each vaccine group will be analyzed for NA.  
The endpoint(s) for the observational objective(s) are presented in Section 9.3.2. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 28 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 28 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 29 of 81 
3 
Investigators and Study Organization 
This study will be conducted in approximately 15 to 20 centers in the EU including Belgium, 
France, and Germany. The Principal Investigators and any sub-investigators at the individual sites 
will be coordinated by 1 Coordinating Investigator in each country or each region. Details of the 
study centers, the Investigators at each center, and the Coordinating Investigator(s) are provided 
in the “List of Investigators and Centers Involved in the Trial” document. 
An internal safety management team (SMT) will perform an analysis of safety data during the 
conduct of the study. 
Monitoring activities on site, development activities for data management, and conduct of the data 
management activities will be conducted by a contract research organization (CRO) under the 
responsibility of Sanofi Pasteur SA. 
No Independent Data Monitoring Committee (IDMC) is planned for this trial as no safety 
concerns emerged during the previous clinical trials conducted with the QIV-HD, and the fact that 
the safety profile of TIV-HD in humans has been shown to be well tolerated with no safety 
concerns, in 25,564 subjects who received at least one dose of TIV-HD in the clinical 
development studies and observational studies as well as after 8 years of post-marketing 
surveillance with more than 90 million doses distributed (see Section 5.1.2). 
The Sponsor’s Responsible Medical Officer (the RMO, the person authorized to sign this protocol 
and any amendments on behalf of the Sponsor) is Sanjay Gurunathan, MD, Associate Vice 
President and Head, Global Clinical Development Centers of Excellence (Europe/North 
America). 
4 
Independent Ethics Committee / Institutional Review Board 
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent forms (ICFs), subject recruitment 
procedures, and any other written information to be provided to subjects must be approved by, 
and / or receive favorable opinion from, the appropriate Independent Ethics Committees (IECs) or 
Institutional Review Boards (IRBs). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and / or 
the Sponsor are responsible for obtaining this approval and / or favorable opinion before the start 
of the study. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator (if 
the Investigator is responsible for the submission of the dossier to the IEC / IRB) to the Sponsor 
together with the composition of the IEC / IRB (the names and qualifications of the members 
attending and voting at the meetings). 
The Investigator or Sponsor will submit written summaries of the status of the study to the IEC / 
IRB annually, or more frequently if requested. All serious adverse events (SAEs) occurring during 
the study will be reported by the Investigator to the IEC / IRB, according to the IEC / IRB policy, 
and according to local regulations. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 29 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 29 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 30 of 81 
5 
Investigational Plan 
5.1 
Description of the Overall Study Design and Plan 
5.1.1 
Study Design 
QHD00011 will be a Phase III, randomized, modified double-blind , active-controlled, 
multi-center study to assess the immunogenicity and safety of the QIV-HD in approximately 1540 
healthy subjects 60 years of age and older in Europe. The goal of this study is to show that 
vaccination with one dose of QIV-HD induces an immune response (as assessed by HAI GMTs) 
that is superior to responses induced by one dose of QIV-SD for the 4 virus strains at 28 days 
post-vaccination in subjects 60 to 64 years of age and in subjects 65 years of age and older. 
In each age group, eligible subjects will be randomized in a 1:1 ratio to receive a single IM 
injection of either QIV-HD or QIV-SD at Day (D)0 as follows: 
1. QIV-HD; stratified by age (60 to 64 years of age; 65 years of age and older) 
2. QIV-SD; stratified by age (60 to 64 years of age; 65 years of age and older) 
For further details concerning the number of subjects allocated to each study group, see Table 6.1. 
All subjects will provide a pre-vaccination (baseline) blood sample at D 0 and a post-vaccination 
blood sample at Visit (V) 02 (D28 [+7 days]) for HAI testing. A randomized subset of these 
subjects (observational subset) will be used for SN and NA testing. 
Solicited injection site and systemic reactions will be collected up to 7 days after vaccination, and 
unsolicited AEs will be collected up to V02, which is the active phase of the trial (V01 to V02 
[D0-D28]). SAEs and adverse events of special interest (AESIsa) will be collected throughout the 
trial (D0 through approximately D180 [6-month follow-up period]). 
Interactive response technology (IRT) will be used to randomly assign subjects to one of the 
2 study groups and to assign subject numbers in each of the groups. In addition, IRT will be used 
to randomly assign subjects to the observational subsets. Electronic data capture (EDC) will be 
used for the collection of data. 
5.1.2 
Justification of the Study Design 
Clinical data generated in studies of TIV-HD or QIV-HD support an indication in persons from 
65 years of age and older. To extend the age indication downwards to 60 to 64 years of age in 
Europe, the QHD00011 study is being proposed to collect and analyze immunogenicity and safety 
data in the 60 to 64 years of age population. In addition, as no data comparing the QIV-HD to the 
QIV-SD standard of care licensed in Europe have been generated to date, a group of subjects 65 
years of age and older is also proposed to be evaluated in QHD00011. 
                                                 
a  Note: AESIs will be captured as SAEs. These include new onset of GBS, encephalitis / myelitis (including 
transverse myelitis), Bell’s palsy, optic neuritis, and brachial neuritis. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 30 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 30 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 31 of 81 
The primary objective of QHD00011 is to demonstrate that QIV-HD induces an immune response 
(as assessed by HAI antibody [Ab] titers of all 4 virus strains on D 28) that is superior to the 
responses induced by QIV-SD in subjects 60 to 64 years of age and in subjects 65 years of age 
and older. 
Given the acceptable safety data generated from over 1800 subjects vaccinated with the QIV-HD 
in the US (Phase III QHD00013 study) and Japan (Phase I/II QHD00008 study), and the fact that 
the safety profile of TIV-HD in humans has been shown to be well tolerated with no safety 
concerns, in 25,564 subjects who received at least one dose of TIV-HD in the clinical 
development studies and observational studies as well as after 8 years of post-marketing 
surveillance with more than 90 million doses distributed, neither an early safety data review nor 
IDMC is planned for this trial. 
The QHD00011 study will be a modified double-blind study with unblinded designated vaccine 
preparer(s)/administrator(s) used at each study site. The designated vaccine 
prepare(s)/administrator(s) will be unblinded given the different volumes in the QIV-HD and 
QIV-SD vaccines (0.7 milliliter [mL] for QIV-HD and 0.5 mL for QIV-SD), but neither the 
subject nor the investigator nor the study staff in charge of vaccination will know which vaccine 
will be administered (the syringes will be masked to maintain the blind of the subjects and other 
members of the clinical site). The unblinded designated vaccine preparer(s)/administrator(s) will 
not be involved in any of the blinded study assessments (eg, immunogenicity, safety). The 
Investigators (or delegates) in charge of safety assessment, the trial staff who collect the safety 
data, and the laboratory personnel who analyze the blood samples will not know which product 
was administered. 
Additional details will be provided in the Operating Guidelines for the study. 
5.1.3 
Study Plan 
The study plan is summarized in the Table of Study Procedures.  
Vaccination 
All eligible subjects will be randomized to receive a single injection of either the QIV-HD vaccine 
or QIV-SD at V01 (D0). 
Blood Sampling 
All subjects will provide a pre-vaccination blood sample at V01 (D0) and a post-vaccination 
blood sample at V02 (D28 [+ 7 days]). 
Collection of Safety Data 
Subjects will be asked to notify the site immediately about any potential SAEs at any time during 
the study. 
All subjects will be observed for 30 minutes after vaccination, and any unsolicited systemic AEs 
occurring during that time will be recorded as immediate unsolicited systemic AEs in the Case 
Report Book (CRB). 
Subjects will record information about solicited reactions (D0-D7), unsolicited AEs (D0-V02), 
SAEs (D0-V02), and AESIs (D0-V02) in a diary card (DC). 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 31 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 31 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 32 of 81 
Staff will review the D0 to V02 safety data with subjects at V02. 
Subjects will continue to collect information on SAEs and AESIs in a memory aid (from V02-
D180). Staff will contact subjects by telephone at D180 (+14 days) post-vaccination to review the 
memory aid and to identify the occurrence of any SAEs and AESIs that had not yet been reported. 
5.1.4 
Visit Procedures 
Visit 1 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) Explain the trial to the subject, answer any of his / her questions and ensure that he / she has 
been informed of all aspects of the trial that are relevant to his / her decision and obtain a 
written informed consent signed by the subject.  
The Investigator / delegate will also sign and date the ICF. The Investigator / delegate will 
then retain one original and give the copy to the subject. 
2) Check all inclusion and exclusion criteria (see Section 5.2.4 and Section 5.2.5, respectively) 
through physical examination and medical interview for eligibility.  
3) Collect relevant demographic information (eg, age, year of birth, gender, and race). 
4) Collect significant medical history and record any planned hospitalization during the trial in 
the CRB and other source documents. 
5) Obtain information about history of influenza vaccination / influenza infection (diagnosis 
laboratory confirmed) in the previous 3 years. 
6) Perform a urine pregnancy test (women of childbearing potential only). 
7) Collect reportable concomitant medications (see Section 6.7). 
8) Perform and document a targeted physical examination per standard site-specific 
immunization practices and record oral temperaturea in the medical chart. 
9) If the subject satisfies all eligibility criteria, contact the IRT to assign to the subject a 12-digit 
subject number and allocate a treatment number (see Section 6.5). At this time, some subjects 
will be assigned to the observational subsets (ie, Full Analysis Set-Seroneutralization 
[FAS-SN] Subset and FAS-NA Subset). 
10) Draw an approximately 10 mL blood sample (This blood sample should be drawn before 
vaccination). Process the blood sample as specified in the “Management of Samples” section 
(see Section 7).  
Note: If the subject withdraws consent before blood sampling (before any invasive procedure 
has been performed), do not vaccinate the subject. The subject should be terminated from the 
study.  
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), then the subject is 
still to be included in the study and vaccinated. 
Note: If the blood sample cannot be obtained, the subject should be given the opportunity to 
                                                 
a  Tympanic and temporal artery thermometer should not be used. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 32 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 32 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 33 of 81 
return to the study site for another attempt, as long as the study is still enrolling subjects and 
as long as the subject continues to remain eligible for the trial and that includes reviewing 
Inclusion/Exclusion criteria, medical history, and ICF process. All attempts should be made 
to obtain a blood sample; however, if the attempts are unsuccessful, the subject should not be 
vaccinated and should be discontinued from the study. 
11) Unblinded designated vaccine administrator administers the appropriate study vaccine by IM 
injection into the region of the deltoid muscle, although it may also be given subcutaneously 
(SC). The vaccine must be administered on the side opposite to that of blood sampling. 
12) Record the injection site / side / route / treatment number in the CRB and affix the detachable 
corresponding label in the source document and vaccination card if any. 
13) Keep the subject under medical surveillance for at least 30 minutes after the injection and 
report the occurrence or non-occurrence of any AE in the CRB. 
14) Give the subject the DC to record any injection site reactions and systemic AEs, together with 
instructions for its completion, including explanations on the definition and use of intensity 
scales for collection of AEs. 
15) Give the subject a ruler to measure the size of any injection site reaction, a thermometer for 
temperature measurement, and instructions on how to use them. 
16) Instruct on the need to promptly report any SAE that may occur at any time during the trial. 
17) Complete the relevant case report forms (CRFs) for this visit and schedule an appointment for 
Visit 2. 
Visit 2 (D28 [+7] days after Visit 1): Collection of Safety Information and Blood Sample 
1) 
Collect and review the DC since Visit 1, including any AEs, medications, or therapy that 
occurred since vaccination. The occurrence of any injection site reaction, systemic 
event/reaction, and/or any SAE (including AESI) should have been reported in the DC. 
2) 
Perform a targeted physical examination, as necessary, based on medical history. 
3) 
Draw an approximately 10 mL blood sample for the titration of Abs.  
Note: If the attempt(s) to collect blood is (are) unsuccessful (3 attempts), the subject should 
be given the opportunity to return to the study site for another attempt within the visit 
window. If a blood sample cannot be obtained, the reason will be recorded in the blood 
sampling page of the CRB. The subject will continue to be followed-up for safety purposes. 
4) 
Provide the subject with a memory aid and review the directions for its use. 
5) 
Remind the subject to expect a safety follow-up telephone call 180 days after Visit 1. 
6) 
Remind the subject to report any SAE (including AESI) that may occur between Visit 2 and 
the 6-month follow-up call. 
7) Complete the V02 termination record of the CRF for all subjects. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 33 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 33 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 34 of 81 
D180 Safety Follow-up Telephone Call (180 days [+14 days], approximately 6 months after 
vaccination): Collection of SAEs 
1) This telephone call must be made by a qualified person, such as a physician or a qualified 
study nurse. 
2) Inquire whether the subject has received any vaccinations since the last contact (to be taken 
into account for the collection of information in the “Concomitant Vaccination” section) (see 
Section 6.7). 
3) Review the memory aid to identify any SAEs and AESIs that occurred since Visit 2 that had 
not yet been reported. Perform follow-up on any SAEs and AESIs. 
4) Explain that this will be the last contact with the site for this trial (except for subjects with 
SAEs (including AESI) that need further follow-up, as stated below). 
5) A follow-up visit can be arranged depending on the information recorded during the phone 
call. 
6) Complete the relevant CRFs for this telephone call. 
If the first contact attempt to complete the last telephone call is unsuccessful, at least 2 separate 
additional attempts, conducted on different days, should be made to contact these subjects. All 
attempts must be documented in the subject’s source notes. If, after at least 3 documented 
attempts, contact cannot be established, the subject should be classified as lost to follow-up (see 
Section 5.2.9 for further details). 
The exceptions for the final phone calls are as follows:  
• 
Subjects who voluntarily withdrew 
• 
Subjects who have been previously classified as lost to follow-up 
Follow-up of Subjects With Related AEs or With AEs That Led to Study/Vaccination 
Discontinuation: 
Unless a subject refuses further contact, each subject who experiences an AE (whether serious or 
non-serious) during the study must be followed until the condition resolves, becomes stable, or 
becomes chronic (even after the end of the subject’s participation in the study) if either of the 
following is true: 
• The AE is considered by the Investigator to be related to the product administered. 
• The AE caused the discontinuation of the subject from the study or from vaccination. 
5.1.5 
Planned Study Calendar 
The following dates are approximate. The actual dates may differ as, for example, the study will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned study period - FVFS (first visit, first subject) to LCLS (last contact, last subject): 
October 2019 to May 2020 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 34 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 34 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 35 of 81 
Planned inclusion period - FVFS to FVLS (first visit, last subject): October 2019 to 
November 2019 
Planned primary vaccination period: October 2019 to November 2019 
Planned end of study: May 2020 
Planned date of final clinical study report: November 2020 
5.2 
Enrollment and Retention of Study Population 
5.2.1 
Recruitment Procedures 
Before the start of the trial, the Investigator or sub-investigator will contact an appropriate pool of 
potential subjects and invite them to participate in the study. The site will ensure that any 
advertisements used to recruit subjects (eg, letters, pamphlets, posters) are submitted to Sanofi 
Pasteur prior to submission to the IEC / IRB for approval. 
5.2.2 
Informed Consent Procedures 
Informed consent is the process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study. Informed consent must be obtained before any study procedures 
are performed. The process is documented by means of a written, signed, and dated ICF. 
In accordance with GCP, prior to signing and dating the consent form, the subject must be informed 
by appropriate study personnel about all aspects of the study that are relevant to making the 
decision to participate, and must have sufficient time and opportunity to ask any questions. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s  willingness to 
continue participation in the study, this will be communicated to him / her in a timely manner. 
Such information will be provided via a revised ICF or an addendum to the original ICF. 
Informed consent forms will be provided in duplicate, or a photocopy of the signed consent will 
be made. The original will be kept by the Investigator, and the copy will be kept by the subject. 
Documentation of the consent process should be recorded in the source documents. 
5.2.3 
Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 35 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 35 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 36 of 81 
5.2.4 
Inclusion Criteria 
An individual must fulfill all of the following criteria to be eligible for study enrollment: 
1) 
Sixty years of age and older on the day of inclusion 
2) 
Informed consent form has been signed and dated 
3) 
Able to attend all scheduled visits and to comply with all trial procedures 
4) 
Covered by health insurance if applicable in the country 
5.2.5 
Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from study enrollment: 
1) 
Subject is pregnant, or lactating, or of childbearing potential and not using an effective 
method of contraception or abstinence from at least 4 weeks prior to vaccination until at 
least 4 weeks after vaccination. To be considered of non-childbearing potential, a female 
must be post-menopausal for at least 1 year, or surgically sterile. 
2) 
Participation at the time of study enrollment (or in the 4 weeks [28 days] preceding the 
trial vaccination) or planned participation during the present trial period in another clinical 
trial investigating a vaccine, drug, medical device, or medical procedure  
3) 
Receipt of any vaccine in the 4 weeks (28 days) preceding the trial vaccination or planned 
receipt of any vaccine prior to V02 
4) 
Previous vaccination against influenza (in the previous 6 months) with either the trial 
vaccine or another vaccine 
5) 
Receipt of immune globulins, blood or blood-derived products in the past 3 months 
6) 
Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, 
within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone 
or equivalent for more than 2 consecutive weeks within the past 3 months) 
7) 
Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the trial or to a vaccine containing any of the 
same substancesa 
8) 
Thrombocytopenia or bleeding disorder, contraindicating IM vaccination based on 
Investigator’s judgment 
9) 
Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
                                                 
a  The components of QIV-HD are listed in Section 6.1 and in the Investigator’s Brochure. The components of 
QIV-SD are listed in Section 6.2 and in the QIV-SD prescribing information.  
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 36 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 36 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 37 of 81 
10) 
Alcohol or substance abuse that, in the opinion of the Investigator might interfere with the 
trial conduct or completion 
11) 
Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completiona  
12) 
Moderate or severe acute illness/infection (according to Investigator judgment) or febrile 
illness (temperature ≥ 38.0°C) on the day of vaccination. A prospective subject should not 
be included in the study until the condition has resolved or the febrile event has subsided. 
13) 
Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (ie, 
parent, spouse, natural or adopted child) of the Investigator or employee with direct 
involvement in the proposed study 
14) 
Personal or family history of Guillain-Barré syndrome (GBS) 
15) 
Neoplastic disease or any hematologic malignancy (except localized skin or prostate 
cancer that is stable at the time of vaccination in the absence of therapy and subjects who 
have a history of neoplastic disease and have been disease free for ≥ 5 years) 
Depending on local or country regulations, if the subject has a primary physician who is not the 
Investigator, the site should contact this physician with the subject’s consent to inform him / her 
of the subject’s participation in the study. In addition, the site should ask this primary physician to 
verify exclusion criteria relating to previous therapies, such as receipt of blood products or 
previous vaccines. 
5.2.6 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
(clinically relevant) medical history (reported as diagnosis) including conditions/illnesses for 
which the subject is or has been followed by a physician or conditions/illnesses that could resume 
during the course of the study or lead to an SAE or to a repetitive outpatient care will be collected 
in the CRB. The significant medical history section of the CRB contains a core list of body 
systems and disorders that could be used to prompt comprehensive reporting, as well as space for 
the reporting of specific conditions and illnesses. 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms in lieu of a diagnosis is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
                                                 
a  Chronic illness may include, but is not limited to, cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychiatric disorders, or chronic infection 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 37 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 37 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 38 of 81 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the 
study. 
5.2.7 
Contraindications for Subsequent Vaccinations 
Not applicable since only one dose of vaccine will be administered in this trial. 
5.2.8 
Conditions for Withdrawal 
Subjects will be informed that they have the right to withdraw from the study at any time. 
A subject may be withdrawn from the study: 
• At the discretion of the Investigator or Sponsor due to safety concerns or significant 
noncompliance with the protocol (based on the Investigator’s judgment), without the subject’s 
permission (withdrawal) 
• At the request of the subject (dropout) 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and in the CRB.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “Adverse Event”) or for another 
reason. 
Withdrawn subjects will not be replaced. 
5.2.9 
Lost to Follow-up Procedures 
In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (ie, documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the source documents. 
5.2.10 Classification of Subjects Who Discontinue the Study 
For any subject who discontinues the study prior to completion, the most significant reason for 
early termination will be checked in the CRB. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion instructions for additional details and 
examples): 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 38 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 38 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 39 of 81 
Adverse Event 
To be used when the subject is permanently terminated from the study 
because of an AE (including an SAE), as defined in Section 9.2.1.1 
Lost to Follow-up 
To be used when the subject cannot be found or contacted in spite of efforts 
to locate him/her before the date of his/her planned last visit, as outlined in 
Section 5.2.9. The certified letter was sent by the investigator and returned 
unsigned, and the subject or parent/guardian did not give any other news 
and did not come to any following visit. 
Protocol Deviation 
To be used: 
• 
In case of significant noncompliance with the protocol (eg, deviation of 
the Inclusion / Exclusion criteria, non-compliance with time windows, 
blood sampling or vaccination refusal, missed injection/treatment, or 
error in the vaccine/treatment administration). 
• 
The subject or the parent/guardian signed the certified letter sent by the 
investigator but did not give any other news and did not come to any 
following visit. 
Withdrawal by Subject or 
Parent / Guardian / 
Legally Acceptable 
Representative 
To be used: 
• 
When the subject or parent/guardian indicated unwillingness to 
continue in the study 
• 
When the subject or parent/guardian made the decision to discontinue 
participation in the study for any personal reason other than an SAE/AE 
(eg, subject is relocating, inform consent withdrawal, etc.) 
5.2.11 Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the study because of an AE or a protocol deviation.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
withdrew informed consent and specified that they do not want to be contacted again and it is 
documented in the source document, the site will not attempt to obtain further safety information. 
If the subject’s status at the end of the study is “Withdrawal by Subject or Parent / Guardian / 
Legally Acceptable Representative”, the site will attempt to contact them for the D180 (6-month) 
follow-up except if they specified that they do not want to be contacted again and it is 
documented in the source document. 
5.2.12 Follow-up and Reporting of Pregnancies 
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy and if at least 1 dose of the study 
vaccine(s) has been administered, the subject will not be discontinued from the study, but no 
further vaccination will be administered until after delivery (if applicable and still within the study 
vaccination window). However, the subject will be followed for safety assessment (and may be 
followed for immunogenicity assessment, if applicable). 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 39 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 39 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 40 of 81 
All pregnancy cases should be reported if they occurred during the study and during the 6 month 
follow-up period. To report the pregnancy case, the Investigator must fill out Pregnancy 
Reporting forms in the EDC system and inform the Sponsor within 1 month of identifying a 
pregnancy case.  
If the EDC system is not available, the investigator must fill out a paper Pregnancy Reporting 
Form (provided by the Sponsor at the start of the study) and inform the Sponsor within 1 month of 
identifying a pregnancy case. 
Study staff must then maintain contact with the subject to obtain information about the outcome 
(ie, details about the delivery and the newborn, or about pregnancy termination) and must update 
the Pregnancy Reporting forms even after the end of the study. This information should be 
provided to the Sponsor within 1 month of delivery. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, blighted 
ovum, fetal death, stillbirth, and congenital anomalies reported in the baby are always considered 
as SAEs, and the information should be provided to the Global Pharmacovigilance (GPV) 
Department regardless of when the SAE occurs (eg, even after the end of the study). 
5.3 
Safety Emergency Call 
If, as per the Investigator's judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor's RMO for advice on how to address any study related medical question 
or problem. If the RMO is not available, then the Investigator may contact the Call Center—
available 24 hours a day, 7 days a week—that will forward all safety emergency calls to the 
appropriate primary or back-up Sanofi Pasteur contact, as needed. The toll-free contact 
information for the Call Center is provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The Investigator is still required to 
follow the protocol-defined process for reporting SAEs to the GPV Department (please refer to 
Section 10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.4. 
5.4 
Modification of the Study and Protocol 
Any amendments to this study plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments (eg, those that affect the conduct of the study or the safety of 
subjects) require IEC / IRB approval, and must also be forwarded to regulatory authorities. 
An administrative / nonsubstantial amendment to a protocol is one that modifies some 
administrative, logistical, or other aspect of the study but does not affect its scientific quality or 
have an impact on the subjects’ safety. Administrative / nonsubstantial changes do not require IEC / 
IRB approval; however, the IEC / IRB must be notified whenever one is made. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 40 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 40 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 41 of 81 
The Investigator is responsible for ensuring that changes to an approved study, during the period 
for which IEC / IRB approval has already been given, are not initiated without IEC / IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.5 
Interruption of the Study 
The study may be discontinued if new data about the investigational product resulting from this or 
any other studies become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, the IECs/IRBs, or the governing regulatory authorities in the countries where the 
study is taking place.  
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by applicable regulatory requirements. The 
Investigator shall promptly inform the study subjects and should assure appropriate subject 
therapy and/or follow-up. 
6 
Products Administered 
Given that different vaccines will be administered to subjects in each group, an unblinded 
administrator will be used at each study site to administer the vaccines. The administrator will not 
be involved in any of the blinded study assessments (eg, safety and immunogenicity). Taking into 
account the fact that the volumes to be injected will be different (0.7 mL for QIV-HD and 0.5 mL 
for QIV-SD), the syringes will be masked to keep the blind of the subjects and other members of 
the clinical site. Additional details will be provided in the Operating Guidelines for the study. 
6.1 
Identity of the Investigational Product  
6.1.1 
Identity of Study Product (QIV-HD) 
The investigational QIV-HD is a split virion quadrivalent influenza vaccine (60 μg HA/strain) 
containing virus strains chosen by the WHO / EU for the NH 2019-2020 influenza season. The 
vaccine contains 2 antigens of type A (H1N1 and H3N2) and 2 antigens of type B (one each from 
Yamagata and Victoria lineages). Each pre-filled syringe contains a total of 240 μg HA antigen 
per 0.7 mL dose provided in sterile suspension for IM injection into the upper arm (deltoid area). 
The QIV-HD vaccine is thimerosal-free and prepared from influenza viruses propagated in 
embryonated chicken eggs. 
6.1.1.1 
Composition 
Each 0.7 mL dose of QIV-HD vaccine contains the following components: 
(Strains are based on WHO / EU recommendations for the 2019-2020 NH influenza season.) 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 41 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 41 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 42 of 81 
Active Substances: 
• A/(H1N1)-like strain 
 
 
60 µg HA 
• A/(H3N2)-like strain 
 
 
60 µg HA 
• B/(Victoria Lineage)-like strain  
60 µg HA 
• B/(Yamagata Lineage)-like strain 
60 µg HA 
Excipients: 
• Octylphenol Ethoxylate (Triton X-100®) 
not more than (NMT) 350 µg 
Diluent: 
• Buffered saline solution  
 
 
quantity sufficient (qs) to appropriate volume 
Preservative is not used in the manufacture of QIV-HD. 
Batch number: to be determined (TBD) 
6.1.1.2 
Preparation and Administration 
Vaccination is not to be performed in subjects allergic to one of the constituents of the vaccine.  
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the CRB. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic, vasovagal, or other immediate allergic reaction. 
6.1.1.3 
Dose Selection and Timing 
The vaccination schedule of a single dose for the influenza season is per standard practice for 
receipt of annual influenza vaccination. 
6.1.2 
Identity of Control Product (Licensed QIV-SD) 
A QIV-SD vaccine licensed in Europe will be the control vaccine. Influvac Tetra is an influenza 
virus surface antigens (haemagglutinin and neuraminidase), inactivated QIV-SD influenza 
vaccine. (https://www.medicines.org.uk/emc/product/9381/smpc). The licensed QIV-SD is a 
subunit quadrivalent influenza vaccine (15 μg HA/strain) containing virus strains chosen by the 
WHO / EU for the NH 2019-2020 influenza season. The vaccine contains 2 antigens of type A 
(H1N1 and H3N2) and 2 antigens of type B (one each from Yamagata and Victoria lineages). 
Each pre-filled syringe contains a total of 60 μg HA antigen per 0.5 mL dose provided in sterile 
suspension for IM injection into the upper arm (deltoid area). QIV-SD vaccine is thimerosal-free 
and prepared from influenza viruses propagated in embryonated chicken eggs. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 42 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 42 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 43 of 81 
6.1.2.1 
Composition 
Each 0.5 mL dose of licensed QIV-SD vaccine contains the following components: 
(Strains are based on WHO / EU recommendations for the 2019-2020 NH influenza season.) 
Active Substances: 
• A/(H1N1)-like strain 
 
 
15 µg HA 
• A/(H3N2)-like strain 
 
 
15 µg HA 
• B/(Victoria Lineage)-like strain  
15 µg HA 
• B/(Yamagata Lineage)-like strain 
15 µg HA 
Excipients: 
• Potassium chloride 
• Potassium dihydrogen phosphate 
• Disodium phosphate dehydrate 
• Sodium chloride 
• Calcium chloride dehydrate 
• Magnesium chloride hexahydrate 
• Water for injection 
Batch number: TBD 
6.1.2.2 
Preparation and Administration 
The procedures for preparing and administering the control product are the same as those 
described for the study product in Section 6.1.1.2. 
6.1.2.3 
Dose Selection and Timing 
The vaccination schedule of a single dose for the influenza season is per standard practice for 
receipt of annual influenza vaccination. 
6.2 
Identity of Other Product 
Not applicable. 
6.3 
Product Logistics 
6.3.1 
Labeling and Packaging 
All products for this modified double-blind trial will be administered by IM injection. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 43 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 43 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 44 of 81 
All study vaccines will be supplied with investigational labeling and packaging. Each single dose 
of investigational product will be identified by a unique treatment number on the label and on the 
carton. The control product will not have a unique identifier on the syringe label. The control 
product will only have a unique identifier on the carton label. The carton label will also have a 
detachable label for the sites to attach to the source documents. See the Operating Guidelines for 
additional label detail. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator or designee will contact the Investigator or a designee to 
determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (ie, verification of the temperature recorders). If there 
is an indication that the cold chain was broken, this person should immediately quarantine the 
product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur to 
use the product. 
6.3.2.2 
Product Storage 
The Investigator will designate an unblinded staff member to assume the product management 
responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the study site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 
6.3.2.3 
Product Accountability 
The unblinded person in charge of product management at the site will maintain records of 
product delivery to the study site, product inventory at the site, the dose(s) given to each subject, 
and the disposal of or return to the Sponsor of unused doses.  
The necessary information on the product labels is to be entered into the source document and the 
CRB. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the study site’s product accountability records against 
the record of administered doses in the CRBs and the communication from the IRT (if 
applicable). 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 44 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 44 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 45 of 81 
In case of any expected or potential shortage of product during the study, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.3.3 
Replacement Doses 
If a replacement dose is required (eg, because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must either contact the IRT to receive the new dose 
allocation, or follow the instructions given in the Operating Guidelines. 
6.3.4 
Disposal of Unused Products 
Unused or wasted products will be either disposed of or returned to the Sponsor in accordance 
with the instructions in the Operating Guidelines. Product accountability will be verified 
throughout the study period. 
6.3.5 
Recall of Products 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
To ensure that objective data are obtained, the trial is designed as a modified double-blind study 
as follows: 
• The unblinded qualified trial staff member, independent of the immunogenicity and safety 
evaluations and other trial evaluations will administer the vaccine 
• The Investigators (or delegates) in charge of safety assessment, the trial staff who collect the 
safety data, and the laboratory personnel who analyze the blood samples will not know which 
product was administered 
• The subject will not know which product was administered 
The Investigator responsible for safety assessment will not attend the vaccination session but will 
be available in case of emergency (eg, anaphylactic shock). 
Treatment numbers will be used to identify each vaccine syringe for the purpose of 
randomization, vaccination and the recording of vaccine administered. Treatment numbers will be 
randomly assigned to QIV-HD and QIV-SD syringes. The IRT vendor will be responsible for 
assigning the treatment group identification and treatment number to be received by the enrolled 
subject. The subject, the Investigator, and study staff members who collect the safety data and 
laboratory personnel who analyze the blood samples will all be blinded to the group assignment. 
The individual responsible for preparing / administering vaccine will not be authorized to collect 
any safety / serology data. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 45 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 45 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 46 of 81 
The code may be broken in the event of an AE only when the identification of the vaccine 
received could influence the treatment of the subject. Code-breaking should be limited to the 
subject(s) experiencing the AE. 
The blind can be broken by the Investigator or a delegate through the IRT system, as explained in 
the code-breaking procedures described in the Operating Guidelines. Once the emergency has 
been addressed by the site, the Investigator or a delegate must notify the Sanofi Pasteur RMO if a 
subject’s code was broken. All contact attempts with the Sponsor prior to unblinding are to be 
documented in the source documents, and the code-breaking CRF is to be completed. 
A request for the code to be broken may also be made: 
• by the GPV Department through an internal system for reporting to health authorities in the 
case of an SAE as described in International Council for Harmonisation (ICH) E2A.a In this 
case, the code will be broken only for the subject(s) in question. The information resulting 
from code-breaking (ie, the subject’s vaccine or group assignment) will not be communicated 
to either the Investigator or the immediate team working on the study, except for the GPV 
representative.  
The IEC / IRB must be notified of the code-breaking. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
In any case, the code will be broken after the first database lock, for the primary statistical 
analysis planned to analyze the data collected within the 28 days following the vaccination, but 
the randomization list will not be provided to Investigators and will be kept internally until the 
final database lock. 
6.5 
Randomization and Allocation Procedures 
The study will be a randomized, modified double-blind study for 2 vaccine groups. Table 6.1 
shows the allocation of subjects to each vaccine group.  
Table 6.1: Randomization of subjects by vaccine group (QIV-HD; QIV-SD) 
 
QIV-HD 
QIV-SD 
 
60 to 64 years 
of age 
≥65 years of 
age 
60 to 64 years 
of age 
≥65 years of 
age 
Subjects to be Randomized per Age 
Group 
385 
385 
385 
385 
Subjects to be Randomized per 
Vaccine Group 
770 
770 
                                                 
a All unexpected and related SAEs submitted to European Union competent authorities must be unblinded. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 46 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 46 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 47 of 81 
Randomization of subjects will be performed with the permuted block method with stratification 
by site and age group. Each subject who meets the inclusion/exclusion criteria and signs the ICF 
will be randomly assigned according to his/her age group, to one of the 2 vaccine groups (either 
the QIV-HD group or the QIV-SD group) via an IRT, according to a 1:1 ratio.  
For the assessment of the immune response by virus SN and enzyme-linked lectin assay (ELLA) 
methods, randomization to the observational subsets (FAS-SN subset and FAS-NA subset) will be 
performed with stratification on vaccine group, age groups (60 through 64 years of age or ≥65 
years of age), and site. The FAS-NA subset is a subset of the FAS-SN subset. 
Table 6.2: Randomization to the Observational Subsets 
 
QIV-HD 
QIV-SD 
Total 
60 to 64 years 
of age 
≥65 years 
of age 
60 to 64 years 
of age 
≥65 years 
of age 
Subjects to be randomized to 
FAS-SN subset 
≥193 
≥193 
≥193 
≥193 
≥386 
Subjects to be randomized to 
FAS-NA subset 
≥50 
≥50 
≥50 
≥50 
≥100 
Site staff will connect to the IRT, enter the identification and security information, and confirm a 
minimal amount of data in response to IRT prompts. The IRT will then provide the group 
assignment and have the site staff confirm it. The full detailed procedures for group allocation are 
described in the Operating Guidelines. If the subject is not eligible to participate in the study, then 
the information will only be recorded on the subject recruitment log. 
Subject numbers that are assigned by the IRT will consist of a 12-digit string (a 3-digit country 
identifier, a 4-digit study center identifier, and a 5-digit subject identifier). For example, 
Subject 250000100005 is the fifth subject enrolled in Center Number 1 in France (250 being the 
country code for France). The 5-digit subject identifier is detailed in the Operating Guidelines. 
The IRT will also indicate inclusion into the observational subsets (FAS-SN and FAS-NA). As 
previously noted, the FAS-NA observational subset is a subset of the FAS-SN observational 
subset.  
Subject numbers should not be reassigned for any reason. The randomization codes will be kept 
securely in the IRT. 
6.6 
Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified study personnel 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 47 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 47 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 48 of 81 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the study site, product inventory at the site, dose(s) given to each 
subject, and the disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications and other therapies (eg, blood products) should be 
recorded in the source document as well as new medications prescribed for new medical 
conditions / AEs during study participation.  
Documentation in the CRB of ongoing concomitant medication(s) will be limited to specific 
categories of medication(s) of interest beginning on the day of vaccination. This may include 
medications of interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRB from the day of vaccination (D0) to the end 
of the solicited and unsolicited follow-up period (D28 +7days). 
Reportable medications include medications that impact or may impact the consistency of the safety 
information collected after any vaccination and/or the immune response to vaccination. Four 
categories of reportable medications are defined: 
• Category 1: medications impacting or that may have an impact on the evaluation of the safety 
(eg, antipyretics, analgesics, and non-steroidal anti-inflammatory drugs [NSAIDs], 
steroids/corticosteroids) 
• Category 2: medications impacting or that may have an impact on the immune response (eg, 
other vaccines, blood products, antibiotic classes that may interfere with bioassays used by the 
Global Clinical Immunology [GCI] department, steroids/corticosteroids, immune-suppressors, 
immune-modulators with immunosuppressive properties, anti-proliferative drugs such as 
DNA synthesis inhibitors) 
• Category 3: medications impacting or that may have an impact on both the safety and the 
immune response (eg, steroids/corticosteroids) 
• Category 4: the statin family of anti-hyperlipidemia medications (eg, atorvastatin, 
rosuvastatin, simvastatin, pravastatin, and fluvastatin)  
The information reported in the CRB for each reported medication will be limited to: 
• Trade name  
• Origin of prescription: prophylaxis Yes/No. Medication(s) prescribed for AE prophylaxis will 
be recorded in the Action Taken of the AE collection tables 
• Medication category (1, 2, 3, or 4) 
• Start and stop dates 
Dosage and administration route, homeopathic medication, topical and inhaled steroids, as well as 
topical, ophthalmic, and ear treatments will not be recorded. Topical analgesics should not be 
applied at the site of vaccination; however, if they are applied inadvertently to the vaccination site, 
they should be recorded as a Category 1 medication in this specific instance. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 48 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 48 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 49 of 81 
Medications given in response to an AE will be captured in the “Action Taken” section of the AE 
CRF only. No details will be recorded in the concomitant medication CRF unless the medication(s) 
received belongs to one of the prelisted categories. Medications will not be coded. 
7 
Management of Samples 
Blood samples for the assessment of antibody responses will be collected at Visit 1 (D0, pre-
vaccination) and at Visit 2 (D28). See the Table of Study Procedures and Section 5.1.3 for details 
of the sampling schedule. 
7.1 
Sample Collection 
At Visits 1 and 2, 10 mL of blood will be collected in tubes provided by or recommended by the 
Sponsor. Immediately prior to the blood draw, the staff member performing the procedure will 
verify the subject’s identity as well as the assigned subject’s number and sampling stage on the 
pre-printed label, and will attach the label to the tube. When vaccination and blood sample 
collection occur at the same visit and vaccine is given only in one of the arms, blood is to be taken 
from the limb opposite to the one that will be used for vaccination, if possible. 
7.2 
Sample Preparation 
Detailed instructions on how to prepare blood samples for assessment of immune response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
Following the blood draw, the tubes are to be left undisturbed, positioned vertically and not 
shaken, for a minimum of one hour and a maximum of 24 hours in order to allow the blood to 
clot. Samples can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be 
refrigerated at a temperature of +2°C to +8°C after the period of clotting at room temperature and 
must be centrifuged within a maximum of 24 hours. 
After centrifugation, the serum is transferred to the appropriate number of aliquoting tubes. These 
tubes are pre-labeled with adhesive labels that identify the trial code, the subject’s number, and 
the sampling stage or visit number. 
The subject’s number, the date of sampling, the number of aliquots obtained, the date and time of 
preparation, and the subject’s consent for future use of his / her samples are to be specified on a 
sample identification list and recorded in the source document. Space is provided on this list for 
comments on the quality of samples. 
7.3 
Sample Storage and Shipment 
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 
during the entire study. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 49 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 49 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 50 of 81 
Shipments to the laboratories will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. Sera will be shipped frozen, using dry ice to 
maintain them in a frozen state, in the packaging container provided by the carrier. Again, 
temperatures will be monitored. Shipments must be compliant with the United Nations (UN) 
Class 6.2 specifications and the International Air Transport Association (IATA) 602 packaging 
instructions. 
Samples will be shipped to GCI at Sanofi Pasteur. The address is provided in the Operating 
Guidelines. 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI responsibility.  
7.4 
Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) for up to 25 years after the end of the study. These samples are being retained in 
long-term storage to support answers to regulatory questions related to the product’s licensure and 
to revalidate the results of the study. 
Subjects will be asked to indicate in the ICF whether they will permit the future use of any unused 
stored serum samples for other tests. If they refuse permission, the samples will not be used for 
any testing other than that directly related to this study. If they agree to this use, they will not be 
paid for giving permission. Anonymity of samples will be ensured. The aim of any possible future 
research is unknown today, and may not be related to this particular study. It may be to improve 
the knowledge of vaccines or infectious diseases, or to improve existing tests or develop new tests 
to assess vaccines. Human genetic tests will never be performed on these samples without specific 
individual informed consent.  
8 
Clinical Supplies 
Sanofi Pasteur will supply the study sites with protocols, ICFs, CRBs, SAE reporting forms, DCs, 
memory aids, and other study documents, as well as with the following study materials: all study 
vaccines, blood collection tubes, cryotubes, cryotube storage boxes, cryotube labels, temperature 
recorders, shipping containers, rulers, and digital thermometers. 
The means for performing EDC will be defined by Sanofi Pasteur. If a computer is provided by 
Sanofi Pasteur, it will be retrieved at the end of the study. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 50 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 50 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 51 of 81 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines.  
9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Safety 
There are no primary objectives for safety. 
9.1.2 
Immunogenicity 
9.1.2.1 
Immunogenicity Endpoints 
The primary endpoints for the evaluation of immunogenicity for subjects in each age group 
(60 to 64 years of age; 65 years of age and older) and for subjects in each vaccine group 
(QIV-HD; QIV-SD) are the following: 
• HAI Ab titers obtained on D28 
9.1.2.2 
Immunogenicity Assessment Methods  
9.1.2.2.1 
Hemagglutination Inhibition 
To support the primary and secondary objectives of this study, HAI Ab titers will be determined 
on all blood samples obtained at D0 and D28. 
Anti-Influenza Virus Ab Titration by Inhibition of Hemagglutination 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI responsibility. The address is provided in the Operating 
Guidelines. 
Test serum samples and quality control sera (sheep, ferret, and/or human sera) are incubated with 
Sigma Type III neuraminidase from vibrio cholerae to eliminate non-specific inhibitors. 
Adsorption of spontaneous anti-species agglutinins is then performed by incubating the test serum 
samples and quality control sera with a red blood cell (RBC) suspension. Following this, the 
mixtures are centrifuged and the supernatants containing the treated sera are collected for testing. 
Ten two-fold dilutions (starting at 1:10) of the treated test serum samples and quality control sera 
are incubated with a previously titrated influenza antigen at a concentration of 4 hemagglutination 
unit (HAU)/25 µL. Influenza antigen is not added to the serum control wells containing only 
serum and RBCs. The mixture is then incubated and a RBC suspension is added. Following 
incubation, the results are read. The endpoint of the assay is the highest serum dilution in which 
complete inhibition of hemagglutination occurred. Each serum sample is titrated in 2 independent 
assay runs, and the 2 values, which cannot differ by more than 1 two-fold dilution, are reported. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 51 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 51 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 52 of 81 
The GMT between the 2 values is calculated at the time of statistical analysis. The lower limit of 
quantitation (LLOQ) is set at the lowest dilution used in the assay, 1:10. Titers below this level 
are reported as < 10 (1/dilution [dil]). If the highest / last serum dilution used in the assay exhibits 
complete inhibition of hemagglutination, the serum Ab titer will be reported as ≥ 10240 (1/dil). 
9.1.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Safety 
9.2.1.1 
Safety Definitions 
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Therefore an AE may be: 
• A new illness 
• The worsening of a pre-existing condition 
• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the actions taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the study period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing medical 
condition worsens following study interventions in frequency or intensity, or if according to the 
Investigator there is a change in its clinical significance, this change should be reported as an AE 
(exacerbation). This applies equally to recurring episodes of pre-existing conditions (eg, asthma) 
if the frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious, which is based on 
subject / event outcome or action criteria usually associated with events that pose a threat to a 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 52 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 52 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 53 of 81 
subject’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose  
• Results in death 
• Is life-threateninga 
• Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability / incapacityc 
• Is a congenital anomaly / birth defect 
• Is an important medical event (IME) 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as IMEs that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the health of the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These IMEs 
should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse, new-onset diabetes, or autoimmune disease. 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ARs. 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
The following additional definitions are used by Sanofi Pasteur: 
Immediate Event/Reaction: 
Immediate events are recorded to capture medically relevant unsolicited systemic AEs (including 
those related to the product administered) that occur within the first 30 minutes after vaccination. 
                                                 
a  The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or outpatient treatment with no hospitalization.  
c  “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 53 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 53 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 54 of 81 
Solicited Reaction: 
A solicited reaction is an “expected” AR (sign or symptom) observed and reported under the 
conditions (nature and onset) prelisted in the protocol and CRB (eg, fever, headache, malaise, 
myalgia, shivering, or injection site pain, erythema, swelling, induration, or bruising). 
By definition, solicited reactions are to be considered as being related to the product administered. 
For injectable vaccines, solicited reactions can either be solicited injection site reactions or 
solicited systemic reactions. 
The assessment of these reactions by the investigator is mandatory. 
Unsolicited AE / AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the CRB in 
terms of diagnosis and/or onset window post-vaccination. For example, if headache between D0 
and D7 is a solicited reaction (ie, prelisted in the protocol and CRB), then a headache starting on 
D7 is a solicited reaction, whereas headache starting on D8 post-vaccination is an unsolicited AE. 
Unsolicited AEs includes both serious (SAEs) and non-serious unsolicited AEs. 
Injection Site Reaction: 
An injection site reaction is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions. They are considered to be related to the product administered. 
Systemic AE: 
Systemic AEs are all AEs that are not injection or administration site reactions. They therefore 
include systemic manifestations such as headache, fever, as well as localized or topical 
manifestations that are not associated with the vaccination or administration site (eg, erythema 
that is localized but that is not occurring at the injection site). 
Adverse Event of Special Interest (AESI): 
An AESI is one of scientific and medical concern specific to the Sponsor’s product or program, 
for which ongoing monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. Depending on the nature of the event, rapid communication by the study Sponsor to 
other parties (eg, regulators) might also be warranted. 
9.2.1.2 
Safety Endpoints 
The secondary endpoints for the evaluation of safety are the description of the following in all 
subjects: 
• Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred term 
[PT]), intensity, and relationship to vaccination of any unsolicited systemic AEs reported in 
the 30 minutes after vaccination. 
• Occurrence, time to onset, number of days of occurrence, intensity, action taken, and whether 
the reaction led to early termination from the study, of solicited (prelisted in the subject’s DC 
and CRB) injection site reactions and systemic reactions occurring up to 7 days after 
vaccination. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 54 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 54 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 55 of 81 
• Occurrence, nature (MedDRA PT), time to onset, duration, intensity, relationship to 
vaccination (for systemic AEs only), and whether the event led to early termination from the 
study, of unsolicited AEs up to 28 days after vaccination. 
• Occurrence, nature (MedDRA PT), time to onset, seriousness criteria, relationship to 
vaccination, outcome, and whether the event led to early termination from the study, of SAEs 
(including AESIs) throughout the study. 
9.2.1.3 
Safety Assessment Methods 
At each visit, the Investigator or a delegate will perform a medically-driven physical examination 
and will ask the subject about any solicited reactions and unsolicited AEs recorded in the DC, as 
well as about any other AEs that may have occurred since the previous visit. All relevant data will 
be transcribed into the CRB according to the instructions provided by the Sponsor. 
9.2.1.3.1 
Immediate Post-vaccination Observation Period 
Subjects will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination observation should be documented in the source document. Any AE that 
occurs during this period will be noted on the source document and recorded in the CRB, as 
follows: 
• Unsolicited systemic AEs will be recorded as immediate AEs in the CRB (presence marked as 
“yes” and details collected). 
• Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded in the CRB in the same way as any reactions starting on the day of vaccination.  
• SAEs will be recorded in the CRB and reported to the Sponsor in the same way as any other 
SAEs, according to the procedures described in Section 10. 
9.2.1.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 7 After Vaccination) 
After vaccination, subjects will be provided with a DC, a digital thermometer, and a flexible ruler, 
and will be instructed how to use them. The following items will be recorded by the subjects in 
the DC on the day of vaccination and for the next 7 days (ie, D 0 through D 7) until resolution: 
• Daily temperature, with the route by which it was taken 
• Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
• Action taken for each event (eg, medication) 
The action(s) taken by the subject to treat and/or manage any solicited reactions will be 
classified in the CRB using the following list (all applicable items should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 55 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 55 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 56 of 81 
Subjects will be contacted by telephone 180 days after vaccination to capture follow-up safety 
data. 
If the timing of the telephone call should fall on a weekend or a holiday, the call should be made 
on the next business day. If contact is not made on the designated day, study staff will continue 
calling until contact is made. Every telephone attempt and its outcome will be documented in the 
source document. 
Table 9.1 and Table 9.2 present, respectively, the injection site reactions and systemic reactions 
that are prelisted in the DCs and CRB, together with the intensity scales. 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 56 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 56 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 57 of 81 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
CRB term 
(MedDRA 
lowest level 
term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
MedDRA 
preferred 
Injection site pain 
Injection site erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Diary card 
term 
Pain 
Redness 
Swelling 
Hardening 
Bruising 
Definition 
Pain either present 
spontaneously or when the 
injection site is touched or 
injected limb is mobilized 
Presence of a redness 
including the approximate 
point of needle entry 
Swelling at or near the 
injection site 
Swelling or edema is caused 
by a fluid infiltration in tissue 
or cavity and, depending on 
the space available for the 
fluid to disperse, swelling may 
be either soft (typically) or 
firm (less typical) to touch and 
thus can be best described by 
looking at the size of the 
swelling 
Hardening at or near the 
injection site. Hardening is 
caused by a slow diffusion of the 
product in the tissue leading to a 
thick or hard area to touch at or 
near the injection site and thus 
can be best described by looking 
at the size of the hardening. 
Bruising is the result of the 
diffusion of blood in the skin 
from ruptured blood vessels 
that forms a purple or black 
and blue spot on the skin. It 
can be best described by 
looking at its size. 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 57 of 82
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 57 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 58 of 81 
CRB term 
(MedDRA 
lowest level 
term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling 
Injection site induration 
Injection site bruising 
Intensity 
scale* 
 
Grade 1: A type of adverse 
event (AE) that is usually 
transient and may require only 
minimal treatment or 
therapeutic intervention. The 
event does not generally 
interfere with usual activities 
of daily living. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
* For the subjective reaction of pain, subjects will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness, swelling, hardening, and 
bruising, they will record just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 58 of 82
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 58 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 59 of 81 
 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
MedDRA 
preferred term 
[PT] 
Pyrexia 
Headache 
Malaise 
Myalgia 
Chills 
Diary card term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Chills 
Definition 
Elevation of temperature to 
≥°38.0°C (≥ 100.4°F) 
Pain or discomfort in the 
head or scalp. Does not 
include migraine. 
General ill feeling. 
Malaise is a generalized 
feeling of discomfort, illness, 
or lack of well-being that can 
be associated with a disease 
state. It can be accompanied 
by a sensation of exhaustion 
or inadequate energy to 
accomplish usual activities. 
Muscle aches and pains are 
common and can involve 
more than one muscle at the 
same time. Muscle pain can 
also involve the soft tissues 
that surround muscles. These 
structures, which are often 
referred to as connective 
tissues, include ligaments, 
tendons, and fascia (thick 
bands of tendons). 
Does not apply to muscle 
pain at the injection site 
which should be reported as 
injection site pain. 
Cold feeling 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 59 of 82
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 59 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 60 of 81 
CRB term 
(MedDRA lowest 
level term [LLT]) 
Fever 
Headache 
Malaise 
Myalgia 
Shivering 
Intensity scale* 
Grade 1: ≥ 38.0°C to 
≤ 38.4°C, 
or ≥ 100.4°F to ≤ 101.1°F 
Grade 1: A type of adverse 
event (AE) that is usually 
transient and may require 
only minimal treatment or 
therapeutic intervention. The 
event does not generally 
interfere with usual activities 
of daily living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
Grade 1: A type of AE that is 
usually transient and may 
require only minimal 
treatment or therapeutic 
intervention. The event does 
not generally interfere with 
usual activities of daily 
living. 
 
Grade 2: ≥ 38.5°C to 
≤ 38.9°C, 
or ≥ 101.2°F to ≤ 102.0°F 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant. 
Grade 2: A type of AE that is 
usually alleviated with 
additional therapeutic 
intervention. The event 
interferes with usual activities 
of daily living, causing 
discomfort but poses no 
significant or permanent risk 
of harm to the research 
participant.  
 
Grade 3: ≥ 39.0°C 
or ≥ 102.1°F 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention. 
Grade 3: A type of AE that 
interrupts usual activities of 
daily living, or significantly 
affects clinical status, or may 
require intensive therapeutic 
intervention 
*  For all reactions but fever, subjects will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the body temperature, and the classification as 
Grade 1, 2, or 3 will be assigned at the time of the statistical analysis based on the unit used to measure the temperature and the intensity scale. 
 
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 60 of 82
Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 60 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 61 of 81 
Important Notes for the Accurate Assessment of Temperature: 
Subjects are to measure body temperature once per day, preferably always at the same time. The 
optimal time for measurement is the evening, when body temperature is the highest. Temperature 
is also to be measured at the time of any apparent fever. The observed daily temperature and the 
route of measurement are to be recorded in the DC / memory aid, and the highest temperature will 
be recorded by the site in the CRB. The preferred route for this study is oral. Pre-vaccination 
temperature is also systematically collected by the investigator on the source document. Tympanic 
thermometers must not be used. 
9.2.1.3.3 
Unsolicited Adverse Events 
In addition to recording solicited reactions, subjects will be instructed to record any other medical 
events that may occur during the 28-day period after vaccination. Space will be provided in the 
DC for this purpose.  
Information on SAEs will be collected and assessed throughout the study, from inclusion until 6 
months after vaccination. Any SAE occurring at any time during the study will be reported by the 
Investigator in the CRB according to the completion instructions provided by the Sponsor; this 
includes checking the “Serious” box on the AE CRF and completing the appropriate Safety 
Complementary Information CRFs. All information concerning the SAE is to be reported either as 
part of the initial reporting or during follow-up reporting if relevant information became available 
later (eg, outcome, medical history, results of investigations, copy of hospitalization reports). 
See Section 10 for further details on SAE reporting. 
For each unsolicited AE (whether serious or non-serious), the following information is to be 
recorded: 
• Start and stop datesa  
• Intensity of the event: 
For measurable unsolicited AEs that are part of the list of solicited reactions, the size of the 
AE as well as the temperature for fever will be collected and analyzed based on the 
corresponding scale used for solicited reactions (see Table 9.1 and Table 9.2). 
All other unsolicited AEs will be classified according to the following intensity scale: 
• Grade 1: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• Grade 2: A type of AE that is usually alleviated with additional therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.  
                                                 
a  The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the study will be 
considered as ongoing at the end of the study. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 61 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 61 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 62 of 81 
• Grade 3: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
• Whether the AE was related to the investigational product (for unsolicited systemic AEs) 
The Investigator will assess the causal relationship between the AE and the investigational 
product as either “Not related” or “Related”, as described in Section 9.2.1.3.6. 
• Action taken for each AE (eg, medication) 
The action(s) taken by the subject to treat and/or manage any unsolicited AEs will be 
classified in the CRB using the following list (all applicable items should be checked): 
• None 
• Medication 
• Health care provider contact 
• Hospitalized 
• Whether the AE was serious 
For each SAE, the investigator will complete all seriousness criteria that apply (outcome, 
elapsed time, and relationship to study procedures) 
• Whether the AE caused study discontinuation 
9.2.1.3.4 
Medically-Attended Adverse Events 
Medically-attended adverse events will not be captured during this study. 
9.2.1.3.5 
Adverse Events of Special Interest 
An AESI is defined as event for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor must be done. AESIs will be captured as SAEs (ie, collected 
throughout the trial). AESIs include the following: 
• new onset of GBS 
• encephalitis / myelitis (including transverse myelitis) 
• Bell’s palsy 
• optic neuritis 
• brachial neuritis 
9.2.1.3.6 
Assessment of Causality  
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
the product administered as either not related or related, based on the following definitions: 
Not related – The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay 
between vaccination and the onset of the AE is incompatible with a causal relationship; or 
the AE started before the vaccination (screening phase, if applicable) 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 62 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 62 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 63 of 81 
Related – There is a “reasonable possibility” that the AE was caused by the product 
administered, meaning that there is evidence or arguments to suggest a causal relationship 
Note: By convention, all AEs reported at the injection site (whether solicited or unsolicited) and 
all solicited systemic AEs are considered to be related to the administered product and therefore 
are referred to as reactions and do not require the Investigator’s opinion on relatedness. 
Adverse events likely to be related to the product, whether serious or not, that persist at the end of 
the study will be followed up by the Investigator until their complete disappearance or the 
stabilization of the subject’s condition. The Investigator will inform the Sponsor of the date of 
final disappearance of the event or the date of “chronicity” establishment. 
9.2.2 
Immunogenicity 
9.2.2.1 
Immunogenicity Endpoints 
For subjects in each age group (60 to 64 years of age; 65 years of age and older) and for subjects 
in each vaccine group (QIV-HD; QIV-SD): 
• HAI Ab titers obtained on D0 and D28 
• Individual HAI titers ratio D28/D0 
• Subjects with titers ≥ 40 [1/dil] at D28 
• Seroconversion (titer < 10 [1/dil] at D0 and post-vaccination titer ≥ 40 [1/dil] at D28, or titer ≥ 
10 [1/dil] at D0 and a ≥ 4-fold increase in titer [1/dil] at D28) 
9.2.2.2 
Immunogenicity Assessment Methods 
The immunogenicity assessment methods for the secondary endpoints are the same as those 
presented in Section 9.1.2.2. 
9.2.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
9.3 
Observational Endpoints and Assessment Methods 
9.3.1 
Safety 
There are no observational objectives for safety. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 63 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 63 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 64 of 81 
9.3.2 
Immunogenicity 
9.3.2.1 
Immunogenicity Endpoints 
9.3.2.1.1 
Immunogenicity Assessment by Seroneutralization  
Neutralizing Ab titers for subjects in the observational subset will be measured for each influenza 
strain with the SN method.   
For each vaccine strain, the secondary immunogenicity endpoints are as follows: 
• Individual neutralization test (NT) Ab titer on D0 and D28  
• Individual NT Ab titer ratio (fold-rise in serum NT post-vaccination relative to D0) at D28  
• Subjects with NT Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28  
• Fold-rise in NT Ab titer [post/pre] ≥ 2 and ≥ 4 at D28  
• Detectable NT (NT Ab titer ≥ 10 [1/dil]) at D0 and D28 
9.3.2.1.2 
Immunogenicity Assessment by ELLA 
Anti-N1and -N2 titers for subjects in the observational subset will be measured for the 2 influenza 
A strains using ELLA.  
For each A strain, the secondary immunogenicity endpoints are as follows: 
• Individual ELLA Ab titer on D0 and D28  
• Individual ELLA Ab titer ratio (fold-rise in serum ELLA post-vaccination relative to D0) at 
D28  
• Subjects with ELLA Ab titers ≥ 20 (1/dil), ≥ 40 (1/dil), ≥ 80 (1/dil) at D28  
• Fold-rise in ELLA Ab titer [post/pre] ≥ 2 and ≥ 4 at D28  
• Detectable ELLA (ELLA Ab titer ≥ 10 [1/dil]) at D0 and D28 
9.3.2.2 
Immunogenicity Assessment Methods 
9.3.2.2.1 
Seroneutralization 
To support the observational objectives of this study, the virus SN method will be used to describe 
the immune response 28 days after vaccination in an observational subset. 
Influenza Virus Neutralization Test 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI responsibility.  
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 64 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 64 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 65 of 81 
This NT measures Abs directed against the viral neutralization epitopes of the influenza virus, 
which may be different from the hemagglutination epitopes, therefore, the NT titers may be 
different from the HAI titers. 
To measure NT, serially diluted, heat-inactivated human serum samples will be pre-incubated 
with a fixed amount of challenge virus prior to the addition of Madin-Darby canine kidney 
(MDCK) cells. After overnight incubation, the viral nucleoprotein production in infected MDCK 
cells is measured by enzyme-linked immunosorbent assay (ELISA), using monoclonal Ab 
specific to either influenza A nucleoprotein or influenza B nucleoprotein. Since serum 
neutralizing Abs to the influenza virus inhibits the viral infection of MDCK cells, the ELISA 
optical density results are inversely proportional to the titers of neutralizing Ab present in the 
serum. The LLOQ is set at the reciprocal of the lowest dilution used in the assay, ie, 10 (1/dil). 
Titers below this level are reported as < 10 (1/dil). Titers > 10240 (1/dil) are pre-diluted, retested, 
and the end titer is reported.  
9.3.2.2.2 
Enzyme-Linked Lectin Assay for the Measurement of Anti-Neuraminidase 
To also support the observational objectives of this study, the ELLA for the measurement of anti-
neuraminidase immune response in subjects in an observational subset. 
Enzyme-Linked Lectin Assay 
Assays will be performed by the Sponsor’s laboratory (GCI, Swiftwater, PA, USA) or at an 
external testing laboratory under GCI responsibility.  
The ELLA measures neuraminidase inhibiting Ab by quantifying enzymatic activity using peanut-
agglutinin (PNA) to bind to terminal galactose moieties that are exposed after enzymatic 
cleavage. 
Serum samples, quality control sera, and a determined amount of virus will be added into 
duplicate wells of a fetuin-coated 96-well plate and incubated overnight. The following day, 
peroxidase-conjugated PNA will be added to the washed plate and incubated, followed by 
washing and color development with o-Phenylenediamine dihydrochloride (OPD) substrate. The 
absence of color indicates inhibition of NA activity due to the presence of NA-specific inhibiting 
Abs. The titer of each determination will be the reciprocal of the last dilution with an optical 
density (OD) equal to or less than the midpoint between the mean OD of the virus only control 
wells and the mean OD of the background wells on each plate. The LLOQ is set at the reciprocal 
of the lowest dilution used in the assay, ie, 10 (1/dil). Titers below this level will be reported as < 
10 (1/dil). There is no defined upper limit of quantification (ULOQ) for the NA1 and NA2 
ELLAs. There are assay ranges which have upper bounds that are established during method 
qualification. Samples which result in titers greater than these upper bounds would be retested 
using an additional 1:8 pre-dilution to bring the titer into the assay range and then back calculated 
to account for the pre-dilution factor of 1:8. 
9.3.3 
Efficacy 
No clinical efficacy data will be obtained in the study. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 65 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 65 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 66 of 81 
10 Reporting of Serious Adverse Events  
To comply with current regulations on SAE reporting to health authorities, the Investigator must 
document all SAEs regardless of causal relationship, and notify the Sponsor and the Clinical 
Research Associate (CRA) within the notification timelines stated in the following sections. The 
Investigator will give access and provide the Sponsor and the CRA with all necessary information 
to allow the Sponsor to conduct a detailed analysis of the safety of the investigational product(s). 
It is the responsibility of the Investigator to request all necessary documentation (eg, medical 
records, discharge summary, physical autopsy report if performed) in order to provide 
comprehensive safety information. All relevant information must then be transcribed onto the AE 
CRF and the appropriate Safety Complementary Information CRFs. 
10.1 Initial Reporting by the Investigator 
Serious adverse events occurring during a subject’s participation in the study or experiment must 
be reported within 24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must 
be reported, even if the Investigator considers that it is not related to the vaccine. The investigator 
(licensed physician [Doctor of Medicine (MD) or Doctor of Osteopathic Medicine (DO)]) must 
validate the information entered on the AE CRF by completing the investigator validation form. 
The Investigator must indicate on the AE CRF that the event was serious and must complete the 
relevant SAE section of this form as well as the appropriate Safety Complementary Information 
CRFs. An e-mail alert will automatically be sent by the EDC system to the GPV mailbox, the 
CRA and the Clinical Team Leader (CTL) with relevant SAE information details. 
If the EDC system is unavailable, the site must notify the Sponsor, using the paper version of the 
CRB, as described in the Operating Guidelines. 
The Investigator must complete the paper copies of the AE CRF and of the appropriate Safety 
Complementary Information CRFs and send them to the Sponsor by one of the following means: 
• By fax, to the following number: +33 4 37 37 71 32 
• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: PV.outsourcing@sanofi.com 
• By express mail, to the following address 
Global PharmacoVigilance, Sanofi Pasteur SA 
14, Espace Henry Vallée 
69007 LYON, France 
When the EDC system becomes available, the Investigator must transcribe the information from 
the paper forms into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact the RMO. If the RMO cannot 
be reached, the Investigator may contact the Call Center as described in Section 5.3.  
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 66 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 66 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 67 of 81 
10.2 Follow-up Reporting by the Investigator 
The AE CRF completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (eg, outcome, precise 
description of medical history, results of the investigation). All relevant information must be 
included directly in the AE CRF and the appropriate Safety Complementary Information CRFs. 
An e-mail alert will be sent automatically to the GPV Department and to the CRA. Copies of 
documents (eg, medical records, discharge summary, autopsy) may be requested by the GPV 
Department. 
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
investigational product(s), other products (eg, a benefit vaccine), or to the experiment must also 
be reported as soon as possible. In such a case, the reporting procedure to be followed is identical 
to that described in Section 10.1. 
10.4 Assessment of Causality 
The causal relationship between the SAE and the product administered will be evaluated by the 
Investigator as described in Section 9.2.1.3.6. 
Following this, the Sponsor’s Global Safety Officer will also assess the causal relationship to the 
product, based on the available information and current medical knowledge. 
The causal relationship to study procedures will be also assessed in the CRB. 
The decision to modify or discontinue the study may be made after mutual agreement between the 
Sponsor and the Investigator(s). 
10.5 Reporting SAEs to Health Authorities and IECs / IRBs 
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO will notify the Investigators in writing of the occurrence of any reportable 
SAEs. The Investigators / Sponsor will be responsible for informing the IECs or IRBs that 
reviewed the study protocol. 
All unexpected and related SAEs submitted to competent authorities will be unblinded by the 
GPV Department through an internal system for reporting to health authorities as described in 
ICH E2A.  In this case, the information resulting from code-breaking (ie, the subject’s vaccine or 
group assignment) will be communicated to health authorities. To maintain the blind, this 
information will not be communicated to either the Investigator or the immediate team working 
on the study, except for the GPV representative. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 67 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 67 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 68 of 81 
11 Data Collection and Management 
11.1 Data Collection and CRB Completion 
Individual DCs, specifically designed for this study by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information as described 
in Section 9.2.1.3. These DCs will include prelisted terms and intensity scales (see Table 9.1 and 
Table 9.2) as well as areas for free text to capture additional safety information or other relevant 
details. Subjects will also be provided with rulers for measuring the size of injection site reactions, 
and with standard digital thermometers for measuring daily temperatures. To ensure consistency 
of reporting, the study sites will instruct subjects on how to correctly use these tools.  
The 6-month follow-up will be done by interviewing subjects either during a visit or over the 
telephone using a questionnaire to capture SAEs and AESIs, if applicable. A memory aid may be 
provided to the subjects at the preceding study visit to help them record information on events 
occurring between this visit and the 6-month follow-up. 
Relevant information will be transcribed into the AE CRF. Any SAEs captured during this 6-
month follow-up period will be reported and followed-up as per the normal process for reporting 
SAEs. 
At specified intervals, the Investigator or an authorized designee will interview the subjects to 
collect the information recorded in the DC, and will attempt to clarify anything that is incomplete 
or unclear. All clinical study information gathered by the study site will be reported electronically 
by the Investigator or authorized designee using a web-based CRB. (Any information that was not 
documented in the DC will first be captured in the source document and then reported 
electronically.) The CRB has been designed specifically for this study under the responsibility of 
the Sponsor, using a validated Electronic Records / Electronic Signature-compliant platform (21 
CFR Part 11). 
To ensure the correct and consistent completion of the CRBs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion instructions will be provided to assist with data entry during the course of the study. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in study personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any study personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry to track all modifications 
and ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRBs; must provide explanations for all missing information; and must sign the CRB using 
an e-signature. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 68 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 68 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 69 of 81 
11.2 Data Management 
Management of SAE and Pregnancy Data 
During the study, SAE data (reported on the AE, Death, and Safety Complementary Information 
CRFs) and pregnancy data (reported by the Investigator on ePregnancy Forms) will be integrated 
into the Sponsor’s centralized GPV database upon receipt of these forms and after a duplicate 
check. Each case will be assigned a case identification number. Each case will be assessed by the 
case management platform or its delegate before being reported to the relevant authorities as 
necessary. The assessment of related cases will be done in collaboration with the Global Safety 
Officer and the RMO. Follow-up information concerning a completed case will be entered into 
the GPV database, and a new version of the case will be created. 
The information from the GPV database cases will be reconciled with that in the clinical database. 
Management of Clinical and Laboratory Data 
Clinical data, defined as all data reported in the CRB, and laboratory data will be handled by the 
Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
During the study, clinical data reported in the CRBs will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and / or consistency checks will be 
systematically applied to detect errors or omissions. In addition, data reviews may be performed 
several times by the Sponsor’s staff in the course of the study. Any questions pertaining to the 
reported clinical data will be submitted to the investigator for resolution using the EDC system. 
Each step of this process will be monitored through the implementation of individual passwords 
to maintain appropriate database access and to ensure database integrity. 
The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical Datawarehouse. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
11.3 Data Review 
A blind review of the data is anticipated through the data review process led by Data Management 
before database lock.  
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 69 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 69 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 70 of 81 
12 Statistical Methods and Determination of Sample Size 
12.1 Statistical Methods 
Clinical database data will be analyzed under the responsibility of the Biostatistics Platform of the 
Sponsor, US, with the Statistical Analysis System (SAS) software, at least version 9.4 (SAS 
Institute, Cary, North Carolina, USA). 
A statistical analysis plan (SAP) will be written and peer reviewed before any analyses are 
performed. In accordance with the protocol, the SAP will describe all analyses to be performed by 
the Sponsor and all the conventions to be taken. 
For the purposes of the statistical methods section, the 4 virus strains in the QIV-HD trial groups 
and the QIV-SD trial groups will be labeled as follows: 
• A/(H1N1)-like strain 
 
 
A1 
• A/(H3N2)-like strain 
 
 
A2 
• B/(Victoria Lineage)-like strain  
B1 
• B/(Yamagata Lineage)-like strain 
B2 
12.1.1 Hypotheses and Statistical Methods for Primary Objective 
12.1.1.1 Immunogenicity 
12.1.1.1.1 Hypotheses 
A superiority approach will be used to compare post-vaccination GMTs between QIV-HD and 
QIV-SD groups for each strain and in each age group using a 1-sided test with Type I error rate of 
0.025 following the individual hypotheses: 
 
where  
s: strain 
If superiority is demonstrated for post-vaccination GMTs for the 4 strains within a same age 
group, then the immunogenicity of QIV-HD will be considered as superior to QIV-SD in the 
corresponding age group. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 70 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 70 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 71 of 81 
12.1.1.1.2 Statistical Methods 
The statistical methodology will be based on the use of the lower bound of the 2 sided 95% 
confidence intervals (CIs) of the ratio of post-vaccination GMTs between the QIV-HD and 
QIV-SD groups. The CIs will be calculated by normal approximation of log-transformed titers for 
GMTs. 
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives 
12.1.2.1 Immunogenicity 
12.1.2.1.1 Hypotheses 
No hypotheses will be tested. 
12.1.2.1.2 Statistical Methods 
Immunogenicity endpoints will be summarized by age group, in pooled age groups, and by 
vaccine group with 95% CIs. The CIs of geometric mean (GM) of titers and individual titer ratios 
will be calculated assuming normal approximation of log-transformed values. CIs of proportions 
will be calculated using the Clopper-Pearson method. Reverse cumulative distribution curves 
against each strain will be performed for each time point. Additional parameters may be displayed 
as appropriate. 
12.1.2.2 Safety 
12.1.2.2.1 Hypotheses 
No hypotheses will be tested. 
12.1.2.2.2 Statistical Methods 
Safety endpoints will be summarized by age group, in pooled age groups, and by vaccine group, 
with 95% CI for the main endpoints. The CIs will be calculated using the Clopper-Pearson 
method. 
12.1.3 Statistical Methods for Observational Objectives 
The analyses will be descriptive. The main parameters will be described by age group, in pooled 
age groups, and by vaccine group with 95% CI. 
12.2 Analysis Sets 
Three main analysis sets will be used: the Per-Protocol Analysis Set (PPAS), the Full Analysis Set 
(FAS), and the safety analysis set (SafAS). 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 71 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 71 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 72 of 81 
12.2.1 Full Analysis Set 
The FAS is defined as the subset of randomized subjects who received one dose of the study 
vaccine and had a post-vaccination blood sample.  
For the assessment of the immune response by virus SN and ELLA method, the analysis will be 
performed on the subjects from the FAS randomized into the respective observational subsets 
(FAS-SN subset and FAS-NA subset). The FAS-NA subset is a subset of the FAS-SN subset.  
12.2.2 Safety Analysis Set 
The SafAS is defined as those subjects who have received one dose of the study vaccine and have 
any safety data available. All subjects will have their safety analyzed according to the vaccine 
they actually received. 
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
12.2.3 Per-Protocol Analysis Set 
The PPAS is a subset of the FAS. The subjects presenting with at least one of the following 
relevant protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria  
• Subject did not receive vaccine 
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• Subject did not receive vaccine in the proper time window 
• Subject did not provide the post-dose serology sample at Visit 2 in the proper time window 
(ie, 28 to 35 days after vaccination) or a post-dose serology sample was not drawn at Visit 2 
• Subject received medications impacting or that may have an impact on the immune response 
(Category 2 or 3) 
The above protocol deviations leading to exclusion from the PPAS may be detailed and 
completed if necessary in the SAP, following the review of protocol deviations during the study 
conduct. In any case, the PPAS definition will be finalized before the first database lock. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 72 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 72 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 73 of 81 
12.2.4 Populations Used in Analyses 
All subjects with data in the CRB will be taken into account in the description of the population 
(eg, the disposition, the demographic or baseline characteristics).  
All immunogenicity analyses from HAI method for primary and secondary objectives will be 
performed on both FAS and PPAS.  
The safety analyses will be performed on the SafAS.  
The observational objective analyses will be performed on subsets of the FAS (FAS-SN and 
FAS-NA subsets). 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No replacement will be done. Nevertheless, a missing relationship will be considered as related at 
the time of statistical analysis. Details will be described in the SAP. 
12.3.2 Immunogenicity 
Missing data will not be imputed. No test or search for outliers will be performed. 
12.3.3 Efficacy 
Missing data will not be imputed. No test or search for outliers will be performed. 
12.4 Interim / Preliminary Analysis 
No formal interim analyses are planned.  
The statistical analysis will be performed in at least 2 steps: 
• First analysis on immunogenicity and safety results obtained on data collected within the 
28 days following the vaccination (from D0 to D28). The study blind will be broken at that 
time. 
• Second analysis after the 6-month data have been collected.  
A limited statistical analysis of the safety and immunogenicity data obtained up to D 28 will be 
conducted once data are available and an interim database lock has been conducted. A final 
analysis will be conducted once the 6-month safety data have been collected and the final 
database lock has occurred. No statistical adjustment is necessary because there are no repeat 
analyses of the same parameter. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 73 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 73 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 74 of 81 
12.5 Determination of Sample Size and Power Calculation 
A total of approximately 1540 adults 60 years of age and older (770 adults 60 to 64 years of age 
and 770 adults 65 years of age and older) will be enrolled. This sample size is determined per 
simulations based on an overall power of 90% for demonstrating the primary objective. The 
thresholds for superiority are defined as 1 for GMTs. No alpha adjustment is needed. Other 
assumptions are listed as follows: 
• Allocation ratio: 1:1 (QIV-HD versus QIV-SD) 
• GMT ratio: 1.5 for all strains 
• Standard deviations of log10-transformed titers in QIV-SD group of 0.6 for 2 strains and 
0.5 for the other 2 strains 
• Attrition rate: 5% in FAS 
It should be noted that the power per strain is 97.7% when the standard deviation is 0.6 and 99.7% 
when the standard deviation is 0.5. 
An arbitrary number of subjects, ie, at least 50% of subjects in each age group and each vaccine 
group will be randomly assigned to the observational subset of subjects for SN testing and at least 
50 subjects in each age group and each vaccine group for NA testing as shown in Table 12.1. 
Table 12.1: Random assignment of subjects to observational subsets 
Vaccine/Assay 
Number of subjects 60 
to 64 years of age 
Number of subjects 65 
years of age and older 
Total 
QIV-HD Group/SN 
≥193 
≥193 
≥386 
QIV-SD Group/SN 
≥193 
≥193 
≥386 
QIV-HD Group/NA 
≥50 
≥50 
≥100 
QIV-SD Group/NA 
≥50 
≥50 
≥100 
13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Study / Good Clinical Practice 
The conduct of this study will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 74 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 74 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 75 of 81 
13.2 Source Data and Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, DCs, medical and hospital 
records, screening logs, informed consent / assent forms, telephone contact logs, and worksheets. 
The purpose of study source documents is to document the existence of subjects and to 
substantiate the integrity of the study data collected. Investigators must maintain source 
documents so that they are accurate, complete, legible, and up to date. 
For missing or discrepant data on a DC, the study coordinator will obtain verbal clarification from 
the subject, enter the response into the “investigator’s comment” page of the DC, and transfer the 
information to the CRB. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the study, regardless of the outcome. 
The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
by the Sponsor or an inspector against the electronic records. Any subsequent changes of an 
electronic record require the record to be re-printed, dated (with an indication of the date of 
change), and signed. Such records must also be kept together with the original printed copy. 
Good Documentation Practice should be followed by the Investigator and the site staff managing 
source documents. 
13.3 Confidentiality of Data, Data Protection, and Access to Subject Records 
Prior to initiation of the study, the Investigator will sign a fully executed confidentiality 
agreement with Sanofi Pasteur. 
In the event a subject’s medical records are not at the investigational site, it is the responsibility of 
the investigator to obtain those records if needed. 
All personal data collected related to subjects, investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). Data 
collected must be adequate, relevant and not excessive, in relation to the purposes for which they 
are collected. Each category of data must be properly justified and in line with the study objective. 
The race of the subjects will be collected in this study because these data are required by 
regulatory agencies (eg, on the African American population for the Food and Drug 
Administration [FDA] in the US or on the Japanese population for the Pharmaceuticals and 
Medical Devices Agency [PMDA] in Japan). 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 75 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 75 of 82

Sanofi Pasteur 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
Confidential/Proprietary Information 
Page 76 of 81 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets that 
are transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical record may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the subjects, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to these data by 
any unauthorized third party. 
13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring 
Before the start of the study (ie, before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the study protocol and the detailed study procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRB completion, and the handling of samples and products. The Sponsor’s 
staff or a representative will ensure and document that all material to be used during the study has 
been received at the site; and that the study investigator team and local Sponsor/delegate staff 
have been properly informed about the study, GCP and regulatory requirements, and the 
Sponsor’s procedures. Specific training sessions for the study investigator team and the CRAs on 
these topics may be performed as necessary, and should be documented. 
The following instruction manuals will be provided: the CRF Completion Instructions for entering 
data into the CRB (available online in the EDC system), and the Operating Guidelines for detailed 
study procedures such as the product management and sample-handling procedures. 
After the start of the study, the Sponsor’s staff or a representative will be in regular contact with 
the investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits, and must allow the Sponsor/delegate staff direct access 
to subject medical files and CRBs. During these visits, the Sponsor/delegate staff will: 
•
Evaluate the quality of the study progress (adherence to protocol and any study-specific
guidelines, quality of data collection and document completion, signature of consent forms,
occurrence of SAEs, sample and product management, cold chain monitoring, archiving)
•
Source-verify completed CRBs and any corresponding answered queries
•
Determine the number of complete or ongoing issues identified at monitoring visits (eg,
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator,
and corrective or preventive actions will be determined, as appropriate.
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 76 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 76 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 77 of 81 
• After all protocol procedures have been completed and the data have been entered into the 
CRB, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the study, a close-out visit will be performed to ensure that: 
• The center has all the documents necessary for archiving 
• All samples have been shipped to the appropriate laboratories 
• All unused materials and products have been either destroyed or returned to the Sponsor 
13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical Quality 
Assessment department (CQA) or by independent auditors to verify that the study has been 
conducted according to the protocol, GCP and ICH requirements, and other applicable 
regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to study documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator and the study site shall retain and preserve 1 copy of the Study File containing 
the essential documents related to the study and records generated during the study (“Study File”) 
for the longer of the 2 following periods (“Retention Period”): 
• 25 years after the signature of the final study report or  
• such longer period as required by applicable regulatory requirements 
If during the Retention Period, the study site is no longer able to retain the Study File due to 
exceptional circumstances (such as bankruptcy), the study site shall contact the Sponsor to 
organize the transfer of the Study File to the Sponsor’s designee at the Sponsor’s expense. 
Following the Retention Period, the Investigator and/or the study site are responsible to dispose of 
the Study File according to the applicable regulations. Patient medical records shall be retained in 
compliance with local regulations. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the study will be kept by the Sponsor in the Trial Master File (TMF). Data 
on AEs are included in the TMF. All data and documents will be made available if requested by 
relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
A Clinical Trial Agreement will be signed by all the parties involved in the study’s performance, 
if relevant. The Sponsor has an insurance policy to cover any liabilities that may arise from use of 
the product and / or the study protocol. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 77 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 77 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 78 of 81 
13.6 Stipends for Participation 
Subjects may be provided with a stipend according to local practice to compensate for the time 
and travel required for trial visits and procedures. 
13.7 Publication Policy 
Data derived from this study are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the study must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the study, any participating center may 
publish or otherwise use its own data provided that any publication of data from the study gives 
recognition to the study group. In addition, Sanofi Pasteur shall be offered an association with all 
such publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this study at least 90 days prior to submission for publication / 
presentation. Any information identified by Sanofi Pasteur as confidential must be deleted prior to 
submission, it being understood that the results of this study are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 78 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 78 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 79 of 81 
14 Reference List 
 
1 
Belshe RB, Coelingh K, Ambrose CS, Woo JC, Wu X. Efficacy of live attenuated influenza 
vaccine in children against influenza B viruses by lineage and antigenic similarity. Vaccine. 
2010:28(9):2149-56 
2 
Glezen WP, Schmier JK, Kuehn CM, Ryan KJ, Oxford J. The burden of influenza B: a 
structured literature review. Am J Public Health. 2013:013(3):e43-51. 
3 
Centers for Disease Control and Prevention. Licensure of a high-dose inactivated influenza 
vaccine for persons aged 65 years and older (Fluzone High-Dose) and guidance for use - 
United States, 2010. MMWR. 2010;59(16):485-6. 
4 
Caini S, Huang QS, Ciblak MA, Kusznierz G, Owen R, Wangchuk S, et al. Epidemiological 
and virological characteristics of influenza B: results of the global influenza B study. IORV. 
2015;Suppl 1:3-12. 
5 
Ambrose CS, Levin MJ. The rationale for quadrivalent influenza vaccines. Human Vaccin 
& Immunother. 2012;8(1):81-8. 
6 
Van der Werf S, Levy-Bruhl D. Influenza - the need to stay ahead of the virus. Euro 
Surveill. 2015;20(5):1-4. 
7 
Heikkinen T, Ikonen N, Ziegler T. Impact of influenza B lineage-level mismatch between 
trivalent seasonal influenza vaccines and circulating viruses. 1999-2012. Clin Infect Dis. 
2014;59(11):1519-24. 
8 
Mereckiene J, Cotter S, Nicoll A, Lopalco P, Noori T, Weber J T et al. Seasonal influenza 
immunization in Europe. Overview of recommendations and vaccination coverage for three 
seasons: pre-pandemic (2008/09), pandemic (2009/10) and post-pandemic (2010/11). Euro 
Surveill. 2014;19(16):20780. 
9 
WHO. Influenza (seasonal). Fact sheet. [homepage on the internet]. 6 November 2018. 
[cited on 20 March 2019]. Available from: http://www.who.int/news-room/fact-
sheets/detail/influenza-(seasonal). 
10 
Lee VJ, Yap J, Ong JB, Chan KP, Lin RT, Chan SP et al. Influenza excess mortality from 
1950-2000 in tropical Singapore. PLoS One. 2009;4(12):e8096. 
11 
Eurosurveillance. Volume 23, Issue 13, Mar 2018. Available at: 
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2018.23.13.18-00146. 
12 
Simonsen L, Fukuda K, Schonberger LB, Cox NJ. The impact of influenza epidemics on 
hospitalizations. J Infect Dis. 2000;181:831-7. 
13 
Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality 
associated with influenza and respiratory syncytial virus in the United States. JAMA. 
2003;289(2):179-86. 
14 
Petola V, Ziegler T, Ruuskanen O. Influenza A and B virus infections in children. Clin 
Infect Dis. 2003;36:299-305. 
15 
Hite LK, Glezen WP, Demmler GJ. Munoz FM. Medically attended pediatric influenza 
during the resurgence of the Victoria lineage of influenza B virus. Int J Infect Dis. 
2007;11:40-7. 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 79 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 79 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 80 of 81 
16 
Greenberg DP, Robertson CA, Noss MJ, Blatter MM, Biedenbender R, Decker MD. Safety 
and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed 
trivalent inactivated influenza vaccines in adults. Vaccine. 2013;31(5):770-6. 
17 
Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind 
controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose 
influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172-80. 
18 
DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, et al. Efficacy 
of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 
2014;371(7):635-45. 
19 
Izurieta, Thadani N, Shay DK, Lu Y, Maurer A, Foppa IM, et al. Comparative effectiveness 
of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and 
older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect 
Dis 2015;15(3):293-300. 
20 
Shay DK, Chillarige Y, Kelman J, Forshee RA, Foppa IM, Wernecke M, et al. Comparative 
effectiveness of high-dose versus standard-dose influenza vaccines among US Medicare 
beneficiaries in preventing post influenza deaths during 2012-2013 and 2013-2014. JID 
2017;215:510-7. 
21 
Richardson DM, Medvedeva EL, Roberts CB, Linkin DR. Comparative effectiveness of 
high-dose versus standard-dose influenza vaccination in community-dwelling veterans.  
Clin Infect Dis. 2015;61(2):171-6. 
22 
Young-Xu Y, van Aalst R, Mahmud SM, Rothman KJ, Snider JT, Westreich D, et al. 
Relative vaccine effectiveness of high-dose versus standard-dose influenza vaccines among 
veterans health administration patients. J Infect Dis. 2018;217(11):1718-27. 
23 
Fluzone High-Dose prescribing information. Swiftwater, Pennsylvania, USA, Sanofi 
Pasteur Inc. June 2018. 
24 
European Centre for Disease Prevention and Control. Seasonal influenza vaccination in 
Europe. Vaccination recommendations and coverage rates in the EU Member States for 
eight influenza seasons: 2007-2008 to 2014-2015. Stockholm: ECDC; 2017. 
 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 80 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 80 of 82

Sanofi Pasteur 
 
QHD00011 
522 – High-Dose Quadrivalent Influenza Vaccine 
Protocol Version 2.0 
 
 
Confidential/Proprietary Information 
Page 81 of 81 
15 Signature Page 
Sanofi Pasteur 
Confidential/Proprietary Information 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 81 of 82
Sanofi Pasteur 
 
Confidential/Proprietary Information 
     
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 81 of 82

Sanofi Pasteur 
 
 
Confidential/Proprietary Information 
               
 
QHD00011
Protocol Version 2.0
522 – High-Dose Quadrivalent Influenza Vaccine
Page 82 of 82