A Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived Quadrivalent VLP Influenza Vaccine in Adults 65 Years of Age and Older
Phase: PHASE3
Conditions: Virus Diseases, RNA Virus Infections, Respiratory Tract Diseases, Respiratory Tract Infections
Sponsor: Medicago

 
 
Confidential Information 
Information in this protocol is confidential and should not be disclosed, other than to those directly involved in the 
execution or the ethical review of the study, without written authorization from Medicago R&D Inc. (herein after 
known as “Medicago”), and its affiliates. This study will be conducted in accordance with applicable Good Clinical 
Practice (GCP) guidelines, the United States Code of Federal Regulations (CFR), and International Conference on 
Harmonization (ICH) guidelines. 
 
Clinical Protocol 
A Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 
Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived 
Quadrivalent VLP Influenza Vaccine in Adults 65 Years of Age and Older 
 
CP-PRO-QVLP-014; Phase 3 
 
Plant-derived Quadrivalent VLP Influenza Vaccine 
 
Name of Sponsor: 
Medicago R&D Inc. 
1020 route de l’Église, bureau 600 
Québec (QC), Canada G1V 3V9 
 
 
 
 
 
 
 
 
Status: 
Final version 1.2 
 
 
Date: 
July 24th, 2018 
 
 
 

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COORDINATING INVESTIGATOR SIGNATURE 
Study Title: 
A Randomized, Observer-blind, Active Comparator-controlled, 
Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and 
Immunogenicity of a Plant-derived Quadrivalent VLP Influenza Vaccine 
in Adults 65 Years of Age and Older 
 
I have read the version 1.2 (dated July 24th, 2018) Protocol No. CP-PRO-QVLP-014 titled, “A 
Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 Study to 
Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived Quadrivalent VLP Influenza 
Vaccine in Adults 65 Years of Age and Older”. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative and I agree to accept the responsibility to act as Coordinating 
Investigator for this study. 
 
Coordinating Investigator: 
 
 
Signature 
 
 
 
 
Date (YYYY-MM-DD) 
 
 
 

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INVESTIGATOR AGREEMENT 
I have read the version 1.2 (dated July 24th, 2018) Protocol No. CP-PRO-QVLP-014 titled, “A 
Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 Study to 
Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived Quadrivalent VLP Influenza 
Vaccine in Adults 65 Years of Age and Older”. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the ethical review of the study, without 
prior written authorization from Medicago. It is, however, permissible to discuss information 
contained in this protocol with a subject in order to obtain consent once institutional review 
board (IRB) approval is obtained. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation (ICH) guidelines, Good Clinical 
Practice (GCP), Investigational New Drug (IND) regulations, and other applicable regulatory 
requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate this study at any 
time for whatever reason and that such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study, I will communicate my 
intention immediately in writing to the Sponsor. 
Principal Investigator: 
Name (typed or 
printed): 
 
Institution and 
Address: 
 
 
 
 
 
Telephone Number: 
 
 
Signature 
 
Date (YYYY-MM-DD) 
 
Note: If the address or the telephone number of the Investigator changes during the course of 
the study, written notification will be provided by the Investigator to the Sponsor, and a 
protocol amendment will not be required. 
 

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TABLE OF CONTENTS 
SIGNATURES ................................................................................................................................ 2 
COORDINATING INVESTIGATOR SIGNATURE .................................................................... 3 
INVESTIGATOR AGREEMENT.................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF TABLES .......................................................................................................................... 9 
SYNOPSIS .................................................................................................................................... 10 
ABBREVIATIONS ...................................................................................................................... 24 
1 
INTRODUCTION ................................................................................................................. 26 
1.1 
Quadrivalent VLP Influenza Vaccine ............................................................................ 27 
1.2 
Pre-clinical Studies ......................................................................................................... 27 
1.3 
Clinical Studies .............................................................................................................. 28 
1.3.1 
Clinical Safety Overview ........................................................................................ 29 
1.3.2 
Immunogenicity Overview ..................................................................................... 30 
1.4 
Overall Rationale for the Study ...................................................................................... 31 
2 
OBJECTIVES ........................................................................................................................ 32 
2.1 
Primary Objectives ......................................................................................................... 32 
2.2 
Secondary Objectives ..................................................................................................... 32 
2.3 
Exploratory Objectives ................................................................................................... 33 
3 
STUDY ADMINISTRATIVE STRUCTURE ...................................................................... 34 
4 
STUDY DESIGN AND RATIONALE ................................................................................. 34 
4.1 
Overview of Study Design ............................................................................................. 34 
4.2 
Rationale of Study Design.............................................................................................. 37 
4.2.1 
Randomization ........................................................................................................ 37 
4.2.2 
Observer-blinding ................................................................................................... 37 
4.2.3 
Age Group Stratification ......................................................................................... 37 
4.2.4 
Dose Selection ........................................................................................................ 37 
4.2.5 
Active Comparator Selection .................................................................................. 37 
4.2.6 
Study Duration ........................................................................................................ 37 
4.2.7 
Efficacy Assessments.............................................................................................. 37 
5 
STUDY POPULATION ........................................................................................................ 38 
5.1 
Inclusion Criteria ............................................................................................................ 38 

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5.2 
Exclusion Criteria ........................................................................................................... 38 
5.3 
Prior and Concomitant Therapy ..................................................................................... 40 
5.4 
Prohibited Therapy ......................................................................................................... 41 
6 
TREATMENT ALLOCATION AND BLINDING .............................................................. 41 
6.1 
Randomization ............................................................................................................... 41 
6.2 
Blinding .......................................................................................................................... 42 
7 
DOSAGE AND ADMINISTRATION .................................................................................. 42 
8 
SPECIMENS AND CLINICAL SUPPLIES ......................................................................... 43 
8.1 
Management of Samples ................................................................................................ 43 
8.2 
Clinical Supplies ............................................................................................................ 43 
9 
TREATMENT COMPLIANCE ............................................................................................ 43 
10 STUDY EVALUATIONS ..................................................................................................... 43 
10.1 Study Procedures ............................................................................................................ 43 
10.1.1 
Overview ................................................................................................................. 43 
10.1.2 
Screening/Vaccination (Visit 1) .............................................................................. 44 
10.1.3 
Day 1 and Day 8 (Telephone Contact) ................................................................... 47 
10.1.4 
Surveillance for Respiratory Illness ........................................................................ 48 
10.1.5 
Day 21 ..................................................................................................................... 50 
10.1.6 
End of Surveillance (Telephone Contact) ............................................................... 51 
10.2 Efficacy .......................................................................................................................... 51 
10.2.1 
Efficacy Evaluations ............................................................................................... 51 
10.2.2 
Efficacy Endpoints .................................................................................................. 53 
10.3 Safety .............................................................................................................................. 54 
10.3.1 
Evaluations .............................................................................................................. 54 
10.3.2 
Safety Endpoints ..................................................................................................... 56 
10.4 Immunogenicity ............................................................................................................. 57 
10.4.1 
Immunogenicity Evaluations .................................................................................. 57 
10.4.2 
Immunogenicity Endpoints ..................................................................................... 57 
11 SUBJECT COMPLETION/WITHDRAWAL ...................................................................... 58 
11.1 Temporary Contraindications ......................................................................................... 58 
11.2 Screening Failures .......................................................................................................... 58 
11.3 Removal of Subjects from Treatment or Assessment .................................................... 59 

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11.3.1 
Follow-up of Discontinuations ............................................................................... 59 
11.3.2 
Lost to Follow-up Procedures ................................................................................. 59 
11.4 Interruption of the Study ................................................................................................ 59 
12 STATISTICAL METHODS.................................................................................................. 60 
12.1 Analysis Populations ...................................................................................................... 60 
12.1.1 
Safety Analysis Set ................................................................................................. 60 
12.1.2 
Full Analysis Set ..................................................................................................... 60 
12.1.3 
Per Protocol Set....................................................................................................... 60 
12.2 Sample Size Determination ............................................................................................ 61 
12.3 Efficacy Analyses ........................................................................................................... 61 
12.3.1 
Analysis of Primary Endpoint ................................................................................. 61 
12.3.2 
Analysis of Secondary Endpoints ........................................................................... 62 
12.3.3 
Analysis of Exploratory Endpoints ......................................................................... 62 
12.4 Baseline and Subject Disposition ................................................................................... 63 
12.5 Safety Analyses .............................................................................................................. 63 
12.5.1 
Analysis of Secondary Endpoints ........................................................................... 63 
12.5.2 
Analysis of Exploratory Endpoint .......................................................................... 63 
12.6 Immunogenicity Analyses .............................................................................................. 64 
12.6.1 
Analysis of Secondary Endpoints ........................................................................... 64 
12.6.2 
Analysis of Exploratory Endpoint .......................................................................... 64 
13 ADVERSE EVENT REPORTING ....................................................................................... 64 
13.1 Definitions ...................................................................................................................... 65 
13.1.1 
Serious Adverse Events .......................................................................................... 65 
13.1.2 
Adverse Events ....................................................................................................... 65 
13.1.3 
Adverse Events of Special Interest ......................................................................... 66 
13.1.4 
New Onset of Chronic Disease ............................................................................... 67 
13.1.5 
Expectedness of an Adverse Drug Reaction ........................................................... 67 
13.1.6 
Initial SAE Reporting by the Investigator .............................................................. 67 
13.1.7 
Follow-up Reporting by the Investigator ................................................................ 68 
13.1.8 
Reporting of SAEs Occurring after Surveillance Period or Study Termination ..... 68 
13.1.9 
Causal Relationship ................................................................................................ 68 
13.1.10 Reporting of SAEs to Health Authorities and IRB ................................................. 69 

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14 INVESTIGATIONAL PRODUCT INFORMATION .......................................................... 69 
14.1 Identity of Investigational Product ................................................................................. 69 
14.1.1 
Study Vaccine Composition ................................................................................... 69 
14.2 Active Comparator ......................................................................................................... 70 
14.3 Preparation and Administration of Study Vaccine ......................................................... 70 
14.4 Preparation, Handling, Storage, and Precautions for Use .............................................. 71 
14.5 Packaging ....................................................................................................................... 71 
14.6 Labeling .......................................................................................................................... 71 
14.7 Drug Accountability ....................................................................................................... 71 
15 STUDY-SPECIFIC MATERIALS........................................................................................ 72 
16 ETHICAL ASPECTS ............................................................................................................ 72 
16.1 Study-Specific Design Considerations ........................................................................... 72 
16.2 Regulatory Ethics Compliance ....................................................................................... 72 
16.2.1 
Investigator Responsibilities ................................................................................... 72 
16.2.2 
Independent Ethics Committee or Institutional Review Board .............................. 73 
16.2.3 
Informed Consent.................................................................................................... 74 
16.2.4 
Privacy of Personal Data ......................................................................................... 74 
17 ADMINISTRATIVE REQUIREMENTS ............................................................................. 75 
17.1 Protocol Amendments .................................................................................................... 75 
17.2 Regulatory Documentation ............................................................................................ 75 
17.2.1 
Regulatory Approval/Notification .......................................................................... 75 
17.3 Source Documentation ................................................................................................... 75 
17.3.1 
Diary and Memory Aid ........................................................................................... 76 
17.4 Case Report Form Completion ....................................................................................... 76 
17.5 Quality Control (Study Monitoring) .............................................................................. 77 
17.6 Quality Assurance .......................................................................................................... 77 
17.7 Record Retention ............................................................................................................ 77 
17.8 Study Completion/Termination ...................................................................................... 78 
17.8.1 
Study Completion ................................................................................................... 78 
17.8.2 
Study Termination .................................................................................................. 78 
17.9 Registration of Clinical Studies and Disclosure of Results............................................ 78 
18 REFERENCES ...................................................................................................................... 79 

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19 APPENDICES ....................................................................................................................... 80 
19.1 Appendix 1 – Sample Ruler to Measure Local Reactions ............................................. 80 
19.2 Appendix 2 – Burden of Disease Questionnaire ............................................................ 81 
19.3 Appendix 3 – Subject Diary and Memory Aid Sample Pages ....................................... 83 
 
LIST OF TABLES 
Table 1 Time and Events Schedule: General Information ............................................................ 21 
Table 2 Time and Events Schedule: Respiratory Illness Onset .................................................... 23 
Table 3 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent 
Influenza VLP Vaccine ..................................................................................................... 28 
Table 4 Study Administrative Structure ....................................................................................... 34 
Table 5 Estimated Blood Volume Drawn ..................................................................................... 44 
Table 6 Severity Grades for Solicited Local and Systemic Reactions .......................................... 55 
 
 
 

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SYNOPSIS 
Sponsor: 
Medicago R&D Inc. 
Investigational Product: 
Plant-derived Quadrivalent VLP Influenza Vaccine 
(Quadrivalent VLP Influenza Vaccine) 
Active Substance(s): 
Mix of recombinant H1, H3, and two B hemagglutinin proteins 
expressed as virus-like particles (VLPs) 
Control Product: 
Active comparator: Fluarix® Tetra (also named Fluarix® 
Quadrivalent) and/or FluLaval® Tetra ( also named FluLaval® 
Quadrivalent) (both produced and/or distributed by 
GlaxoSmithKline Inc.); 2018-2019 influenza virus strains 
Protocol Title: 
A Randomized, Observer-blind, Active Comparator-controlled, 
Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and 
Immunogenicity of a Plant-derived Quadrivalent VLP Influenza 
Vaccine in Adults 65 Years of Age and Older 
Protocol Number: 
CP-PRO-QVLP-014 
Development Phase: 
Phase 3 
Study Center(s): 
The study will be conducted at multiples sites in several 
countries. 
Study Rationale: 
The elderly population (65 years of age and older) is at an 
increased risk of complications due to seasonal influenza 
infection. This population generally has a poor humoral 
response to immunization and, due to the combined humoral and 
cell-mediated immune (CMI) response induced by the 
Quadrivalent VLP Influenza Vaccine, it is anticipated that this 
vaccine can provide greater protection in the elderly. This Phase 
3 study is intended to assess the efficacy of the Quadrivalent 
VLP Influenza Vaccine in elderly adults with no acute or 
evolving medical problems and to support the use of the vaccine 
in the elderly population. 
Planned Study Period: 
Screening and vaccination will start in August or September, 
2018. A follow up call will be performed at the end of the 
surveillance period, approximately the end of April 2019 (the 
duration of surveillance period may be adjusted, based on the 
observed epidemiology during the season in participating 
countries). 
Throughout the influenza season, the number of RT-PCR 

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confirmed influenza cases will be reviewed periodically by a 
team who will be independent of study conduct and analysis. In 
the event of an insufficient attack rate of confirmed influenza 
(minimum of 198 cases), the study will be either continued or 
extended into another season to enrol more subjects and a 
protocol amendment will be issued to address changes to the 
enrolment plan.  
Study Objectives 
  Primary Objective: 
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, against protocol-defined influenza-like illness (ILI) 
caused by any RT-PCR-confirmed influenza case. 
  Secondary Objectives: 
Efficacy: 
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, against laboratory-confirmed protocol-defined 
influenza-like illness (ILI) caused by vaccine-matched strains 
based on sequential RT-PCR and antigenic characterization 
for confirmation of vaccine matched and mismatched flu 
cases; 
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, against protocol-defined respiratory illness caused 
by vaccine-matched strains based on sequential RT-PCR and 
antigenic characterization for confirmation of vaccine 
matched and mismatched flu cases ; 
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, against RT-PCR-confirmed protocol-defined 
respiratory illness caused by any influenza viral case.  
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine , as measured by the incidence of subjects presenting 
with symptoms of protocol-defined ILI, regardless of 
laboratory results. 
Safety: 
• To assess the safety and tolerability, relative to an active 
comparator, of a single 30 µg/strain dose of the Quadrivalent 
VLP Influenza Vaccine. 
Immunogenicity: 
• To assess, in a subset of 420 subjects (210 subjects per 
treatment group), the immunogenicity of a single 30 µg/strain 
dose of Quadrivalent VLP Influenza Vaccine and of an active 

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comparator, as measured by hemagglutination inhibition (HI) 
assay, microneutralization (MN) assay, and single radial 
hemolysis (SRH) assay against homologous and heterologous 
(HI only) influenza strains. 
The immunogenicity endpoints for all four homologous 
influenza antigens (HI serology) will be compared between 
groups using descriptive statistics.  
  Exploratory Objectives: 
Efficacy: 
• To evaluate the efficacy, relative to an active comparator, of a 
single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, against protocol-defined respiratory illness due to 
mismatched influenza strains based on sequential RT-PCR 
and antigenic characterization for confirmation of vaccine 
matched and mismatched flu cases; 
• To determine the efficacy, relative to an active comparator, of 
a single 30 µg/strain dose of the Quadrivalent VLP Influenza 
Vaccine, as measured by the incidence of subjects presenting 
with symptoms of protocol-defined respiratory illness, 
regardless of laboratory results. 
Safety: 
• To evaluate respiratory illness outcome, occurrences of 
pneumonia, new onset or exacerbations of cardio-respiratory 
conditions, and health care utilization of subjects administered 
the Quadrivalent VLP Influenza Vaccine at a dose of 
30 µg/strain relative to subjects administered an active 
comparator. 
Immunogenicity: 
• To assess the CMI response against homologous and 
heterologous strains of a single 30 µg/strain dose of 
Quadrivalent VLP Influenza Vaccine and of an active 
comparator on Days 0 and 21 in a subset of 420 subjects 
(same subset as the immunogenicity subset; 210 subjects per 
treatment group). 
Number of Planned 
Subjects: 
Approximately 12,120 subjects are planned for randomization in 
a 1:1 ratio to receive the Quadrivalent VLP Influenza Vaccine at 
a dose of 30 µg/strain or the active comparator. Prior to 
randomization into the two treatment groups, subjects will be 
stratified by age into two groups (65 to 74 years of age and 75 
years of age and older) and enrolled in a 2:1 ratio. 
Sample Size 
The sample size of approximately 12,120 subjects (6060 

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Determination: 
subjects per treatment group) was selected to have 80 % power 
to determine non-inferiority, based on the assumption of 20 % 
vaccine efficacy (VE), a 2 % or greater influenza attack rate in 
the active comparator (ARVC) for protocol-defined ILI due to 
RT-PCR-confirmed influenza caused by any viral type/subtype 
and a 10 % dropout rate. Non-inferiority will be concluded if the 
lower bound of the two-sided 95 % confidence interval (CI) is 
greater than -20 %. 
Please note that the sample size of 12,120 subjects will also 
provide sufficient power (over 80 %) for the secondary endpoint 
(protocol-defined respiratory illness caused by any influenza 
viral type/subtype). 
In the event of an insufficient attack rate of confirmed influenza 
(minimum of 198 cases), the study will be either continued or 
extended into another season to enrol more subjects and a 
protocol amendment will be issued to address changes to the 
enrolment plan.   
Study Population: 
Non-institutionalized male and female subjects 65 years of age 
and older, with no acute or evolving medical problems and with 
no clinically significant disease at the time of vaccination, will 
be included in this study. 
Dosage and 
Administration: 
On Day 0, subjects will receive one intramuscular (IM) injection 
into the deltoid region of the arm of 0.5 mL of 30 µg/strain of 
the Quadrivalent VLP Influenza Vaccine or 0.5 mL of the  
15 µg/strain of the Quadrivalent comparator vaccine (eg: 
Fluarix Tetra/Quadrivalent/® and/or FluLaval® 
Tetra/Quadrivalent). 
Study Design: 
This is a randomized, observer-blind, active comparator-
controlled, multicenter, Phase 3 efficacy study. 
The influenza strain composition of the vaccines used in this 
study will be based on the recommended World Health 
Organization (WHO) strains for vaccination in the 2018-2019 
season in the northern hemisphere. 
Subjects will participate in this study for approximately eight to 
ten months, during which a first visit will be scheduled on Day 0 
for screening and vaccine administration. A phone contact will 
be made on Days 1 and 8, specifically for review of the subject’s 
safety and concomitant medication data. A visit to the 
investigator site will occur on Day 21 for immunogenicity 
assessments (CMI, HI, MN, and SRH) for a subset of 420 
subjects from pre-defined sites in North America (210 subjects 

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per treatment group). A final phone contact will be made at the 
end of the study (approximately the end of April 2019) for a 
safety assessment. 
Active and passive surveillance will be conducted in the study 
from Day 14 until approximately the end of April 2019 (end of 
the surveillance period). For passive surveillance, subjects will 
be instructed to report symptoms meeting the definition of a new 
or worsening respiratory illness and ILI. For active surveillance, 
subjects will be contacted at least once per week and asked 
about symptoms of a new or worsening respiratory illness and 
ILI. The frequency of active surveillance contacts will vary 
slightly with region: 
• North America and Europe: Prior to the start of the influenza 
season (the start of influenza season will be determined by 
Medicago through local epidemiology and clinical 
experience), subjects will be contacted at least once per week, 
using the contact method most likely to be successful 
(e.g. subject's preferred method [phone, text, e-mail]). During 
the influenza season, subjects will be contacted a minimum of 
two times per week; at least one of these weekly contacts will 
be through a scripted telephone call, with the remaining 
contacts via the method most likely to be successful; 
• Asia: Since there generally is no clearly defined influenza 
season, contacts will be made a minimum of two times per 
week, with at least one of these weekly contacts through a 
scripted telephone call, with the remaining contacts via the 
method most likely to be successful (e.g. subject's preferred 
method [phone, text, e-mail]).  
Efficacy Evaluations: 
Following randomization and vaccination, subjects will report 
respiratory symptoms from Day 14 until the end of the study 
(through active or passive surveillance). Respiratory illness will 
be defined as the occurrence of a new onset of one or more of 
the following symptoms that persist(s) for or reoccur(s) after a 
period of at least 12 hours: 
• Sneezing; 
• Stuffy or runny nose (nasal congestion); 
• Sore throat; 
• Cough; 
• Sputum production; 
• Wheezing; 
• Difficulty breathing. 
The site will collect nasopharyngeal (NP) swabs (two per 

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subject per event) for any subject who reports any respiratory 
illness under the following conditions: 
• North America and Europe: only after the start of influenza 
season (as determined by Medicago through local 
epidemiology and clinical experience); 
• Asia: after the start of active and passive surveillance (Day 14 
and onwards). 
The swabs will be collected within 36 hours (preferably within 
24 hours) of the reporting of a respiratory illness. If swabs 
cannot be collected within 36 hours after reporting of the 
respiratory symptoms, NP swabs should still be collected if the 
subject still has at least one respiratory illness symptom. 
A swab will be submitted for analysis by multiplex reverse 
transcription polymerase chain reaction (RT-PCR). If the RT-
PCR result is positive, additional testing will be done (influenza 
virus culture, sero-subtyping, detailed antigenic characterization, 
and vaccine match analysis of the isolates). 
Any respiratory illness must be followed up for 30 days 
following the start date (through the planned active surveillance 
contacts), using a phone script. At the end of the 30-day follow-
up, subjects will complete a disease burden questionnaire 
(Section 19.2); subjects will be provided with a memory aid 
(Section 19.3) that they can use during the 30 days to facilitate 
accurate reporting. 
Some degree of site investigator discretion will be permitted in 
defining new episodes (e.g. a non-productive cough and fatigue 
persisting for ten days from one episode, with a new onset of 
myalgia, headache, and sore throat would constitute the onset of 
a valid new episode). 
ILI will also be monitored during the study, but the presence of 
a respiratory illness symptom as described above will be the 
trigger for swab collection. A subject will be considered to have 
ILI if he/she meets the protocol-defined ILI (≥ 14 days post-
vaccination) conditions: 
• At least one of the following respiratory symptoms: 
• 
Sore throat; 
• 
Cough; 
• 
Sputum production; 
• 
Wheezing; 
• 
Difficulty breathing; 

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AND  
• At least one of the following systemic symptoms: 
• 
Fever (defined as temperature > 99.0 °F or > 37.2 °C); 
• 
Chills; 
• 
Tiredness; 
• 
Headache; 
• 
Myalgia. 
The subjects will also be given a memory aid listing the 
symptoms of respiratory illness and systemic symptoms and 
contact information for the study site. 
Safety Evaluations: 
Safety and tolerability endpoints will include immediate 
complaints (15 minutes post-vaccination), solicited local and 
systemic reactions (up to seven days post-vaccination), 
treatment-emergent adverse events (TEAEs) up to Day 21, and 
serious adverse events (SAEs), adverse events (AEs) leading to 
withdrawal, and new onset of chronic diseases (NOCDs) up to 
the end of the surveillance period. A questionnaire will be 
completed for subjects with respiratory illness regarding disease 
burden.  
Immunogenicity 
Evaluations: 
Immunogenicity will be evaluated by the immune response 
induced in a subset of 420 subjects (210 from each of the two 
treatment groups) as measured by the serum HI, MN, and SRH 
antibody titers on Day 0 and Day 21. The number of subjects in 
each age group (65 to 74 years of age and 75 years of age and 
older) included in the immunogenicity analyses will be similar 
in proportion to that of the overall study. 
A blood sample for exploratory CMI analyses will be collected 
on Days 0 and 21 for a subset of 420 subjects (the same subset 
as for HI, MN, and SRH analysis). 
The North American sites selected for immunogenicity sample 
collection for this subset of 420 subjects will be pre-defined 
prior to study start and will target providing a representative age 
distribution. 
Primary Endpoint: 
Efficacy: 
Vaccine efficacy (VE), as calculated below in Statistical 
Methods, determined by differences between subjects who 
received the Quadrivalent VLP Influenza Vaccine or the active 
comparator vaccine In the occurrences of protocol-defined ILI 
due to RT-PCR-confirmed influenza (≥ 14 days post-

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vaccination) caused by any influenza virus.  
Secondary Endpoints: 
Efficacy:  
As above: differences between subjects who received the 
Quadrivalent VLP Influenza Vaccine or the active comparator 
vaccine in the occurrence of: 
• RT-PCR-confirmed influenza illnesses (according to protocol 
defined ILI; ≥ 14 days post-vaccination) caused by influenza 
viral types/subtypes that are matched (and/or antigenically 
similar) to the strains covered in the vaccine formulation; 
• RT-PCR-confirmed influenza illnesses (according to protocol 
defined respiratory illness; ≥ 14 days post-vaccination) caused 
by any influenza viral types/subtypes (matched, mismatched, 
and un-typed); 
• RT-PCR-confirmed influenza illnesses (according to protocol 
defined respiratory illness; ≥ 14 days post-vaccination) caused 
by influenza viral types/subtypes that are matched (and/or 
antigenically similar) to the strains covered in the vaccine 
formulation; 
• protocol-defined ILI ≥ 14 days post-vaccination (confirmed or 
not by laboratory testing). 
Safety: 
• Percentage, intensity, and relationship to vaccination of 
immediate complaints (15 minutes post-vaccination); 
• Percentage, intensity, and relationship to vaccination of 
solicited local and systemic signs and symptoms (for seven 
days following study vaccine administration); 
• Percentage, intensity, and relationship of TEAEs for 21 days 
following study vaccine administration; 
• Occurrences of deaths, SAEs, AEs leading to withdrawal, and 
NOCDs up to the end of the surveillance period. 
Immunogenicity (subset of subjects): 
• HI antibody response induced against the homologous and 
heterologous influenza strains on Days 0 and 21 will be 
assessed in a subset of 420 subjects (210 from each of the two 
treatment groups). HI antibody titers will be analyzed using 
the following parameters: geometric mean titer (GMT), 
seroconversion (SC) rate, seroprotection (SP) rate, and 
geometric mean fold rise (GMFR). The immunogenicity 
endpoints for all four homologous influenza antigens in the 
VLP vaccine will be compared between groups using 
descriptive statistics; 

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• MN antibody response induced by the Quadrivalent VLP 
Influenza Vaccine against the homologous influenza strains 
on Days 0 and 21, in a subset of subjects, will be analyzed 
using the following parameters: GMT, SC rate, and GMFR; 
• SRH antibody response induced by the Quadrivalent VLP 
Influenza Vaccine against the homologous strains on Days 0 
and 21, in a subset of subjects, will be analysed using the 
following parameters: geometric mean area (GMA), SC rate, 
SP rate, and GMFR. 
Exploratory Endpoints: 
Efficacy: 
As above: differences between subjects who received the 
Quadrivalent VLP Influenza Vaccine or the active comparator 
vaccine in the occurrence of: 
• RT-PCR-confirmed influenza illnesses (according to protocol 
defined respiratory illness; ≥ 14 days post-vaccination) caused 
by mismatched influenza viral strains; 
• respiratory illnesses ≥ 14 days post-vaccination (confirmed or 
not by laboratory testing). 
Safety: 
• Information on respiratory illness outcome, occurrences of 
pneumonia, new onset or exacerbations of cardio-respiratory 
conditions, and health care utilization during the entire trial 
follow up period. 
Immunogenicity (subset of subjects): 
• CMI response induced by the Quadrivalent VLP Influenza 
Vaccine against homologous and heterologous strains on Day 
21 (subset of 420 subjects), as measured by the number of 
CD4+ T cells expressing each of three functional markers: 
interferon gamma (IFN-γ), interleukin-2 (IL-2), and tumor 
necrosis factor alpha (TNF-α), as well the number of cells 
producing at least one of these cytokines and the number of 
cells producing two or more of these cytokines. 
Statistical Methods: 
Populations: 
Statistical analyses will be performed on pre-defined population 
sets (the safety analysis set [SAS], the full analysis set [FAS], 
and the per protocol [PP] set) according to the statistical analysis 
plan (SAP). 
The analyses of all efficacy endpoints will be performed using 
the PP set and the FAS. The analysis in the PP set will be 
considered the primary analysis for these objectives. 

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All safety analyses will be performed using the SAS. 
The immunogenicity analyses will be performed using a subset 
of the PP set that includes only subjects with valid 
immunogenicity samples collected within the specified time 
window. 
 
Statistical Analyses: 
In general, categorical data will be summarized using the 
number and percent of subjects in each category and continuous 
data will be summarized using descriptive statistics (mean or 
geometric mean, median, SD, minimum, and maximum). 
Immunogenicity endpoints will also be compared between the 
VLP vaccine group and the active comparator group. 
Efficacy Analyses: 
For the primary endpoint, VE will be evaluated as the relative 
risk of subjects vaccinated with a VLP vaccine (30 µg/strain) 
or an active comparator to develop protocol-defined ILI ≥14 
days after vaccination caused by any RT-PCR-confirmed 
influenza strain.  
 
• VE will be calculated using the following formula: 
VE=(1-ARVV/ARVC)*100 % 
Where: 
ARVV = attack rate in subjects vaccinated with the 
Quadrivalent VLP Influenza Vaccine; and 
ARVC = attack rate in subjects vaccinated with an active 
comparator. 
Non-inferiority will be concluded if the lower limit of the two-
sided 95 % CI for relative VE is > -20 % for the primary 
endpoint. If non-inferiority is demonstrated, VE of the VLP 
vaccine will be tested for superiority over the active comparator 
as an exploratory analysis (VE for superiority testing will use 
the same definitions as in the primary endpoint). Superiority will 
be concluded if the lower limit of the two-sided 95 % CI for 
relative VE is > 9 % for the primary endpoint. 
VE will also be calculated for the secondary and exploratory 
objectives, using other definitions. Non-inferiority will be tested 
using the same criterion as with the primary endpoint; 
superiority testing will be conducted if non-inferiority is 
concluded (the same criterion as with the primary endpoint will 

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be used for superiority testing). 
Safety Analyses: 
Safety endpoints will be tabulated, listed, and compared with the 
active comparator group using descriptive statistics. 
Immunogenicity Analyses: 
For the immunogenicity analyses, point estimates and two-sided 
95 % CI for serologic and cellular outcomes against homologous 
and heterologous strains will be calculated and responses in the 
Quadrivalent VLP Influenza Vaccine and active comparator 
vaccine groups will be compared using descriptive statistics. 
 
 

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ABBREVIATIONS 
AE 
adverse event 
ARVC 
attack rate in subjects vaccinated with an active comparator 
ARVV 
attack rate in subjects vaccinated subjects with the Quadrivalent 
VLP Influenza Vaccine 
BMI 
body mass index 
BP 
blood pressure 
CBER 
Center for Biologics Evaluation and Research 
CI 
confidence interval 
CMI 
cell-mediated immune (response) 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMA 
geometric mean area 
GMFR 
geometric mean fold rise or seroconversion factor 
GMT 
geometric mean titer 
HI 
hemagglutination inhibition 
HR 
heart rate 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ILI 
influenza-like illness 
IM 
intramuscular 
IEC 
independent ethics committee 
IRB 
institutional review board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
microneutralization 
NOCD 
new onset of chronic disease 
OT 
oral temperature 
PBMC 
peripheral blood mononuclear cell 
PP 
per protocol 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SAS® 
Statistical Analysis System® 
SC 
seroconversion 
SP 
seroprotection 

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SRH 
single radial hemolysis 
TEAE 
treatment-emergent adverse event 
VE 
vaccine efficacy 
VLP 
virus-like particle 
WHO 
World Health Organization 
USA 
United States 
 
 
 

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1 
INTRODUCTION 
Seasonal influenza is a potentially serious infection associated with a wide range of clinical 
outcomes across the entire human lifespan. The influenza virus genome is an eight-segment 
single-stranded RNA with high potential for in situ recombination and mutations for host 
adaptation. Two segments code for the hemagglutinin and neuraminidase antigens that play an 
essential role in virus infectivity. At present, 17 hemagglutinin and ten neuraminidase subtypes 
are known in bird populations and some subtypes routinely circulate in humans, such as the 
H1N1, H3N2, and B influenza viruses. When a new subtype acquires the capacity for human-to-
human transmission, this can give rise to a major pandemic like the one caused by an H1N1 
strain in 1918 referred to as the Spanish flu. Antibodies that bind to the hemagglutinin molecule 
can prevent or modify infection and are the basis on which influenza vaccines are formulated 
every year. 
Despite continuing advances in understanding of the immune response to natural infection and 
immunization, the disease remains a major cause of morbidity and mortality worldwide. The 
elderly (≥ 65 years) are considered to be among the highest at risk, with recent estimates of 
seasonal flu-related hospitalizations and deaths of 54 % to 70 % and 71 % to 85 %, respectively, 
in this population (CDC, 2017). In the United States (USA) alone, influenza is responsible for 
approximately 36,000 deaths per year and the World Health Organization (WHO) estimates that 
influenza causes three to five million cases of severe illness and 250,000 to 500,000 deaths per 
year (Palache, 2011). Influenza is also responsible for a massive economic burden, with a total 
cost for each winter influenza season estimated at over 87 billion dollars (Molinari et al., 2007) 
in the USA alone. 
The main strategy for prevention and control of seasonal and pandemic influenza is still 
vaccination. In 2012, the Advisory Committee on Immunization Practices issued the first 
recommendation of national universal seasonal influenza vaccination (Osterholm et al., 2012). 
Licensure of influenza vaccines is based either on efficacy studies or on surrogate correlates of 
protection. The latter are primarily based on their ability to induce hemagglutination inhibition 
(HI) titers. Despite the existence of these surrogate correlates of protection, recent reviews and 
meta-analyses suggest that the overall efficacy of licensed trivalent vaccines is highly variable 
and depends, among other factors, on the ‘match’ between circulating strains and the strains used 
for vaccine production. One such analysis produced efficacy estimates from 43 % to 89 % in 
well-matched seasons and from 38 % to 85 % in poorly-matched seasons (< 25 % of isolates 
matched the vaccine strains) (DiazGranados et al., 2012), suggesting that there is still great room 
for improvement. 
The elderly population is particularly problematic with respect to vaccine efficacy (VE). In the 
elderly, the traditionally measured humoral immune response due to immunization may not be 
representative of VE (McElhaney, 2011), but may confer some degree of protection; a 
retrospective review found that immunization with a well-matched vaccine may provide minimal 
protection against influenza, but may result in a significant improvement with respect to seasonal 
flu-related hospital admissions and complications (Jefferson et al., 2005). 

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For the 2012-2013 influenza season, VE numbers were particularly discouraging. When 
stratified by age group, the overall VE against influenza A and B viruses ranged from 27 % in 
persons 65 and older to 64 % in children (six months to 17 years of age). When specific strains 
and age groups were examined (e.g. H3N2 in the elderly), efficacy estimates could be as low as 
9 % (95 % confidence interval [CI]: -84 % to 55 %). Preliminary efficacy estimates for the H3N2 
strain in the early 2014-2015 influenza season were even lower: hovering at or even below 0 % 
due to a significant mismatch between vaccine and circulating strains (Skowronski et al., 2015). 
In the on-going 2017-2018 influenza season, we are again experiencing a low VE due to 
problems with currently-available vaccines; this time due to the fact that vaccine-strain viruses 
often carry mutations that occur during growth in eggs (Zost et al., 2017). 
1.1 
Quadrivalent VLP Influenza Vaccine 
Medicago R&D Inc. has developed a plant-derived system (Nicotiana benthamiana) for transient 
expression of two type A and two type B influenza strains to produce the Quadrivalent VLP 
Influenza Vaccine intended for active immunization for the prevention of influenza disease 
caused by the influenza A subtype viruses and type B virus strains covered in the vaccine. This 
vaccine may be able to address some limitations of the currently licensed vaccines: 
• The hemagglutinin proteins in each monovalent virus-like particle (VLP) is based on the 
genetic sequence of circulating human influenza viruses selected by the WHO; in contrast, 
influenza strains grown in embryonic eggs or tissue culture tend to mutate for optimal 
growth in these substrates; 
• Medicago’s clinical trial program has revealed that plant-derived VLP vaccines induce 
long-lasting and cross-reactive T cell responses that could be pivotal for protection against 
both matched and diverse influenza strains, particularly in the elderly who often derive 
significant benefit from vaccination despite little evidence of a humoral response 
(McElhaney, 2011). 
Nicotiana benthamiana is a non-transgenic plant that is a distant wild relative from Australia of 
the tobacco plant, Nicotiana tabacum. The transfer vector used to move targeted DNA constructs 
into the plant cells is the bacterium Agrobacterium tumefaciens. This vector then directs the 
expression of the protein(s) of interest, in this case the hemagglutinin protein. The hemagglutinin 
proteins are assembled into trimers in the intracellular secretory pathway, aligned at the plant 
plasma membrane via a transmembrane domain, and finally bud out of the plant plasma 
membrane in the form of VLPs. Thus, the viral hemagglutinin proteins are anchored in a lipid 
bilayer of plant cell origin. The VLPs accumulate in the space between the plasma membrane 
and plant cell wall. 
1.2 
Pre-clinical Studies 
Medicago has conducted several preclinical studies in rats with monovalent, trivalent, and 
quadrivalent formulations. All strains included in the quadrivalent vaccine are immunogenic at 
doses ranging from 0.001 to 10 μg in the rat model. 

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No pre-clinical findings have been observed that would suggest the Quadrivalent VLP Influenza 
Vaccine could represent an important risk to human health. Based on pre-clinical results, the 
anticipated benefits from vaccination with the Quadrivalent VLP Influenza Vaccine outweigh the 
risk. For more comprehensive preclinical information regarding the safety and toxicity of the 
Quadrivalent VLP Influenza Vaccine, refer to the current investigator’s brochure (IB). 
1.3 
Clinical Studies 
Under the clinical development program for the Quadrivalent VLP Influenza Vaccine, Medicago 
has completed five clinical trials to date (CP-Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, 
CP-Q14VLP-009, and CP-Q14VLP-010) and has two trials that are considered to be ongoing 
(CP-PRO-QVLP-011 [clinical portion complete; statistical analyses and report pending] and CP-
PRO-QVLP-012). Study designs and statuses are summarized in Table 3. 
Table 3 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent 
Influenza VLP Vaccine 
Study / Status 
Phase Design 
Population 
N 
Treatment groups 
CP-Q12VLP-004 / 
Completed 
1-2 
Single-center, observer-
blind, randomized, 
dose-ranging, placebo-
controlled study 
Healthy adults 18 to 
49 years of age, 
both genders 
90 (VLP; ratio 
1:1:1); 
30 (placebo) 
3 μg VLP; 
9 μg VLP; 
15 μg VLP; 
placebo 
CP-Q13VLP-007 / 
Completed 
2a 
Multicenter, observer-
blind, randomized, 
dose-ranging, placebo-
controlled study 
Healthy adults 18 to 
49 years of age, 
both genders 
225 (VLP; ratio 
1:1:1); 
75 (placebo) 
15 µg VLP; 
30 µg VLP; 
60 µg VLP; 
placebo 
CP-Q13VLP-008 / 
Completed 
2 
Multicenter, observer-
blind, randomized, 
dose-ranging, placebo-
controlled study  
Healthy subjects of 
50 years of age or 
older, both genders 
375 (VLP; ratio 
1:1:1:1:1); 
75 (placebo) 
15 µg VLP; 
30 µg VLP; 
60 µg VLP; 
7.5 µg VLP + Alhydrogel®; 
15 µg VLP + Alhydrogel®; 
placebo 
CP-Q14VLP-009 / 
Completed 
2 
Multicenter, observer-
blind, randomized, dose 
ranging, active-
comparator clinical 
study 
Healthy adults of 18 
to 64 years of age, 
both genders 
604 (VLP; ratio 
1:1); 
296 (active 
comparator) 
15 µg VLP; 
30 µg VLP; 
15 µg/strain dose of 
FluLaval® Tetra 
CP-Q14VLP-010 / 
Completed 
2 
Multicenter, observer-
blind, randomized, dose 
ranging, active-
comparator clinical 
study 
Healthy subjects of 
65 years of age or 
older, both genders 
499 (VLP; ratio 
1:1); 
250 (active 
comparator 1) 
252 (active 
comparator 2) 
30 µg VLP; 
60 µg VLP; 
15 µg/strain dose of 
FluLaval® Tetra; 
60 µg/strain dose of 
Fluzone® High Dose 
CP-PRO-QVLP-011 / 
Ongoing 
3 
Multicenter, observer-
blind, randomized, lot 
consistency study 
Healthy adults of 18 
to 49 years of age, 
both genders 
1200 (VLP; 1:1:1 
ratio to one of 
three lots) 
30 µg VLP (three lots) 
CP-PRO-QVLP-012 / 
Ongoing 
3 
Multicenter, observer-
blind, randomized, 
placebo-controlled 
efficacy study 
Healthy adults of 18 
to 64 years of age, 
both genders 
~5000 (VLP); 
~5000 (placebo) 
30 µg VLP; 
placebo 

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In the five completed studies, a total of 1793 healthy subjects have received a single dose of the 
Quadrivalent Influenza VLP vaccine: 1106 subjects from 18 to 64 years of age and 687 subjects 
65 years of age and older. Approximately 6200 subjects have received the VLP vaccine 
(30 µg/strain) in the two ongoing studies. 
An overview of the available safety and immunogenicity findings from these studies are 
summarized in Section 1.3.1 and Section 1.3.2, respectively. For detailed information on these 
findings, please refer to the current version of the IB. 
1.3.1 Clinical Safety Overview 
This section summarizes the safety data obtained from the five clinical trials performed to date 
(CP Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, CP Q14VLP-009, and CP-Q14VLP-
010); see Table 3 for a description of the basic design of these studies, status, and exposure. No 
deaths were reported for either the adults (N = 1106) or the elderly subjects (N = 687) 
administered the Quadrivalent VLP Influenza Vaccine in the five completed studies. In one of 
the ongoing clinical trials (CP-PRO-QVLP-012), two deaths (cervical spine fracture and lung 
mass) have been reported; both were considered to be not related to the study vaccine. Since the 
study is still blinded, the treatment group (30 µg/strain VLP vaccine or placebo) is not available 
at this time. 
In the five completed trials, a total of 21 serious adverse events (SAEs) were reported for 
subjects who received the Quadrivalent VLP Influenza Vaccine: 18 for subjects who received a 
single dose of non-adjuvanted VLP vaccine (all dose levels combined, N = 1642) and three for 
subjects who received a single dose of adjuvanted VLP vaccine (both dose levels combined, 
N = 151). None were considered by the Investigator to be vaccine-related. No subject withdrew 
from any of the studies due to a treatment-emergent adverse event (TEAE) and none of the new 
onset of chronic diseases (NOCDs) reported for subjects who received the VLP vaccine were 
considered to be vaccine-related. In the two ongoing trials, no vaccine-related SAEs have been 
reported to date. 
The incidence of local and systemic reactions observed within seven days post-vaccination in the 
five completed studies was consistent with the known safety profile for commercial influenza 
vaccines. The most frequently reported unsolicited TEAEs included nasopharyngitis, upper 
respiratory tract infection, aspartate aminotransferase increased (minor increase), headache, and 
oropharyngeal pain; no notable differences in the incidence of these events were observed 
between the VLP groups and the active comparators or placebo groups. No safety issues and no 
notable trends were observed with respect to vital signs, clinical laboratory, or physical 
examinations in any of the five studies conducted. 
As a precaution, subjects were monitored for TEAEs with a hypersensitivity component 
(reported events were searched using both narrow and broad standardized Medical Dictionary for 
Regulatory Activities (MedDRA®) queries for a possible hypersensitivity component). Based on 
the data from the five studies conducted to date, there is no evidence of anaphylactic reactions 
associated with use of the Quadrivalent VLP Influenza Vaccine in humans: a small number of 
subjects had potential hypersensitivity reactions judged to be related to vaccine administration 

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(no more than 0.3 % of subjects in any given VLP treatment group experienced one of these 
events) and the events were distributed fairly evenly among treatment groups, including the 
placebo and the active comparator groups. However, since severe reactions are considered to be 
an important potential risk (based on the theoretical risk that using plants for the production of 
biotherapeutics may induce hypersensitivity) the sponsor will continue to require that appropriate 
medical treatment and supervision are available to manage any possible anaphylactic reactions. 
Safety results from the five clinical trials performed to date show that the Quadrivalent VLP 
Influenza Vaccine was well-tolerated, with a safety profile similar to that of the active 
comparators and to the placebo for systemic reactions and TEAEs. 
1.3.2 Immunogenicity Overview 
This section summarizes the immunogenicity data obtained from the five studies conducted to 
date with adult (up to 64 years of age) and/or elderly (65 years of age and older) populations. 
Studies CP-Q12VLP-004, CP-Q13VLP-007, and CP-Q14VLP-009 were conducted in an adult-
only population (18 to 49 years for the first two studies and 18 to 64 years for CP-Q14VLP-009), 
CP-Q13VLP-008 was conducted in a combined adult and elderly population (50 years and 
older), and CP-Q14VLP 010 was conducted in an elderly-only population (65 years of age and 
older). See Table 3 for a description of the basic design of these studies and exposure. 
1.3.2.1 Antibody Response 
Overall, the immunogenicity data from the studies conducted to date show that the Quadrivalent 
Influenza VLP Vaccine induced a strong antibody response in healthy adults (18 to 64 years); in 
the elderly, the humoral response appeared lower than in adults (for the VLP as well as the active 
comparator used in both adult and elderly studies). The 30 μg/strain dose level appeared to be the 
lowest dose to be the most consistent in meeting the Center for Biologics Evaluation and 
Research (CBER) criteria in the adult (18 to 64 years of age population) and the lowest dose to 
be the most comparable with the commercial licensed vaccines. As a result, the 30 μg/strain dose 
level has been selected for evaluation during this Phase 3 efficacy study to be conducted in an 
elderly population. 
A summary of the Day 21 HI response data for the 30 μg/strain dose level is presented below: 
• In the combined immunogenicity results of the CP-Q13VLP-007 (all subjects) and 
CP-Q13VLP-008 (50 to 64 years old strata), the 30 μg/strain VLP dose level met the CBER 
criteria for both seroconversion (SC) rate and seroprotection (SP) rate against all four 
homologous strains (the sample size of elderly subjects in study CP-Q13VLP-008 was too 
small to allow a thorough evaluation); 
• In study CP-Q14VLP-009, conducted in adults from 18 to 64 years of age, the 30 μg/strain 
VLP vaccine met the CBER criteria for both SC rate and SP rate against all four 
homologous strains tested; 
• In study CP-Q14VLP-010, conducted in elderly subjects 65 years of age and older, the 
humoral response observed was weaker than that observed with the adult population, with  

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the 30 μg/strain VLP vaccine meeting the CBER SP rate criterion against H1N1 and H3N2 
and the CBER SC rate criterion against only H3N2. However, in this study, none of the 
treatment groups, including FluLaval® Tetra and Fluzone® HD, met the CBER criteria for 
SC rate for all of the homologous strains included in the respective vaccines. 
For all of these studies, the HI response may have been underestimated due to the limited 
availability of assay reagents unaffected by the use of eggs for production (even when cell-based 
reagents are available, their history often includes an initial expansion in embryonic-eggs). These 
reagents often include mutations of glycosylation site loss in the receptor binding domain, which, 
in turn can affect the assay results, particularly for the B strains. In consequence, the ability of 
the VLP vaccine to elicit an HI response against the B strains may have been underestimated. 
Further assessment of the humoral immune response induced by the VLP vaccine included 
microneutralization (MN) and single radial hemolysis (SRH) assays, conducted in a subset of 
subjects. For both assays, the VLP vaccine showed notable Day 0 to Day 21 increases in 
geometric mean titer (GMT) against all four of the homologous strains and the overall pattern of 
responses confirms the 30 μg/strain dose selected for this Phase 3 study. 
In addition to the results above, HI and MN data from the studies conducted to date show that the 
Quadrivalent VLP Influenza Vaccine also elicits some cross-reactive antibodies against 
heterologous influenza strains (current IB version). 
1.3.2.2 Cell-mediated Immune Response 
In order to further define immune response induced by the VLP vaccine, the cell-mediated 
immune (CMI) response was measured in a small subset of subjects in the five studies. In spite 
of the small sample sizes, a clear and consistent vaccine-related Day 21 poly-functional CD4+ 
T cell response was observed with the VLP vaccine against all four homologous strains in all 
studies and in both the adult and elderly populations. With advancing age, these T cell responses 
were generally much better maintained than antibody responses. Overall, the 30 μg/strain dose 
level showed the highest response of the VLP vaccines; in contrast, an active comparator 
(FluLaval® Tetra) showed a lesser response against the H1N1 and H3N2 strains. The response 
against the two B strains was similar among treatments. Further, the CMI response induced by 
the VLP vaccines appeared to be both durable (up to Day 201) and cross-reactive. 
1.4 
Overall Rationale for the Study 
The elderly population (65 years of age and older) is at an increased risk of complications due to 
seasonal influenza infection. This population generally has a poor humoral response to 
immunization and, due to the combined humoral and cell-mediated immune response induced by 
the Quadrivalent VLP Influenza Vaccine, it is hoped that this vaccine can provide greater 
protection in the elderly. This study is intended to assess the efficacy of the Quadrivalent VLP 
Influenza Vaccine in non-institutionalized elderly adults with no acute or evolving medical 
problems and to support the licensure of the vaccine in the elderly population. 

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1.5 
Benefits and Risk Assessment 
No non-clinical findings suggesting that the administration of the Quadrivalent VLP Influenza 
Vaccine could represent an important risk to human health have been observed.  Based on non-
clinical results, the anticipated benefits from vaccination with the Quadrivalent VLP Influenza 
Vaccine outweigh the risks.   
During the Phase 3 study CP-PRO-QVLP-014, blood samples will be collected from a subset of 
subjects for humoral immunogenicity analysis.  Since blood sample collection is a minimally 
invasive procedure and the amount of blood collected will be a relatively small amount, the 
benefits of obtaining this data outweigh the small level of risk associated with the collection of 
samples that may not require analysis. 
The balance between the anticipated benefits from vaccination with the Quadrivalent VLP 
Influenza Vaccine versus the potential risk appears favorable, based on the cumulative clinical 
safety data.  Indeed, the Quadrivalent VLP Influenza Vaccine was shown to have a safety profile 
similar to that of commercially available influenza vaccines, and the immunogenicity data shows 
that the vaccine induces a robust (humoral and cell-mediated) immune response.  The 
immunogenicity data and safety data collected to date support continuing the clinical 
development of the VLP Vaccine. 
Since the use of a placebo would raise ethical concerns for individuals 65 years of age and older, 
who are considered at risk of complications from seasonal influenza, the control selected for the 
Phase 3 study CP-PRO-QVLP-014 study is an active comparator.  The active comparator will be 
either Fluarix® (produced by GlaxoSmithKline and marketed as Fluarix® Tetra or Fluarix® 
Quadrivalent in different regions) and/or FluLaval® (produced by ID Biomedical of Quebec and 
distributed by GlaxoSmithKline Inc as either FluLaval® or FluLaval® Quadrivalent in different 
regions). All are quadrivalent influenza vaccines licensed in one or more of the targeted 
countries that represent the most widely used dose type of vaccine in elderly subjects.  In 
addition, this type of quadrivalent influenza vaccine has been well-studied and has well-
established immunogenicity, efficacy, and safety profiles for this population.   
A complete risk:benefits assessment is provided in the Investigator’s Brochure (Section 6.1). 
2 
OBJECTIVES 
2.1 
Primary Objectives 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, against protocol-defined influenza-like illness 
(ILI) caused by any influenza viral type/subtype (RT-PCR); 
2.2 
Secondary Objectives 
Efficacy: 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, against laboratory-confirmed protocol-defined 

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influenza-like illness (ILI) caused by vaccine-matched strains (sequential RT-PCR & 
serotyping); 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, against  laboratory-confirmed protocol-defined 
respiratory illness caused by vaccine-matched strains (sequential RT-PCR & serotyping); 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, against laboratory-confirmed protocol-defined 
respiratory illness caused by any influenza viral types/subtypes (matched, mismatched, and 
un-typed) (sequential RT-PCR & serotyping); 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined ILI, regardless of laboratory results. 
Safety: 
• To assess the safety and tolerability, relative to an active comparator, of a single 
30 µg/strain dose of the Quadrivalent VLP Influenza Vaccine. 
Immunogenicity: 
• To assess, in a subset of 420 subjects (210 subjects per treatment group), the 
immunogenicity of a single 30 µg/strain dose of Quadrivalent VLP Influenza Vaccine, as 
measured by HI assay, MN assay, and SRH assay against homologous and heterologous 
(HI only) influenza strains. 
2.3 
Exploratory Objectives 
Efficacy: 
• To evaluate the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, against protocol-defined respiratory illness due to 
mismatched influenza strains (sequential RT-PCR & serotyping); 
• To determine the efficacy, relative to an active comparator, of a single 30 µg/strain dose of 
the Quadrivalent VLP Influenza Vaccine, as measured by the incidence of subjects 
presenting with symptoms of protocol-defined respiratory illness, regardless of laboratory 
results. 
Safety: 
• To evaluate respiratory illness outcome, occurrences of pneumonia, new onset or 
exacerbations of cardio-respiratory conditions, and health care utilization of subjects 
administered the Quadrivalent VLP Influenza Vaccine at a dose of 30 µg/strain relative to 
subjects administered an active comparator. 

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Immunogenicity: 
• To assess the CMI response against homologous and heterologous strains of a single 
30 µg/strain dose of Quadrivalent VLP Influenza Vaccine on Days 0 and 21 in a subset of 
420 subjects (same subset as the immunogenicity subset; 210 subjects per treatment group). 
3 
STUDY ADMINISTRATIVE STRUCTURE 
Table 4 Study Administrative Structure 
Role 
Name and Address 
Sponsor 
Medicago R&D Inc. 
1020, route de l’Église, bureau 600, 
Sainte-Foy (QC) Canada G1V 3V9 
 
 
 
 
4 
STUDY DESIGN AND RATIONALE 
4.1 
Overview of Study Design 
This randomized, observer-blind, active comparator-controlled Phase 3 study will be conducted 
at multiple sites. The composition of the Quadrivalent VLP Influenza Vaccine to be used in this 
study includes a mix of recombinant H1, H3, and two B hemagglutinin proteins expressed as 
VLPs (see Investigational Product Management Manual) and will be based on the 2018-2019 
recommended WHO strains for vaccination. The composition of the active comparator is also 
based on the 2018-2019 recommended WHO strains for vaccination. 
Approximately 12,120 non-institutionalized male and female subjects 65 years of age and older 
with no acute or evolving medical problems will be randomized in a 1:1 ratio into one of two 
parallel treatment groups, such that approximately 6060 subjects will receive the Quadrivalent 
VLP Influenza Vaccine at a dose of 30 µg/strain and approximately 6060 subjects will receive an 
active comparator. Within the two treatment groups, subjects will be randomized by age into two 
strata (65 to 74 years of age and 75 years of age and older) in a 2:1 ratio. 
A basic outline of the study design is presented in Figure 1. 
PPD
PPD

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Figure 1 Flowchart of Study Procedures 
Subjects will participate in this study for approximately eight to ten months, during which a first 
visit will be scheduled on Day 0 for screening and vaccine administration; subjects will be 
instructed on how to record reactions, adverse events (AEs), concomitant medication use, and 
respiratory illness symptoms in their diary and memory aid, as applicable. A phone contact will 
be made on Days 1 and 8, specifically for review of the subject’s safety and concomitant 
medication data. A visit to the investigator site will occur on Day 21 for a subset of 420 subjects 
from pre-defined sites in North America (210 subjects per treatment group) for serology 
sampling and immunogenicity assessments (CMI, HI, MN, and SRH). A final phone contact will 
be made for a safety assessment at approximately the end of April 2019 (the end of the 
surveillance period; however, the duration of the surveillance period may be adjusted, based on 
the observed epidemiology during the season in participating countries). 
Active and passive surveillance will be conducted from Day 14 until approximately the end of 
April 2019 (end of the surveillance period). For passive surveillance, subjects will be instructed 
to report symptoms meeting the definition of a new or worsening respiratory illness and ILI. For 
active surveillance, subjects will be contacted at least once per week and asked about symptoms 
of a new or worsening respiratory illness and ILI. The frequency of active surveillance contacts 
will vary slightly with region: 
• North America and Europe: Prior to the start of the influenza season (the start of influenza 
season will be determined by Medicago through local epidemiology and clinical 
experience), subjects will be contacted at least once per week, using the contact method 
most likely to be successful (e.g. subject's preferred method [phone, text, e-mail]). During 
the influenza season, subjects will be contacted a minimum of two times per week; at least 
one of these weekly contacts will be through a scripted telephone call, with the remaining 
contacts via the method most likely to be successful; 

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• Asia: Since there generally is no clearly defined influenza season, contacts will be made a 
minimum of two times per week, with at least one of these weekly contacts through a 
scripted telephone call and the remaining contacts via the method most likely to be 
successful (e.g. subject's preferred method [phone, text, e-mail]). 
Reports of respiratory illness will be followed up for the collection of information regarding 
symptoms, concomitant medication use, and disease burden and the collection of two 
nasopharyngeal swabs. For subjects in North America and Europe, swabs will only be collected 
for cases of respiratory illness that occur after the start of the influenza season (as determined by 
Medicago through local epidemiology and clinical experience); for subjects in Asia, swabs will 
be collected for any cases of respiratory illness reported during the surveillance period (Day 14 
and onwards). Figure 2 outlines the process to be followed for reports of respiratory illness. 
 
 
Figure 2 Flowchart of Process of Respiratory Illness Report 
Throughout the influenza season, the number of laboratory-confirmed influenza cases will be 
reviewed periodically by selected members of Medicago and the CRO who will be independent 
of study conduct and analysis. In the event of an insufficient attack rate of confirmed influenza 
(minimum of 198 cases), the study will be either continued or extended into another season to 
enrol more subjects and a protocol amendment will be issued to address changes to the 
enrolment plan.  

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4.2 
Rationale of Study Design 
4.2.1 Randomization 
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (e.g. demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. 
4.2.2 Observer-blinding 
Observer-blinded treatment will be used to reduce potential bias during data collection and 
evaluation of the clinical endpoints. 
4.2.3 Age Group Stratification 
Since age can affect the immune response, subjects will be randomized into each treatment group 
by age in two strata (65 to 74 years of age and 75 years of age and older) in a 2:1 ratio in order to 
ensure a representative age distribution within each treatment group. 
4.2.4 Dose Selection 
The dose of 30 µg/strain was selected based on data from previous studies as the lowest dose to 
consistently meet the historical CBER criteria and the dose most comparable with the most 
commonly used commercial licensed vaccines. 
4.2.5 Active Comparator Selection 
The active comparators (FluLaval® Tetra/Quadrivalent and/or Fluarix® Tetra/Quadrivalent (all 
produced and/or distributed by GlaxoSmithKline Inc) were selected on the basis that these 
products are approved quadrivalent influenza vaccines and represent the most widely used dose 
in elderly subjects. In addition, these products have been well-studied and have well-established 
immunogenicity, efficacy, and safety profiles for this population.  
4.2.6 Study Duration 
The duration of this study will be approximately eight to ten months post-vaccination for all 
subjects in order to capture the maximal number of cases of influenza caused by vaccine-
matched strains in a single influenza season. 
4.2.7 Efficacy Assessments 
The efficacy endpoint for this study (ie: sequential reverse transcription polymerase chain 
reaction [RT-PCR] and serotyping to define influenza types/subtypes) is standard to demonstrate 
influenza VE. The regional differences in the timing of NP swab collection (for cases of 
respiratory illness that occur after the start of the influenza season for subjects in North America 
and Europe) was included in order to minimize unpleasant study procedures that would have 

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minimal benefit [i.e. prior to influenza season] and to maximize subject compliance during peak 
influenza season in these regions with well-defined influenza seasons. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study; no protocol waivers are allowed: 
1. Subjects must have read, understood, and signed the informed consent form (ICF) prior to 
participating in the study; subjects must also complete study-related procedures and 
communicate with the study staff at visits and by phone during the study; 
2. Subject must have a body mass index (BMI) ≤ 35 kg/m2; 
3. Subjects are considered by the Investigator to be reliable and likely to cooperate with the 
assessment procedures and be available for the duration of the study; 
4. Male and female subjects must be 65 years of age and older at the Screening/Vaccination 
visit (Visit 1); 
5. Subjects must be non-institutionalized (e.g. not living in rehabilitation centres or old-age 
homes; living in an elderly community is acceptable) and have no acute or evolving medical 
problems prior to study participation and no clinically relevant abnormalities that could 
jeopardize subject safety or interfere with study assessments, as assessed by the Principal 
Investigator or sub-Investigator (thereafter referred as Investigator) and determined by 
medical history, physical examination, and vital signs; 
Note: Subjects with a pre-existing chronic disease will be allowed to participate if the disease 
is stable and, according to the Investigator’s judgment, the condition is unlikely to confound 
the results of the study or pose additional risk to the subject by participating in the study. 
Stable disease is generally defined as no new onset or exacerbation of pre-existing chronic 
disease three months prior to vaccination. Based on the Investigator’s judgment, a subject 
with more recent stabilization of a disease could also be eligible. 
5.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participating in this study; 
no protocol waivers are allowed: 
1. According to the Investigator’s opinion, history of an ongoing acute or evolving medical or 
neuropsychiatric illness. ‘Evolving’ is defined as: 
• 
Requiring a new medical or surgical treatment during the three months prior to study 
vaccine administration unless the criteria outlined in inclusion criterion no. 5 can be met 
(i.e. the Investigator can justify inclusion based upon the innocuous nature of 
medical/surgical events and/or treatments); 
• 
Requiring any significant change in a chronic medication (i.e. drug, dose, frequency) 
during the three months prior to study vaccine administration due to uncontrolled 
symptoms or drug toxicity unless the innocuous nature of the medication change meets 

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the criteria outlined in inclusion criterion no. 5 and is appropriately justified by the 
Investigator. 
2. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug 
abuse that would render the subject unable to provide informed consent or unable to provide 
valid safety observations and reporting, including methadone (methadone as treatment for 
opioid dependence may be acceptable if the subject has been otherwise opioid-free for at 
least three years); 
3. Any autoimmune disease other than hypothyroidism on stable replacement therapy 
(including, but not limited to rheumatoid arthritis, systemic lupus erythematosus, Crohn’s 
disease, type 1 diabetes, and inflammatory bowel disease) or any confirmed or suspected 
immunosuppressive condition or immunodeficiency including known or suspected human 
immunodeficiency virus (HIV), Hepatitis B or C infection, the presence of 
lymphoproliferative disease; 
4. Any history of status asthmaticus or ongoing serious problems with asthma, hospitalization 
for asthma control, or recurrent asthma episodes requiring medical attention in the last three 
years (one or more episodes per year); 
5. Administration or planned administration of any non-influenza vaccine within 30 days prior 
to randomization up to blood sampling on Day 21. Immunization on an emergency basis 
will be evaluated case-by-case by the Investigator; 
6. Administration of any adjuvanted or investigational influenza vaccine within one year prior 
to randomization or planned administration prior to the completion of the study; 
7. Administration of any ‘standard’, non-adjuvanted influenza vaccine (e.g. live attenuated 
trivalent/quadrivalent inactivated influenza vaccine or split trivalent/quadrivalent 
inactivated influenza vaccine administered by intranasal, intradermal, or intramuscular [IM] 
route) within six months prior to randomization and up to completion of the study; 
8. Use of any investigational or non-registered product within 30 days or five half-lives, 
whichever is longer, prior to randomization or planned use during the study period. Subjects 
may not participate in any other investigational or marketed drug study while participating 
in this study until after the study; 
9. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or 
equivalent) per day for more than seven consecutive days or for ten or more days in total, 
within one month of study vaccine administration; any other cytotoxic or 
immunosuppressant drug, or any immunoglobulin preparation within three months of 
vaccination and until the completion of the study. Low doses of nasal or inhaled 
glucocorticoids are allowed. Topical steroids are permitted; 
10. Any significant disorder of coagulation including, but not limited to, treatment with 
warfarin derivatives or heparin. Persons receiving prophylactic anti-platelet medications 
(e.g. low-dose aspirin [no more than 100 mg/day]), and without a clinically apparent 
bleeding tendency are eligible. Subjects treated with new generation drugs that do not 
increase the risk of IM bleeding (e.g. clopidogrel) are also eligible; 
11. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine,  
any components of the active comparator quadrivalent vaccine, or tobacco; 

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12. History of anaphylactic allergic reactions to plants or plants components (including fruits 
and nuts); 
13. Use of antihistamines within 48 hours prior to study vaccination; 
14. Daily use of large doses of medication for pain control or inflammation (e.g. opioids, 
nonsteroidal anti-inflammatory drugs [NSAIDs]). Use of a singular regular dose either in 
the morning or at bedtime would not be exclusionary; 
15. Use of prophylactic medications (e.g. acetaminophen/paracetamol, aspirin, naproxen, or 
ibuprofen) within 24 hours of randomization to prevent or pre-empt symptoms due to 
vaccination; 
16. Planned use of influenza antiviral treatment medication before the collection of NP swabs 
(e.g. oseltamivir, zanamivir, rapivab); 
17. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at 
the injection site that may interfere with injection site reaction rating; 
18. Subjects who have received a blood transfusion within 90 days prior to study vaccination; 
19. Subjects with abnormal vital signs (systolic blood pressure [BP] ≥ 150 mmHg and/or 
diastolic BP ≥ 95 mmHg for individuals taking antihypertensive medication and 
≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg for individuals not taking antihypertensive 
medication; heart rate [HR] ≤ 45 beats/min and ≥ 100 beats/min) evaluated by an 
Investigator to be clinically significant. A subject with abnormal vital signs results may be 
included in the study based on Investigator’s judgment (e.g. a resting HR ≤ 45 in highly 
trained athletes); 
20. Presence of any febrile illness (including an oral temperature [OT] ≥ 38.0 ˚C within 24 
hours prior to vaccination; 
21. Cancer or treatment for cancer within three years prior to study vaccine administration. 
Persons with a history of cancer who are disease-free without treatment for three years or 
more are eligible. However, individuals with conditions such as treated and uncomplicated 
basal cell carcinoma of the skin or non-treated, non-disseminated local prostate cancer may 
be eligible; 
22. Subjects identified as an Investigator or employee of the Investigator or clinical site with 
direct involvement in the proposed study, or identified as an immediate family member 
(i.e. parent, spouse) of the Investigator or any employee of Medicago (or their family 
members); 
23. Subjects with a history of Guillain-Barré Syndrome. 
5.3 
Prior and Concomitant Therapy 
New or changed medications reported by the subject post-vaccination and through to the end of 
the study will be recorded in the source documents and transcribed in the electronic case report 
form (eCRF) as a concomitant medication as per the conditions outlined in the next paragraph. 
Since AEs may be secondary to new medications, the Investigator will explore the reasons for 
the change or for the new medication intake and document these AEs, if any. 
Concomitant medications must be reported in the eCRF (reason for use, dates of administration, 
dosage, and route) if the use meets the following conditions: 

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• Within 30 days preceding vaccination: any treatments and/or medications specifically 
contraindicated (e.g. influenza vaccines, any immunoglobulins or other blood products, or 
any immune modifying drugs, etc.); 
• From randomization to Day 21, inclusive: any medication (including, but not limited to, 
over-the-counter medicines such as aspirin or antacids), vitamins, and mineral supplements; 
• From Day 22 to the end of the study, inclusive: any concomitant medication(s) 
administered to treat a NOCD (see Section 13.1.4 for definition of NOCD), SAE, or AE 
leading to withdrawal; any concomitant medication used to treat an AE that occurred before 
Day 21 and that is still being used afterwards (i.e. ongoing use); and any concomitant 
medications used to treat a protocol-defined respiratory illness or ILI; 
• Any vaccine not foreseen in the study protocol. 
Please refer to the eCRF completion guidelines for details of data entry requirements. 
5.4 
Prohibited Therapy 
Please refer to Section 5.2 (exclusion criteria numbers 3, 4, 6, 7, 8, 9, 10, 13, 15, 16, and 21) for 
details on medications or therapies prohibited prior to randomization, prior to NP swab 
collection, and/or during the conduct of this study. 
Given that an important objective of this study is to evaluate the tolerability of the study vaccine, 
the use of prophylactic medications to prevent or pre-empt symptoms due to vaccination is 
specifically prohibited up to Day 7 (end of collection of solicited symptoms). A prophylactic 
medication is a medication administered in the absence of ANY symptom and in anticipation of 
a reaction to the vaccination (e.g. an antipyretic is considered to be prophylactic when it is given 
in the absence of fever or any other symptoms, to prevent fever from occurring, vitamins used to 
boost immune system, etc.). 
The use of influenza antiviral treatment (e.g. oseltamivir, zanamivir, rapivab) is not permitted 
until the NP swabs are collected. 
6 
TREATMENT ALLOCATION AND BLINDING 
6.1 
Randomization 
Potential study subjects will be screened and assigned a subject number. Once all screening 
procedures, including Day 0 pre-randomization procedures, have been completed and the study 
eligibility is confirmed by the Investigator, the randomization numbers will be allocated to 
subjects within the appropriate treatment group by the randomization system. 
Subjects will be randomized to one of two treatment groups, based on a computer-generated 
randomization schedule prepared by or under the supervision of Medicago before the study. Prior 
to randomization into the two treatment groups, subjects will be stratified by age into two groups 
(65 to 74 years of age and 75 years of age and older) and enrolled in a 2:1 ratio. 

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Once a randomization number has been assigned, it will not be re-used for any reason. No 
subjects will be randomized into the study more than once. If a randomization number is 
allocated incorrectly, no attempt will be made to remedy the error once the study vaccine has 
been dispensed: the subject will continue on the study with the assigned randomization number 
and associated treatment. The study staff will notify the Sponsor Contact as soon as the error is 
discovered without disclosing the study vaccine administered. Admission of subsequent eligible 
subjects will continue using the next unallocated number in the sequence. 
The randomization number and treatment will be recorded along with the six-digit subject 
number for each subject in the investigational product accountability log. The Investigator will 
not be provided with randomization codes, but it will be possible to unblind the treatment in an 
emergency situation. 
6.2 
Blinding 
This is an observer-blind study: the subjects, the Investigators, and those responsible for study 
endpoint evaluations or review or analysis of the study data will not have access to the 
randomization codes. Any code break will be documented and reported to Medicago (or its 
designee) in a timely manner. In a medical emergency, the Investigator may unblind the 
treatment for that subject without prior consultation with the Sponsor. In such an event, the 
Investigator will need to contact the responsible Medical Officer as soon as possible after the 
unblinding to discuss the case. 
Since there will be differences in the VLP vaccine and the active comparator preparations 
(e.g. multi-dose vial versus single-dose syringe, possibly physical appearance), the site staff 
involved in the preparation and administration of the treatments will not be involved in any 
activity that could introduce a bias, such as the evaluations of respiratory symptoms, ILI, AEs, or 
reactogenicity of the subjects following vaccination. 
This study is blinded through to the end of the surveillance period of the last subject. The 
randomization code, will not be available during the course of the study to any investigator or 
any person directly involved in the clinical conduct of the study (including data cleaning and 
data analysis) except the independent team from the contract research organization (CRO) and 
selected individuals from Medicago. The selected individuals will be independent of study 
conduct and analysis and will review the number of influenza cases to allow for discussion of the 
clinical data and critical business decisions (e.g. extension of recruitment for another season) 
prior to study completion. It is anticipated that approximately five people from Medicago and the 
CRO will have access to the number of cases in a unblinded manner. Also, the central 
laboratories and the staff at the clinical site (except the staff involved in the 
preparation/administration of the study vaccine, the quality assurance auditor, and the quality 
control reviewers) will remain blinded throughout the entire study duration. 
7 
DOSAGE AND ADMINISTRATION 
On Day 0, subjects will receive one IM injection, into the deltoid region of the non-dominant 
arm (if possible), of their assigned treatment (30 μg/strain of Quadrivalent VLP Influenza 

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Vaccine or comparator Fluarix® Tetra/Quadrivalent  and/or FluLaval® Tetra/Quadrivalent 
[15 μg/strain]). The volume of injection will be 0.5 mL for both the VLP vaccine and 
comparators. 
8 
SPECIMENS AND CLINICAL SUPPLIES 
8.1 
Management of Samples 
Between vaccination and the end of the surveillance period, NP swabs will be collected from any 
subject who reports a new or a worsening respiratory illness (as defined in Section 10.2.1); these 
swabs will be collected each time a subject reports such an event within the specified regional 
timeframe (Section 4.1), so multiple collections may be required from some subjects. Two swabs 
will be collected per subject per event. 
On Days 0 and 21, a blood sample for CMI (peripheral blood mononuclear cell [PBMC] assay) 
and humoral immunity analysis will be collected for a pre-defined subset of 420 subjects. 
Bioanalysis of the NP swabs and immunogenicity blood samples will be conducted at central 
laboratories. 
Complete information on the handling, storage, and shipment of all laboratory samples will be 
described in the study-specific documentation. 
8.2 
Clinical Supplies 
Study centers will be provided with or be responsible for the provision of supplies for NP swabs 
and blood collection and shipment (e.g. aliquot tubes, aliquot labels, aliquot storage, shipping 
boxes, and accompanying manifests) as described in the study-specific documentation. Sites will 
be authorized to use their own materials if agreed to by Medicago (or its designee). 
9 
TREATMENT COMPLIANCE 
Treatment compliance is expected to be 100 %, since the study treatments will be administered 
IM at each Investigator site by site staff. In addition, the Investigator or designated study center 
personnel will maintain a log of all study treatments dispensed and returned during the study. 
Study drug supplies for each subject will be inventoried and accounted for throughout the study 
(details will be provided in the study-specific documentation). 
10 
STUDY EVALUATIONS 
10.1 
Study Procedures 
10.1.1 Overview 
The Time and Events Schedule: General Information (see Table 1) summarizes the frequency 
and timing of scheduled assessments applicable to this study. 
The Time and Events Schedule: Respiratory Illness Onset (see  
 

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Table 2) summarizes the frequency and timing of scheduled assessments associated with the 
onset of a respiratory illness (as defined in Section 10.2.1). 
Most subjects will have no blood sampled; the subset of subjects included in the immunogenicity 
analyses and who complete to the Day 21 visit will have blood volumes drawn of approximately 
120 mL over a period of 21 days (Table 5). 
Table 5 Estimated Blood Volume Drawn 
Type of Sample 
Volume per Sample 
(mL) 
Number of Samples per 
Subject 
Total Volume of Blood 
per Subject (mL) 
CMI response 
50 
2* 
100* 
HI, MN, and SRH titers 
10 
2* 
20* 
* Day 0 and Day 21 samples to be collected for a pre-defined subset of 420 subjects. 
10.1.2 Screening/Vaccination (Visit 1) 
Emergency equipment must be available on site and appropriate treatment must be instituted as 
soon as possible in the event of anaphylaxis or any other immediate hypersensitivity reaction. 
The Investigator will be on-site on vaccine administration days and for the duration of the 
observation period (minimum of 15 minutes after vaccination) for the last subject dosed on that 
day. The Investigator will be available on call for the remainder of the study. A physician should 
be immediately available at the clinical site to administer treatment or to apply procedures for 
any immediate AEs/SAEs. 
10.1.2.1 Prior to Vaccination 
The following procedures will be performed on Day 0 (Visit 1) prior to vaccination: 
• Review and proceed with the signature of the ICF. The Investigator or his/her designee, 
will fully inform the subject of the nature and scope of the study, potential risks and 
benefits of participation, and the study procedures involved and will answer all questions 
prior to requesting the subject’s signature on the ICF. The subject’s consent must be 
obtained prior to performing any study-related procedures; this must be clearly recorded 
and a copy of the signed ICF retained in the source documents. A copy of the ICF must be 
provided to the subject; 
• Collect and review demographics (gender, date of birth, age, race, and ethnicity) and body 
measurements (BMI, weight [kg or lbs], and height [cm or inches]) data. BMI is to be 
calculated as body weight (kg) divided by the square of height (m); the BMI result will be 
rounded to one decimal place using the standard convention. For the measurement of body 
weight, subjects will be lightly clothed, without shoes; 
• Collect and review medical history, including the grade of any medical conditions (medical 
conditions are to be graded using the same scale as for AEs; see Section 13.1.2). The 
medical history should record significant problems active at the time of screening and 
present within the preceding six months. Problems that have been clinically inactive for 
more than six months preceding screening, but which might alter the subject’s current or 

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future medical management, should also be noted (e.g. known mitral valve prolapse or a 
remote history of a seizure disorder); 
• Review and record current and previous medication use (up to 30 days prior to study 
vaccine administration); 
• Record influenza vaccinations received within 24 months prior to the administration of the 
study vaccine; 
• Perform a vital signs measurement, including resting BP, HR, and OT. OT will be collected 
in degrees Celsius or Fahrenheit using a digital thermometer. The OT measurement should 
not be collected immediately following consumption of a hot or cold beverage or after 
smoking. The BP will be taken after the subject has been in a seated position as per the 
site’s standard procedure. The BP should be taken by cuff (manual or automated are both 
acceptable). BP and HR may be repeated once if judged necessary. All measurements 
(including any repeats) will be recorded in the source documents. Inclusion of subjects with 
an out-of-range BP or HR measurement will be based on the Investigator’s judgment; 
• Perform a history- or symptom-directed physical examination (required if there are medical 
history conditions that can affect subject safety or the evaluation of the study vaccine). The 
physical exam will be performed by the Investigator; 
• Review the inclusion and exclusion criteria and determine the subject’s eligibility to 
participate in this study. The eligibility must be confirmed by the Investigator after review 
of all procedures and findings and prior to randomization; 
• If the subject is judged eligible for the study and is still willing to participate in the study, 
randomize the subject into the study; 
• Only for subjects included in the immunogenicity subset (humoral and cellular immunity 
assessment): after confirmation of eligibility and randomization, collect baseline blood 
samples for CMI, HI, MN, and SRH assessments and prepare and store these samples until 
shipment to the analytical laboratory. 
10.1.2.2 Vaccination 
Once all pre-vaccination procedures have been completed and subject eligibility determined, the 
study vaccine will be administered (on Day 0) IM into the deltoid muscle of the non-dominant (if 
possible) arm, as described in the Investigational Product Management Manual. In order to 
prevent possible confounding of vaccination site reactions, whenever possible, blood samples 
will not be collected from the same arm as the one used for vaccination. The arms used, both for 
blood collection and vaccination, will be documented in the source documents. For subjects with 
BMI <30, a needle of at least 1 inch (25mm) can be used to administer the vaccine. For subjects 
with BMI≥30, a needle of at least 1.5 inches (35mm) must be used to ensure intramuscular (IM) 
delivery.  

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10.1.2.3 Fifteen Minutes Post-vaccination 
The following safety observation procedures will be performed for all subjects immediately 
following study vaccine administration: 
• Subjects will remain in the clinic for at least 15 minutes post-vaccination for observation. 
The observation period will include an assessment of immediate solicited local and 
systemic reactions. Any unusual signs or symptoms reported during the initial 15 minutes 
post-vaccination will result in continued close monitoring. Based on their condition, 
subjects may be asked to remain in the clinic for their safety for more than 15 minutes after 
vaccination (the reason will be recorded in the source documents). All data (including the 
assessment of solicited local and systemic reactions) will be recorded during and after the 
observation period. Refer to Section 10.3.1 for details regarding the assessment of AEs 
and/or solicited local and systemic reactions; 
• During the observation period, subjects will be provided with a measurement device 
template (Section 19.1) for measuring (in mm) solicited local reactions of erythema 
(redness) and swelling and an oral digital thermometer for recording daily temperature (in 
degrees Celsius or Fahrenheit). Subjects will also be provided with a diary and will be 
shown how to enter their data in the diary. Each subject will be provided with the following 
instructions on the measurements they are to make: 
• 
How to collect his/her OT in degrees Celsius or Fahrenheit with the provided digital 
thermometer: 
• 
From the evening of Day 0 to the evening of Day 7, the subject will measure his/her OT 
at approximately the same time each evening and will record the results; 
• 
The OT should not be collected immediately following consumption of a hot or cold 
beverage or after smoking. 
• 
The subject is to also take his/her OT if he/she feels feverish and to record the highest 
temperature of the day. In the event that a temperature ≥ 38.0 °C or ≥ 100.4 °F is 
obtained, the subject will be allowed to take over-the-counter antipyretics 
(e.g. acetaminophen/paracetamol, aspirin, naproxen, or ibuprofen) and will be advised 
to increase the frequency of OT measurements to approximately every four hours, until 
he/she is no longer febrile (fever is defined as a temperature of ≥ 38.0 ºC or ≥ 100.4 °F). 
The subject is to document medication intake, which will be reviewed by the site 
personnel; 
• 
How to measure any solicited local reactions, including erythema (redness) and swelling 
diameter at the injection site using the measurement template supplied for this purpose; 
subjects will also be requested to evaluate pain at the injection site. Local reactions will 
be assessed every day starting in the evening of Day 0 and up to the evening of Day 7 and 
the results will be recorded. The severity of solicited local reactions will be graded 
according to the Food and Drug Administration (FDA) Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials (FDA, 2007), as presented in Table 6. 

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• 
How to grade, on a daily basis from the evening of Day 0 through to the evening of 
Day 7, each of the solicited systemic reactions and their severity (as per the same 
guidance used for solicited local reactions; see Table 6) (FDA, 2007) and to record the 
worst grade of the day for each of these solicited systemic reactions. The instructions will 
include how to examine and grade swelling in the neck and axilla and to record any 
unusual feeling and/or swelling; 
• 
Subjects will be advised that they will be asked about the occurrence of any symptoms or 
events requiring medical attention and the use of any concomitant medication during the 
21-day post-vaccination period and until the end of the surveillance period; 
• 
Subjects will be instructed to contact the clinical site for any unsolicited AEs and/or 
solicited local and systemic reactions of greater than Grade 2 (moderate). Based on their 
condition, the Investigator may request that the subject return to the clinic for evaluation; 
• 
Subjects will be advised on emergency contact information and instructions for 
contacting study personnel. Subjects will be advised to immediately contact the 
Investigator (or his/her designee) in the event of an SAE or a medical emergency. 
Subjects will be provided with a phone contact number and be instructed to call if any 
suspected reaction to the vaccination is felt to be significant or of concern; 
• 
Subjects will be advised to notify their health care professional(s) (e.g. primary care 
physician) that they are participating in a clinical research study of an influenza vaccine; 
• After the 15-minute observation period (allowed window of + 15 minutes) is completed, 
measure vital signs (BP, HR, and OT) as described in Section 10.3.1.3. Any out-of-range 
measurements will be assessed by the Investigator (or his/her designee) and any further 
action will be determined upon his/her medical decision; 
• Instruct the subjects to perform measurements of local and systemic reactions at 
approximately the same time each day from Day 0 to Day 7 (preferably in the evening); 
• Provide subjects with a memory aid that they can use to help them accurately report 
respiratory illness and ILI and safety information (after Day 21); 
• Provide appointments (date and time) for the next planned visit to the clinical site (Day 21), 
when applicable, and also for the Days 1 and 8 phone contacts and passive and active 
surveillance periods; 
• The subject will be released from the clinical site once all Day 0 post-vaccination 
procedures have been completed and the subject is in stable condition. 
10.1.3 Day 1 and Day 8 (Telephone Contact) 
The following procedures will be performed during the phone contact (acceptable interval of 
+ 1 day for Day 1 and ± 1 day for Day 8): 
• Ask the subjects about any difficulties in recording their data, any change in health, any 
visits to health care facilities and/or medical practitioners, and any use of concomitant 
medications. Record the information in the source documents; 

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• For any unsolicited AEs and/or solicited local and systemic reactions of greater than 
Grade 2 (moderate), the Investigator should be informed within 48 hours of the time the 
clinical site is made aware of the event. The Investigator may request that the subject return 
to the clinic for evaluation; 
• Advise subjects to immediately contact the Investigator (or his/her designee) in the event of 
any AE that requires medical attention. Subjects will be provided with a phone contact 
number and be instructed to call if any suspected reaction to the vaccination is felt to be 
significant or of concern; 
• Remind the subjects how to measure and record any solicited local and systemic reactions. 
Subjects should also be reminded to record any changes in health, including changes in 
AEs and changes in medications; 
• Remind subjects to immediately report any new or worsening respiratory illness, as defined 
in Section 10.2.1. Ensure that subjects have the memory aid listing the respiratory illness 
symptoms and contact information for the study site; 
• Remind subjects to immediately report any symptoms that meet the definition of an ILI, as 
defined in Section 10.2.1. Ensure that subjects have the memory aid listing the symptoms 
of ILI and contact information for the study site; 
• Remind subjects of their next appointment (date and time) for the clinical visit and/or the 
next phone contact. Subjects will also be reminded to record their data in the electronic 
system in a timely manner. 
In the event that a subject cannot be reached via phone, he/she may be contacted by text message 
or via e-mail (if these contacts are available). However, the phone should be the initial and 
preferred means of communication. At least three attempts within allowed time window should 
be made in order to reach the subject. 
10.1.4 Surveillance for Respiratory Illness 
From Day 14 following randomization and vaccination, passive and active surveillance will be 
performed until the end of the end of the surveillance period (approximately the end of April, 
2019): 
• Passive surveillance: subjects will be instructed to contact the clinical site within 24 hours 
in case of any new or worsening respiratory illness as defined in Section 10.2.1; 
• Active surveillance: subjects will be contacted a minimum of once per week: 
• 
North America and Europe: Prior to the start of the influenza season (the start of 
influenza season will be determined by Medicago through local epidemiology and 
clinical experience), subjects will be contacted at least once per week, using the contact 
method most likely to be successful (e.g. subject's preferred method [phone, text, 
e-mail]). During the influenza season, subjects will be contacted a minimum of two times 
per week; at least one of these weekly contacts will be through a scripted telephone call, 
with the remaining contacts via the method most likely to be successful; 

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• 
Asia: Since there generally is no clearly defined influenza season, contacts will be made a 
minimum of two times per week, with at least one of these weekly contacts through a 
scripted telephone call and the remaining contacts via the method most likely to be 
successful (e.g. subject's preferred method [phone, text, e-mail]). 
Note: An episode of respiratory illness is considered to extend from the first day of the first 
symptom to the last day of the last symptom. In most cases, a new episode can only begin 
after resolution of all symptoms of the previous episode, with a separation of a seven-day 
symptom-free interval between episodes. However, some degree of site investigator discretion 
will be permitted in defining new episodes (e.g. a non-productive cough and fatigue persisting 
for ten days from one episode, with a new onset of myalgia, headache, and sore throat would 
constitute the onset of a valid new episode). When Investigator judgement is required in the 
definition of a new episode of respiratory illness, this judgement should be recorded in the 
source documents. 
If a subject reports a new or worsening respiratory illness: 
• 
Collect information regarding the respiratory illness, including all applicable symptoms 
and the onset date: 
• 
The onset date is defined as the first date when one or more of the qualifying symptoms 
(see above) occurred and persisted for at least 12 hours; 
• 
Symptoms collected should also include the presence or absence of concurrent systemic 
symptoms (i.e. fever, feverishness [feeling of warmth], chills [shivering], tiredness 
[fatigue], headache, myalgia [muscle aches], nausea, vomiting, or diarrhea); 
• 
Collect information on any associated concomitant medication use; 
• 
Schedule a time when the subject can return to the clinic site for the collection of NP 
swabs. The NP swabs are to be collected within 36 hours (preferably within 24 hours) 
after reporting of the respiratory symptoms and according to regional specifications: only 
for cases of respiratory illness that occur after the start of the local influenza season 
(subjects in North America and Europe) or for any cases of respiratory illness reported 
during the surveillance period (i.e. Day 14 onwards; subjects in Asia); 
Note: If swabs cannot be collected within 36 hours after reporting of the respiratory 
symptoms, NP swabs should still be collected if the subject still has at least one respiratory 
illness symptom. 
• Respiratory illnesses that start on or after Day 14 will be followed up for 30 days after the 
illness start date. This follow-up will be conducted via the planned active surveillance 
contacts (telephone and text messaging). All follow-up information should be collected, 
regardless of whether NP swabs could be obtained. Information from more than 30 days 
from respiratory illness onset does not need to be collected. As part of this follow up, the 
following information will be needed: 
• 
Collect any new information regarding the evolution of the respiratory illness, including 
symptoms and any associated concomitant medication use; 

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• 
Collect data regarding the end date (if resolved). The end date is defined as the date on 
which the last symptom resolved; 
• 
Collect information regarding disease burden and health care information: 
• 
Document whether the illness required consultation at a clinic or with a general 
practitioner or family physician and if so, how many consultations; 
• 
Document whether the illness required consultation at an emergency department and if 
so, how many consultations; 
• 
Document whether the illness required hospitalization and if so, for how many days; 
• 
Document any other medical interventions associated with the illness; 
• 
Any clinical diagnoses in association with the respiratory illness (e.g. pneumonia, new 
onset or exacerbations of pre-existing cardio-respiratory conditions); 
• 
Document whether the illness resulted in missed work days (if applicable) and if so, 
how many; 
• 
Document any disease sequelae (including long-term); 
• Ask subjects if they have any ILI symptoms, as defined in Section 10.2.1; 
• Ensure subjects have the memory aid listing the symptoms of ILI and contact information 
for the study site; ensure subjects use the diary or memory aid, as applicable, to record 
reportable information. 
In case a subject cannot be reached via phone, he/she may be contacted by text message or via 
e-mail (if these contacts are available). However, other than for planned text message contacts, 
the phone should be the initial and preferred means of communication for respiratory illness 
follow-up. 
10.1.5 Day 21 
For all subjects a safety follow-up will be performed on or shortly after Day 21 (- 2/+ 3 days): 
• Review the subject’s safety data and ensure all updates on concomitant medication usage 
and any changes in the subject’s health (AEs, SAEs, or NOCDs) are recorded 
appropriately; 
• Advise the subjects to immediately contact the Investigator or his/her designee, in the event 
of any AE that requires a visit to an emergency room and/or hospitalization; 
• Ask the subjects to return their diary to the clinic site (the method of return will be defined 
in the study-specific documentation); 
• Remind the subjects of their next phone contact. 
Note: This safety follow-up will be performed during one of the surveillance telephone 
contacts either on or shortly after Day 21. For the subset of subjects participating in the CMI 
and humoral immunity assessment, this follow-up can be done during the Day 21 visit. 
The following procedures will be performed during the Day 21 (- 2/+ 3 days) visit for the subset 
of 420 subjects included in the immunogenicity analyses: 

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• Collect blood samples for CMI, HI, MN, and SRH assessments and prepare and store these 
samples until shipment to the central analytical laboratory; 
• Perform Day 21 safety follow-up (as described above) if it is to be done during this visit. 
Note: This visit might replace one of the phone contacts planned for that week. 
10.1.6 End of Surveillance (Telephone Contact) 
The following procedures will be performed during the end of surveillance telephone contact 
(approximately the end of April; the duration of surveillance period may be adjusted, based on 
the observed epidemiology during the season in participating countries; acceptable interval of 
± 3 days): 
• Record updates on any change in the subject’s health and report any SAEs, NOCDs, or AEs 
leading to subject withdrawal; 
• Record updates on any concomitant medications used to treat AEs that started before Day 
21 and were still ongoing after Day 21, SAEs, AEs leading to withdrawal from the study, or 
NOCDs, as well as prohibited medication use (if any) and any medication taken for a 
respiratory illness; 
• Confirm that the subject has continued to comply with protocol requirements (e.g. no use of 
prohibited concomitant medications, reporting of any respiratory illness or ILI symptoms). 
Any subject who withdraws consent from the study will be asked to participate in the final 
telephone contact within two weeks of withdrawal, if the subject agrees. 
10.2 
Efficacy 
10.2.1 Efficacy Evaluations 
Following randomization and vaccination, subjects will be instructed to report respiratory 
symptoms and symptoms meeting the definition of ILI from Day 14 until the end of the 
surveillance period (passive surveillance). The subjects will be given a memory aid listing the 
symptoms of respiratory illness and ILI and contact information for the study site. During this 
same period, active surveillance will also be performed to solicit respiratory illness symptoms a 
minimum of once per week: 
• North America and Europe: Prior to the start of the influenza season (the start of influenza 
season will be determined by Medicago through local epidemiology and clinical 
experience), subjects will be contacted at least once per week, using the contact method 
most likely to be successful (e.g. subject's preferred method [phone, text, e-mail]). During 
the influenza season, subjects will be contacted a minimum of two times per week; at least 
one of these weekly contacts will be through a scripted telephone call, with the remaining 
contacts via the method most likely to be successful; 
• Asia: Since there generally is no clearly defined influenza season, contacts will be made a 
minimum of two times per week, with at least one of these weekly contacts through a 

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scripted telephone call and the remaining contacts via the method most likely to be 
successful (e.g. subject's preferred method [phone, text, e-mail]). 
A respiratory illness will be defined as the occurrence of a new onset of one or more of the 
following symptoms that persist(s) for or reoccur(s) after a period of at least 12 hours: 
• 
Sneezing; 
• 
Stuffy or runny nose (nasal congestion); 
• 
Sore throat; 
• 
Cough; 
• 
Sputum production; 
• 
Wheezing; 
• 
Difficulty breathing. 
An episode is considered to extend from the first day of the first symptom to the last day of the 
last symptom. As outlined in Section 10.1.4, in most instances a new episode can only begin 
after resolution of all symptoms of the previous episode, with a separation of a seven-day 
symptom-free interval between episodes. 
Within 36 hours (preferably within 24 hours) after the reporting of a respiratory illness, the clinic 
site will collect nasopharyngeal (NP) swabs from the subject (two per subject per event) if the 
start of the respiratory illness falls in the indicated regional timeframe: 
• North America and Europe: after the start of influenza season; 
• Asia: after the start of active and passive surveillance (Day 14 and onwards). 
The swabs must be collected prior to the use of any influenza antiviral treatment medication 
(e.g. oseltamivir, zanamivir, rapivab). If the respiratory illness starts prior to Day 14, swabs are 
not to be collected, even if symptoms persist beyond Day 14. 
A swab will be submitted for analysis by multiplex RT-PCR. In the event of a positive RT-PCR 
result (positive for A or B strains), additional testing will be done to attempt to isolate the virus 
or for additional cell-culture testing (typing, subtyping, and strain identification and genetic 
sequencing using HI assay against a panel of known standard ferret reference antisera to different 
viral strains) to determine if the virus detected is matched or similar to any of the strains covered 
in the vaccine formulation for the respective season. A positive RT-PCR result will be 
considered a laboratory-confirmed case of influenza. The NP swabs will be analyzed in a central 
laboratory; information on processing and the central laboratories will be provided in the study-
specific documentation. 
Any respiratory illness must be followed up for 30 days following the start date; this follow up 
will be conducted via the planned active surveillance contacts (telephone and text messaging), 
using a script. At the end of the 30-day follow up, a questionnaire regarding disease burden due 
to the respiratory illness will be completed (Section 19.2); subjects will be provided with a 
memory aid (Section 19.3) for use over the 30 days, to facilitate accurate reporting at the end of 
the follow-up period. 

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ILI will also be monitored during this study. A subject will be considered to have protocol-
defined ILI if the following two conditions are both met between Day 14 and the end of the 
surveillance period: 
• He/she has at least one of the following pre-defined respiratory symptoms: 
• 
Sore throat; 
• 
Cough; 
• 
Sputum production; 
• 
Wheezing; or 
• 
Difficulty breathing; 
AND 
• He/she has at least one of the following systemic symptoms: 
• 
Fever (defined as a temperature > 37.2 °C or > 99.0 °F); 
• 
Chills; 
• 
Tiredness; 
• 
Headache; or 
• 
Myalgia. 
In addition, information on the following uncommon ILI symptoms will be collected for any 
subjects with a protocol-defined respiratory illness during the surveillance period: nausea, 
vomiting, and diarrhea. 
10.2.2 Efficacy Endpoints 
10.2.2.1 Primary Endpoint 
Vaccine efficacy will be defined as per the applicable regulatory region-specific case definition, 
as follows: 
• Occurrences of protocol-defined ILI due to laboratory-confirmed influenza (≥ 14 days post-
vaccination) caused by any influenza viral type/subtype (RT-PCR). 
10.2.2.2 Secondary Endpoints 
• Occurrences of laboratory-confirmed influenza illnesses (according to protocol defined ILI; 
≥ 14 days post-vaccination) caused by influenza viral types/subtypes that are matched 
(and/or antigenically similar) to the strains covered in the vaccine formulation (sequential 
RT-PCR & serotyping); 
• Occurrences of laboratory-confirmed influenza illnesses (according to protocol defined 
respiratory illness; ≥ 14 days post-vaccination) caused by any influenza viral 
types/subtypes (matched, mismatched, and un-typed) (sequential RT-PCR & serotyping); 
• Occurrences of laboratory-confirmed influenza illnesses (according to protocol defined 
respiratory illness; ≥ 14 days post-vaccination) caused by influenza viral types/subtypes 

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that are matched (and/or antigenically similar) to the strains covered in the vaccine 
formulation (sequential RT-PCR & serotyping); 
• Occurrences of protocol-defined ILI ≥ 14 days post-vaccination (confirmed or not by 
laboratory testing). 
Exploratory Endpoints 
• Occurrences of laboratory-confirmed influenza illnesses (according to protocol defined 
respiratory illness; ≥ 14 days post-vaccination) caused by mismatched influenza viral 
strains (sequential RT-PCR & serotyping); 
• Occurrences of respiratory illnesses ≥ 14 days post-vaccination (confirmed or not by 
laboratory testing). 
10.3 
Safety 
10.3.1 Evaluations 
Safety and tolerability will be evaluated by solicited local and systemic reactions (immediate 
complaints within 15 minutes post-vaccination and solicited reactions up to seven days post-
vaccination), unsolicited AEs up to 21 days post-vaccination, and SAEs and NOCDs, and AEs 
leading to withdrawal up to the end of the surveillance period. In addition, events will be 
monitored for a possible hypersensitivity component, from all reported events during the study 
(collected AEs, SAEs, NOCDs, and AEs leading to withdrawal). 
10.3.1.1 Solicited Local and Systemic Reactions 
Subjects will be monitored for both solicited local reactions (erythema, swelling, and pain at the 
injection site) and solicited systemic reactions (fever, headache, fatigue, muscle aches, joint 
aches, chills, a feeling of general discomfort, swelling in the axilla, and swelling in the neck) 
from the time of vaccination through Day 7. While the subjects remain in the clinic following 
vaccine administration, staff will monitor them for local and systemic reactions; after release 
from the clinic facility, from the evening of Day 0 to the evening of Day 7, subjects will measure 
and record their local and systemic reactions in their diary. 
The intensity of the solicited local and systemic reactions will be graded as: mild (1), moderate 
(2), severe (3), or potentially life threatening (4) (please refer to Table 6). Their causal 
relationship with the study vaccine will be assessed by the Investigator (definitely not related, 
probably not related, possibly related, probably related or definitely related); see Section 13.1.9 
for the definition of the causal relationships. 

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Table 6 Severity Grades for Solicited Local and Systemic Reactions 
Symptoms 
Severity 
None 
Grade 1  
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially life-
threatening) 
Injection Site Reactions (Local Reactions) 
Erythema (redness) 
< 25 mm 
25 - 50 mm 
51 - 100 mm 
> 100 mm 
Necrosis or 
exfoliative 
dermatitis  
Swelling 
< 25 mm 
25 - 50 mm and 
does not interfere 
with activity 
51 – 100 mm or 
interferes with 
activity 
> 100 mm or 
prevents daily 
activity  
Necrosis 
Pain 
None 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever for more 
than 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Solicited Systemic Reactions 
Fever (ºC or ºF) 
 
< 38.0 ºC 
< 100.4 ºF 
38.0 - 38.4 ºC 
100.4 - 101.1 ºF 
38.5 - 38.9 ºC 
101.2 - 102.0 ºF 
39.0 - 40.0 ºC 
102.1 - 104.0 ºF 
> 40.0 ºC 
> 104.0 ºF 
Headache 
None 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever for more 
than 24 hours or 
some interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Fatigue  
None 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Muscle aches 
None 
No interference 
with activity  
Some interference 
with activity  
Significant; 
prevents daily 
activity  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
Joint aches, chills, 
feeling of general 
discomfort or 
uneasiness (malaise), 
swelling in the axilla, 
swelling in the neck 
None 
No interference 
with activity 
Some interference 
with activity not 
requiring medical 
intervention  
Prevents daily 
activity and 
requires medical 
intervention  
Results in a visit 
to emergency 
room (ER) or 
hospitalization 
10.3.1.2 Adverse Events 
All spontaneous AEs occurring within 21 days after vaccination will be reported in the “Adverse 
Event” screen in the subject’s eCRF, irrespective of intensity or whether or not they are 
considered to be vaccination-related. Thereafter, from Day 22 to the end of the surveillance 
period, SAEs, AEs leading to withdrawal, and NOCDs will be monitored and reported in the 
eCRF. 

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The intensity of AEs will be graded as: mild (1), moderate (2), severe (3) or potentially life 
threatening (4), according to the FDA Guidance for Industry (FDA, 2007). Their causal 
relationship with the study vaccine will be assessed by the Investigator (definitely not related, 
probably not related, possibly related, probably related or definitely related); see Section 13.1.9 
for a definition of these causal relationships. 
10.3.1.3 Vital Signs 
Vital signs measurements (resting BP, HR, and OT) will be performed as part of screening 
procedures (prior to eligibility assessment on Day 0) and after the post-vaccination surveillance 
period. 
OT will be collected in degrees Celsius or Fahrenheit using a digital thermometer provided by 
the Sponsor. The OT measurement should not be collected immediately following consumption 
of a hot or cold beverage or after smoking. 
BP will be taken after the subject has been in a seated position as per the site’s standard 
procedure. BP should be taken by cuff (manual or automated are both acceptable). BP and HR 
may be repeated once if judged necessary. All measurements (including any repeats) will be 
recorded in the source documents. 
10.3.1.4 Physical Examinations 
If applicable, a history- or symptom-directed physical examination will be performed by the 
Investigator as part of screening procedures (prior to eligibility assessment on Day 0). 
10.3.2 Safety Endpoints 
10.3.2.1 Secondary Endpoints 
• Percentage, intensity, and relationship to vaccination of immediate complaints (15 minutes 
post-vaccination); 
• Percentage, intensity, and relationship to vaccination of solicited local and systemic signs 
and symptoms (for seven days following study vaccine administration); 
• Percentage, intensity, and relationship of TEAEs for 21 days following study vaccine 
administration; 
• Occurrences of deaths, SAEs, AEs leading to withdrawal, and NOCDs up to the end of the 
surveillance period. 
10.3.2.2 Exploratory Endpoint 
• Information on respiratory illness outcome, occurrences of pneumonia, new onset or 
exacerbations of cardio-respiratory conditions, and health care utilization during the entire 
trial follow up period. 

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10.4 
Immunogenicity 
10.4.1 Immunogenicity Evaluations 
Immunogenicity will be evaluated by the humoral immune response (HI, MN, and SRH assays) 
and the CMI response induced in subjects on Days 0 and 21 in a subset of 420 subjects (210 
from each treatment group) from selected sites. The North American sites selected for this subset 
of 420 subjects will be pre-defined prior to study start and will target providing a representative 
age distribution. The number of subjects in each age group (65 to 74 years of age and 75 years of 
age and older) included in the immunogenicity analyses will be similar in proportion to that of 
the overall study. 
The blood samples for immunogenicity will be analyzed in one or more central laboratories; 
information on processing and the central laboratories will be provided in the study-specific 
documentation. 
10.4.2 Immunogenicity Endpoints 
Unless otherwise mentioned, point estimates and 95% CI will be calculated for all The 
immunogenicity endpoints and responses in the Quadrivalent VLP Influenza Vaccine 
recipients will be compared with the active comparator group using descriptive statistics.  . 
10.4.2.1 Secondary Endpoints 
• HI antibody response induced against the homologous and heterologous influenza strains 
on Days 0 and 21 in a subset of 420 subjects (210 from each of the two treatment groups). 
HI antibody titers will be analyzed as follows: 
• 
GMT of HI antibody on Days 0 and 21; 
• 
SC rate: the proportion of subjects in a given treatment group with either a ≥ 4-fold 
increase in reciprocal HI titers between Day 0 and Day 21 or a rise of undetectable HI 
titer (i.e. < 10) pre-vaccination (Day 0) to an HI titer of ≥ 40 on Day 21; 
• 
SP rate: the proportion of subjects in a given treatment group attaining a reciprocal HI 
titer of ≥ 40 on Day 21 (the percentage of vaccine recipients with a serum HI titer of at 
least 1:40 following vaccination); 
• 
Geometric mean fold rise (GMFR): the geometric mean of the ratio of GMTs (Day 
21/Day 0). 
• MN antibody response induced by the Quadrivalent VLP Influenza Vaccine against the 
homologous influenza strains on Days 0 and 21, in the subset of subjects, will be analysed 
as follows: 
• 
GMT of MN antibody on Days 0 and 21; 
• 
SC rate on Day 21 (as defined above for HI); 
• 
GMFR (Day 21/Day 0). 
• SRH antibody response induced by the Quadrivalent VLP Influenza Vaccine against the 
homologous strains on Days 0 and 21 in a subset of subjects, will be analysed as follows: 

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• 
Geometric mean area (GMA) of SRH antibody on Days 0 and 21; 
• 
SC rate: proportion of subjects in a given treatment group showing at least 50 % increase 
in GMA between Days 0 and 21; 
• 
SP rate: the proportion of subjects in a given treatment group attaining an area diameter 
≥ 25 mm2 following vaccination (Day 21); 
• 
GMFR: the geometric mean of the ratio of GMA (Day 21/Day 0). 
10.4.2.2 Exploratory Endpoint 
• CMI response induced by the Quadrivalent VLP Influenza Vaccine against homologous 
and heterologous strains on Day 21 (subset of 420 subjects), as measured by the number of 
CD4+ T cells expressing each of three functional markers: interferon gamma (IFN-γ), 
interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α), as well the number of cells 
producing at least one of these cytokines and the number of cells producing two or more of 
these cytokines. 
11 
SUBJECT COMPLETION/WITHDRAWAL 
11.1 
Temporary Contraindications 
Some exclusion criteria that render subjects ineligible for the study may be temporary in nature: 
• Temperature ≥ 38.0 ºC or ≥ 100.4 ºF within 24 hours prior to randomization; 
• Acute cold symptoms such as upper respiratory tract infection symptoms, with or without 
fever, that resolve at least 48 hours prior to randomization. 
If, on the day of Screening, a subject is considered ineligible due to one of these “temporary 
contraindications”, the subject should be considered as a screening failure. Following the 
resolution of such conditions, a subject may be rescreened (including the informed consent 
process) under a new number and, if considered eligible by the Investigator, be enrolled in the 
study. 
11.2 
Screening Failures 
Screening failures are subjects who have signed the study-specific ICF but are not eligible for 
enrolment (subjects who are not vaccinated), due to failure on one or more of the inclusion or 
exclusion criteria or because the subject withdrew consent prior to randomization. Eligible/not 
treated subjects are subjects that have signed the ICF and are eligible for enrolment, but were 
either not randomized or randomized and not treated. 
Recording of screening failures and eligible/not treated subjects will be carried out in the study 
records maintained at the participating clinical sites. Neither of these subject classes will receive 
a safety follow-up. 
Any subjects who are considered as a screening failure should be indicated as such. A screening 
failure subject can be rescreened (under a new number). If the subject is rescreened, a new 
subject number will be allocated. 

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11.3 
Removal of Subjects from Treatment or Assessment 
Subjects will be advised that they are free to withdraw from the study at any time without 
prejudice to their future medical care by the physician or the institution. Subjects who withdraw 
or are withdrawn from the study after vaccination will not be replaced. 
Every reasonable effort will be made to ensure that each subject complies with the protocol and 
completes all study visits. However, a subject may withdraw or be withdrawn from participation 
if: 
• The subject withdraws consent; 
• The subject displays non-compliance to the terms of their participation in the clinical study 
(based on Investigator’s or Medicago’s [or its designee’s] opinion); 
• Safety reasons as judged by the Investigator and/or Medicago (or its designee); 
• Medicago or the regulatory authority(ies) terminates the clinical study. 
Withdrawal subjects will be those who leave the study before the end of the surveillance period, 
for whatever reason; withdrawal subjects will not be replaced. Any subject who withdraws 
consent from the study will be asked to participate in the final telephone contact within two 
weeks of withdrawal and at the end of the surveillance period, if the subject agrees. The 
procedures performed for the final assessment will comprise those for the end of surveillance 
telephone contact, if permitted by the subject. All withdrawal subjects must be reported to 
Medicago (and/or its designee). The reason for withdrawal should be documented in the 
subjects’ records and in the appropriate section of the eCRF. The eCRF must be completed up to 
and including the time of the drop-out/final assessment. 
11.3.1 Follow-up of Discontinuations 
All subjects who receive a study vaccine will be followed for safety until the end of the 
surveillance period, if permitted by the subject. 
11.3.2 Lost to Follow-up Procedures 
Every attempt will be made to contact study subjects who are lost to follow-up. At least three 
contacts will be attempted and recorded in the source documents. As a last resort, one registered 
letter requesting contact with the site will be sent to any subject with whom the clinic staff no 
longer has contact. All attempts at contact will be documented in the subject’s source documents. 
11.4 
Interruption of the Study 
The Investigator (in consultation with Medicago [or its designee]), Medicago, or Regulatory 
Authorities may interrupt or terminate this study for any reason. The Investigator will 
immediately, on discontinuance of the clinical study at the clinical site, inform both the study 
subjects and the institutional review board (IRB) responsible for the study of the discontinuance, 
provide them with reasons for the discontinuance and advise them in writing of any potential 
health risks to the subjects themselves or to other persons. It is Medicago’s (or its designee’s) 
responsibility to report discontinuance of the study to the local regulatory agencies within the 

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appropriate timeframe, providing them with the reasons for the discontinuance and advising 
them in writing of any potential health risks to the study subjects or to other persons. Medicago 
(or its designee) must then inform the Investigator that the appropriate notifications were done. 
12 
STATISTICAL METHODS 
A general description of the statistical methods used to analyze the efficacy, safety, and 
immunogenicity data is outlined below. Complete details will be provided in the statistical 
analysis plan (SAP), which will be finalized prior to database lock. 
12.1 
Analysis Populations 
12.1.1 Safety Analysis Set 
The safety analysis set (SAS) is defined as all subjects who received either the Quadrivalent VLP 
Influenza Vaccine or the active comparators. All safety analysis will be performed using the 
SAS, according to the treatment the subjects actually received. 
12.1.2 Full Analysis Set 
The full analysis set (FAS) will consist of the subset of subjects in the SAS who were 
successfully contacted at least once during the surveillance period. Subjects who received the 
wrong treatment will be analyzed as randomized. 
12.1.3 Per Protocol Set 
The per protocol (PP) set will consist of the subjects who participated in the study until at least 
the end of the peak period (approximately the end of February for Europe and North America) or 
for at least five months or until the end of the surveillance period (other countries); had no major 
protocol deviations related to subject eligibility, the ability to develop a valid immune response, 
prohibited medication use, or the efficacy analyses; and who received the VLP vaccine or the 
active comparator. Major protocol deviations will be identified and documented during a blinded 
data review prior to database lock and confirmed at the time of database lock. The PP set will be 
the primary analysis population for the efficacy and immunogenicity endpoints. Subjects who 
received the wrong treatment, but for whom the treatment received can be unequivocally 
confirmed, will be analyzed as treated, provided they have no other deviations that compromise 
their data. 
The analyses of all efficacy endpoints will be performed using the efficacy PP population and the 
FAS population. 
The immunogenicity PP set will consist of the subset of subjects who participated in the 
immunogenicity portion of the study, who had a Day 21 immunogenicity sample collection; who 
had no major deviations related to subject eligibility, the ability to develop a valid immune 
response, prohibited medication use, or the immunogenicity analyses; and who received the 
vaccine or the active comparator. Subjects who received the wrong treatment, but for whom the 

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treatment received can be unequivocally confirmed, will be analyzed as treated, provided they 
have no other deviations that compromise their data. 
12.2 
Sample Size Determination 
The sample size of approximately 12,120 subjects (6060 subjects per treatment group) was 
selected to have 80 % power to determine non-inferiority, based on the assumption of 20 % VE, 
a 2 % or greater attack rate in the active comparator (ARVC) for protocol-defined ILI caused by 
any influenza viral types/subtypes, and a 10 % dropout rate. Non-inferiority will be concluded if 
the lower bound of the two-sided 95 % CI is greater than -20 %. 
In the event of an insufficient attack rate of confirmed influenza (minimum of 198 cases), the 
study will be either continued or extended into another season to enrol more subjects and a 
protocol amendment will be issued to address changes to the enrolment plan. 
12.3 
Efficacy Analyses 
Efficacy endpoints are described in Section 10.2.2. 
All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System® (SAS®) software (version 9.3 or higher). Details of the statistical analyses will be 
provided in the SAP, finalized prior to unblinding subject treatment assignment and database 
lock. Summary tables will present data for the overall population and for each age stratum, as 
applicable. 
12.3.1 Analysis of Primary Endpoint 
The primary efficacy endpoints are defined in Section 10.2.2.1. 
For the primary endpoint, VE will be evaluated as the relative risk of subjects vaccinated with 
Quadrivalent VLP Influenza Vaccine (30 µg/strain) or an active comparator to develop protocol-
defined ILI as a result of laboratory-confirmed infection with any influenza virus (RT-PCR) ≥14  
days after vaccination 
VE will be calculated using the following formula: 
VE=(1-ARVV/ARVC)*100 % 
Where: 
  ARVV = attack rate in subjects vaccinated with the Quadrivalent VLP Influenza Vaccine; and 
  ARVC = attack rate in subjects vaccinated with an active comparator. 
Non-inferiority will be concluded if the lower limit of the two-sided 95 % CI for relative VE is 
> -20 % for the primary endpoint. If non-inferiority is demonstrated, VE of the VLP vaccine will 
be tested for superiority over the active comparator as an exploratory analysis (VE for superiority 
testing will use the same definitions as in the primary endpoint). Superiority will be concluded if 
the lower limit of the two-sided 95 % CI for relative VE is > 9 % for the primary endpoint. 

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12.3.2 Analysis of Secondary Endpoints 
The secondary efficacy endpoints are defined in Section 10.2.2.2. 
VE will be calculated for the following endpoints, using the same formula indicated for the 
primary efficacy analysis: 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to develop protocol-defined ILI as a result of laboratory-confirmed influenza 
infection ≥ 14 days after vaccination with a viral type/subtype that is matched and/or 
antigenically similar to the strains covered in the vaccine formulation (sequential RT-PCR 
& serotyping); 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to develop a respiratory illness caused by a laboratory-confirmed influenza 
strain ≥14 days after vaccination caused by a viral type/subtype that is matched and/or 
antigenically similar to the strains covered in the vaccine formulation) (sequential RT-PCR 
& serotyping); 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to develop a respiratory illness caused by any laboratory-confirmed influenza 
strain ≥ 14 days after vaccination (RT-PCR & serotyping); 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to present with ILI ≥14 days after vaccination, regardless of the laboratory 
results (i.e. the proportion of subjects with at least one episode of protocol-defined ILI). 
Non-inferiority will be tested using the same criterion as with the primary endpoint; superiority 
testing will be conducted if non-inferiority is concluded (the same criterion as with the primary 
endpoint will be used for superiority testing). 
12.3.3 Analysis of Exploratory Endpoints 
The exploratory efficacy endpoints are defined in Section 10.2.2.3. 
VE will be calculated for the following endpoints, using the same formula indicated for the 
primary efficacy analysis: 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to become infected with a protocol-defined respiratory illness caused by a 
laboratory-confirmed, mismatched influenza strain ≥14 days after vaccination (i.e. the 
proportion of subjects with one or more episode of respiratory illness shown to be caused 
by viral types/subtypes that are not antigenically similar to the strains covered in the 
vaccine formulation) (sequential RT-PCR & serotyping); 
• The relative risk of subjects vaccinated with a VLP vaccine (30 µg/strain) or an active 
comparator to present with respiratory illness symptoms ≥14 days after vaccination 
regardless of the laboratory results (i.e. the proportion of subjects with at least one episode 
of protocol-defined respiratory illness). 

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Non-inferiority will be tested using the same criterion as with the primary endpoint; superiority 
testing will be conducted if non-inferiority is concluded (the same criterion as with the primary 
endpoint will be used for superiority testing). 
12.4 
Baseline and Subject Disposition 
Demographic data and influenza immunization history will be presented in listings and 
summarized by treatment. Continuous variables including age, weight, height, and BMI will be 
summarized with mean, median, standard deviation, minimum, and maximum. Count and 
percentage of subjects will be presented for categorical variables such as sex, race, ethnicity, and 
immunization history. 
The number of subjects in different study disposition statuses will be summarized by number 
and, when applicable, percentage (based on vaccinated subjects). Subjects’ 
completion/discontinuation status will be listed (including subject identifier, date of 
completion/early discontinuation and, for those who discontinued early, the specific reason(s) for 
discontinuation). 
12.5 
Safety Analyses 
The safety endpoints are defined in Section 10.3.2. 
12.5.1 Analysis of Secondary Endpoints 
The secondary safety endpoints are defined in Section 10.3.2.1. 
Safety and tolerability endpoints (immediate complaints, solicited local and systemic reactions, 
and TEAEs, deaths, SAEs, AEs leading to subject withdrawal, and NOCDs) will be summarized 
by treatment using descriptive statistics. 
The original terms used in the eCRFs by Investigators to identify AEs will be coded using the 
MedDRA® dictionary. All eCRF reported AEs with onset post-vaccination will be included in 
the safety analyses. 
Special attention will be given to those subjects who die, who discontinue from the study due to 
an AE, who experience an SAE (e.g. summaries, listings, and narrative preparation may be 
provided, as appropriate), or who experience an allergic or allergic-like reaction (see 
Section 13.1.3). 
12.5.2 Analysis of Exploratory Endpoint 
The exploratory safety endpoint is defined in Section 10.3.2.2. 
The occurrences of medical visits, hospitalizations, and workdays missed (if applicable) will be 
summarized by treatment using descriptive statistics. 

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12.6 
Immunogenicity Analyses 
Unless otherwise mentioned, point estimates and 95% CI will be calculated for all 
immunogenicity endpoints and responses in the Quadrivalent VLP Influenza Vaccine recipients 
will be compared with the active comparator group using descriptive statistics.   
12.6.1 Analysis of Secondary Endpoints 
The secondary immunogenicity endpoints are defined in Section 10.4.2.1.  
The following analyses for the HI assay (homologous strains) will be performed on the 
immunogenicity PP: 
• GMT (Day 21): The point estimates and the corresponding two sided 95 % CI by treatment 
group and strain will be calculated as the antilog of the mean and 95 % CI of log 
transformed titer values; 
• SC rate (Day 0 and Day 21): The point estimates and the corresponding two-sided 95 % CI 
for subjects achieving SC by treatment group and strain will be calculated to determine 
whether the lower bound of the CI will meet or exceed 30 %; 
• SP rate (Day 21): The point estimates and the corresponding two-sided 95 % CI for 
subjects achieving SP by treatment group and strain will be calculated to determine whether 
the lower bound of the CI will meet or exceed 60 %. 
The analyses for the MN and SRH assays (homologous strains) will be performed on the 
immunogenicity PP. The GMT, GMFR, and SC rate of the MN antibody assay and the GMA, 
GMFR, SC rate, and SP rate for the SRH antibody assay will be compared between the treatment 
groups using descriptive statistics and 95 % CI. For SC rate and SP rate, Fisher’s exact tests or 
chi square tests will be used. GMT and GMFR for MN and GMA and GMFR for SRH will be 
compared using appropriate analysis of variance models. 
12.6.2 Analysis of Exploratory Endpoint 
The exploratory immunogenicity endpoint is defined in Section 10.4.2.2. 
The CMI response will be compared between the treatment groups using appropriate non-
parametric (Wilcoxon) models. Additional details will be provided in the SAP. 
13 
ADVERSE EVENT REPORTING 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, Investigators, and the Sponsor, and are mandated by 
regulatory agencies worldwide. 

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13.1 
Definitions 
13.1.1 Serious Adverse Events 
An SAE is any untoward medical occurrence (whether or not considered to be related to the 
study vaccine) that, at any dose: 
• Results in death; 
• Is life-threatening (at the time of the event); 
Note: the term “life-threatening” in the definition of an SAE refers to an event that put the 
subject at risk of death at the time of the event; it does not refer to an event that hypothetically 
might have caused death if it were more severe; 
• Requires inpatient hospitalization (≥ 24 hours) or prolongation of existing hospitalization 
(elective hospitalizations/procedures for pre-existing conditions that have not worsened are 
excluded); 
• Results in persistent or significant disability/incapacity; 
• Is a congenital abnormality/birth defect; 
• Is another medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but that may jeopardize the subject’s health 
or may require an intervention to prevent one of the other outcomes listed in the definition 
above. These events should be considered serious. Examples of such events are intensive 
treatment in an emergency room for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or the development of drug dependency or drug abuse. See 
Section 13.1.6 for initial SAE reporting by the Investigator. 
13.1.2 Adverse Events 
An AE or adverse experience is defined as any untoward medical occurrence in a subject or 
clinical investigation subject who was administered a pharmaceutical product, with or without a 
causal relationship with the treatment. An AE can be any favorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
related to a medicinal product. 
Information such as the date and time of onset and resolution (duration), intensity (defined 
below), seriousness, any required treatment or action taken, outcome, causal relationship to the 
investigational vaccine, and whether the AE caused withdrawal from the study will be collected. 
The intensity of all AEs will be graded as mild (1), moderate (2) severe (3), or potentially life 
threatening (4), according to the FDA Guidance for Industry: Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA, 2007) for 
the events covered in the guidance and the following definitions for all other events: 

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Mild (Grade 1): 
The AE is easily tolerated and does not interfere with usual 
activity; 
Moderate (Grade 2): 
The AE interferes with daily activity, but the subject is still able 
to function; 
Severe (Grade 3): 
The AE is incapacitating and the subject is unable to work or 
complete usual activity; 
Potentially life-threatening 
(Grade 4): 
The AE is likely to be life-threatening if not treated in a timely 
manner. 
The Investigator will be instructed to closely monitor each subject who experiences an AE 
(whether ascribed to the investigational product or not) until the outcome of the AE has been 
determined. 
If any of the solicited local or systemic reactions persist beyond Day 7, these will also be 
recorded as AEs. In this case, the AE start will be set as eight days post-vaccination. The subject 
will be requested to note when the AE resolves and to report this information to the Investigator 
or clinic staff at the next visit at the clinical site or contact. 
The clinical importance of AEs will be determined based upon the Investigator’s judgment. The 
Investigator must ensure that any sample obtained to follow up on an AE is properly labeled and 
stored. The Investigator and others responsible for care of the subjects should institute any 
supplementary investigations of significant AEs based on the clinical assessment of the likely 
causative factor. This may include seeking the opinion of a specialist in the field of the AE. 
All AEs occurring within 21 days after vaccination must be reported in the “Adverse Event” 
screen in the subject’s eCRF, irrespective of intensity or whether or not they are considered to be 
vaccination-related. Thereafter, from Day 22 through to the end of the surveillance period, SAEs, 
AEs leading to withdrawal, and NOCDs (see Section 13.1.4 for definition) will be monitored and 
reported in the eCRF. Additional details on eCRF entries can be found in the eCRF completion 
guidelines. 
The SAEs and NOCDs will be followed up until complete resolution or stabilization. Follow-up 
of unresolved SAEs, AEs leading to withdrawal, or NOCDs after the end of the surveillance 
period will continue under the discretion of the Investigator. 
13.1.3 Adverse Events of Special Interest 
In the five studies conducted to date, all reported events were monitored for a possible 
hypersensitivity component (events were searched using both narrow and broad standardized 
MedDRA® queries). Based on these data, there is no evidence of anaphylactic reactions 
associated with use of the Quadrivalent VLP Influenza Vaccine in humans: a small number of 
subjects had potential hypersensitivity reactions judged to be related to vaccine administration 
(no more than 0.3 % of subjects in any given VLP treatment group experienced one of these 
events) and the events were distributed fairly evenly among treatment groups, including the 
placebo and the active comparator groups. However, since severe reactions are considered to be 
an important potential risk (based on the theoretical risk that using plants for the production of 

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biotherapeutics may induce hypersensitivity) the sponsor will continue to require that appropriate 
medical treatment and supervision are available to manage any possible anaphylactic reactions. 
To collect additional data on these events, Medicago will closely monitor and assess allergic or 
allergic-like reactions as AEs of special interest. Thus, to collect specific data under this 
protocol, the Investigator should, whenever possible, take a picture of any occurrence of allergic 
or allergic-like reactions and send the anonymized images to Medicago as described in the study-
specific documentation. 
13.1.4 New Onset of Chronic Disease 
In the context of this study, all NOCDs that may plausibly have an allergic, autoimmune or 
inflammatory component are to be reported. Plausibility should be interpreted broadly however; 
the only clear exceptions are degenerative conditions such as osteoarthritis, age-related 
physiologic changes (e.g. benign prostatic hypertrophy) and life-style diseases (e.g. alcohol-
associated cirrhosis, bronchitis in a smoker, etc.). In this context, most cancers, cardiac 
conditions, and kidney diseases should be reported. 
NOCDs will be collected from vaccination on Day 0 to the end of the surveillance period and 
reported as an AE or SAE, as applicable. 
13.1.5 Expectedness of an Adverse Drug Reaction 
An “unexpected” adverse reaction is one in which the nature or severity of the event is not 
consistent with information in the current version of the IB. Expedited reporting to the regulatory 
authorities is required if an SAE occurs that is both unexpected and considered possibly, 
probably, or definitely related to the study vaccine. 
13.1.6 Initial SAE Reporting by the Investigator 
Details on safety reporting are defined in the safety management plan (SMP), including SAE 
processing, country-specific reporting requirements, regulatory unblinding, roles and 
responsibilities of different stake holders, and contact details of personnel responsible for safety 
reporting. A brief summary of salient information is presented below. 
SAEs related to pre-treatment study procedures will be reported from the time the ICF is signed. 
All post-vaccination SAEs (treatment-emergent SAEs) will be reported from the time of 
receiving the study vaccine on Day 0 through to the end of the surveillance period (final 
scheduled phone contact). The Investigator (or designee) must report, by phone or e-mail, all 
SAEs, whether considered related to the study vaccine or not to Medicago (or its designee) 
within 24 hours of the Investigator learning of the event. The Investigator must also complete, 
sign, and date the paper SAE report form, and send, via e-mail, a copy to the Medicago safety e-
mail address and the appropriate regional e-mail address within 24 hours of awareness of event: 
Medicago Safety e-mail address: 
Medicago-Safety@medicago.com 
 
 

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Sponsor Safety Contact: 
 
 
 
Serious AEs will be reported to the local (or contract) IRB by the Investigator according to the 
IRB’s policy and procedures. 
13.1.7 Follow-up Reporting by the Investigator 
All SAEs, regardless of causality, will be followed as described in Section 13.1.2. When 
appropriate, documentation of any medical tests or examinations performed will be provided to 
document resolution/stabilization of the event. 
13.1.8 Reporting of SAEs Occurring after Surveillance Period or Study Termination 
All SAEs occurring during the safety follow up period will be followed until the end of the 
surveillance period. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection 
period (post surveillance period). Active follow-up for AEs or SAEs will continue until the end 
of the surveillance period for all subjects. However, after the end of the surveillance period, if 
the Investigator learns of any SAE, including death, at any time after a subject has been 
discharged from the study, and he/she considers the event to be reasonably related to the 
investigational product, the Investigator will promptly notify the Sponsor Safety Contacts for 
Reporting SAEs. 
13.1.9 Causal Relationship 
The Investigator must make the determination of relationship to the study vaccine for each AE. 
The Investigator should decide whether, in his/her medical judgment, there is a reasonable 
possibility that the event may have been caused by the investigational vaccine. If there is any 
valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the investigational vaccine and the occurrence of the AE, then the AE 
should be considered “definitely related”, “probably related”, or “possibly related”. Otherwise, if 
no valid reason exists for suggesting a possible relationship, then the AE should be classified as 
“probably not related” or “definitely not related”. The following guidance should be followed: 
Definitely Not 
Related: 
The AE is clearly not related to the administration of the study vaccine. 
Another cause of the event is most plausible; and/or a clinically 
plausible temporal sequence is inconsistent with the onset of the event 
and the study vaccine administration; and/or a causal relationship is 
considered biologically implausible. 
Probably Not 
Related: 
There is no medical evidence to suggest that the AE is related to the 
study vaccine. The event can be readily explained by the subject’s 
underlying medical condition or concomitant therapy or lacks a 
plausible temporal relationship to the study vaccine. 
PPD

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Possibly Related: 
A direct cause and effect relationship between the study vaccine and the 
AE has not been demonstrated but there is a reasonable possibility that 
the event was caused by the study vaccine. 
Probably Related: 
There probably is a direct cause and effect relationship between the AE 
and the study vaccine. A plausible biologic mechanism and temporal 
relationship exist and there is no more likely explanation. 
Definitely Related: 
There is a direct cause and effect relationship between the AE and the 
study vaccine. Reactions at the injection site (redness, swelling, and 
pain) will automatically be entered as definitely related to the study 
vaccine. 
AE outcomes will be classified as recovered/resolved, not recovered/not resolved, 
recovered/resolved with sequelae, recovering/resolving, or death. 
13.1.10Reporting of SAEs to Health Authorities and IRB 
Medicago or its designee will be responsible for reporting SAEs that are deemed both possibly 
related to the study vaccine and considered to be unexpected (‘unexpected’ refers to events that 
do not appear in the package labeling or in the study vaccine IB) to the regulatory authorities in 
an expedited manner. 
The Investigator will be responsible for reporting the SAEs that meet IRB reporting requirements 
directly to the relevant ethical review board as soon as possible, and will also provide the ethical 
review board with any safety reports prepared by Medicago or its designee. 
All SAEs that are suspected, unexpected serious adverse reactions (SUSARs) should be reported 
to regulatory authorities by facsimile or electronic transmission as soon as possible but, in no 
event, later than seven calendar days for deaths and life-threatening events, and 15 calendar days 
for other SAEs after Medicago's (or its designee’s) initial receipt of the information. These 
events should be followed to resolution, stabilization, or return to baseline, regardless of 
conclusion of the study. 
14 
INVESTIGATIONAL PRODUCT INFORMATION 
14.1 
Identity of Investigational Product 
The study vaccine is a Quadrivalent VLP Influenza Vaccine composed of recombinant H1, H3, 
and two B proteins (hemagglutinin) expressed as VLPs. 
14.1.1 Study Vaccine Composition 
The Quadrivalent VLP Influenza Vaccine consists of a mix of VLPs from four strains, each 
bearing the hemagglutinin of one of the recommended virus strains (2018-2019 influenza 
season), in a phosphate buffered saline (PBS) solution (100 mM NaKPO4, 150 mM 
NaCl) and 0.01 % polysorbate 80 at pH 7.4). The Quadrivalent VLP Influenza Vaccine will be 
supplied in type 1 glass pre-filled syringes. 

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14.2 
Active Comparator 
The active comparator will be either Fluarix® (produced by GlaxoSmithKline and marketed as 
Fluarix® Tetra or Fluarix® Quadrivalent in different regions) and/or FluLaval® (produced by ID 
Biomedical of Quebec and distributed by GlaxoSmithKline Inc as either FluLaval® Tetra or 
FluLaval® Quadrivalent in different regions). These quadrivalent influenza vaccines contains 
four split-virion, inactivated influenza virus strains propagated in embryonated chicken eggs, 
based on the influenza strains recommended by WHO for the 2018-2019 influenza season. Each 
0.5 mL dose of vaccine contains 15 µg of hemagglutinin of each of the four influenza virus 
strains. 
14.3 
Preparation and Administration of Study Vaccine 
The study treatment (including both the VLP vaccine and the active comparator) will be prepared 
by unblinded staff members at the clinical site as described in the Investigational Product 
Management Manual. The prepared study treatment will subsequently be administered to 
subjects by an unblinded staff member. 
Note: The personnel responsible for treatment preparation can also perform the vaccination (if 
certified and qualified to do it) as this person would already be unblinded. The unblinded staff 
members must not be involved in the evaluation of any AEs or reactogenicity evaluations 
following vaccination. 
The products to be used for study treatment administration will be handled in a clean 
environment in an aseptic manner for preparation for injection as follows: 
• For the administration of the 30 μg/strain vaccine dose, the site will use a pre-filled syringe; 
• For the administration of the 15 μg/strain active comparator, 0.5 mL (15 µg/strain), the site 
will prepare and administer the vaccine as per the manufacturer’s information. 
All study treatments will be administered as an IM injection of 0.5 mL. The needle to be used for 
the injection should be of sufficient length to reach the substance of the muscle. According to 
randomization scheme, subjects will receive either the Quadrivalent VLP Influenza Vaccine 
(30 μg/strain) or the active comparator in the deltoid muscle of (preferably) the non-dominant 
arm. Whenever possible, the injection will be given in the opposite arm from which blood 
samples are drawn, when applicable. 
The product administered will be recorded in the Investigational Product Accountability Records 
form (refer to Investigational Product Management Manual) by the clinical site, which will be 
separate from the study medication record for drug preparation. After drug accountability 
monitoring and reconciliation has been completed by the site and unblinded monitor, all study 
treatments (unused syringes and used and unused vials) will be destroyed locally upon 
Medicago’s approval or returned to Medicago (or its designee) in accordance with instructions 
provided in the Investigational Product Management Manual. 
Further specific information relating to treatment preparation, storage, and shipment is provided 
in the Investigational Product Management Manual. 

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14.4 
Preparation, Handling, Storage, and Precautions for Use 
The study treatment should be stored in an access-restricted area between 2 ºC and 8 ºC and 
protected from light; the vaccine should, however, be at room temperature before administration 
(i.e. the vaccine should not be administered cold and should be taken out of the refrigerator at 
least five minutes prior to administration). In the event of a storage temperature deviation outside 
of the permitted window of 2 ºC to 8 ºC, the study treatment should be quarantined (at the 
required storage temperature) and Medicago (or its designee) contacted immediately. 
Note: The vaccine must NEVER be frozen, since freezing destroys activity; any vaccine that 
has been frozen must not be used. 
Note: The vaccine must NEVER be shaken or vortexed. 
Note: The treatments must NOT be administered intravenously, subcutaneously, or 
intradermally. 
The Investigational Product Management Manual provides additional details on treatment 
preparation, handling and storage. 
14.5 
Packaging 
The Quadrivalent VLP Influenza Vaccine will be packaged in boxes containing pre-filled 
syringes of the same treatment. The active comparator will be provided as packaged by the 
manufacturer. 
14.6 
Labeling 
The pre-filled syringes and the vials will have a product and study-specific label containing 
information that meets the applicable regulatory requirements. The study dispensing labels will 
include study identifier, name of treatment (or code), directions for use, route of administration, 
storage conditions, and a period of use. 
Blinding measures will be applied to maintain the observer-blindness of the blinded staff and to 
allow identification of the study treatment only by staff involved in the 
preparation/administration of the study vaccine/active comparator. 
14.7 
Drug Accountability 
The Investigator is responsible for ensuring that all study treatments received at the site are 
inventoried and accounted for throughout the study. The dispensing of study treatment to each 
subject must be documented on the Investigational Product Accountability Records form. 
The study treatments or drugs must be handled in strict accordance with the Investigational 
Product Management Manual and the syringe and vial label and will be stored in a limited access 
area or in a locked cabinet under appropriate environmental conditions. All unused study drugs 
must be available for verification by Medicago’s (or its designee’s) unblinded site monitor 
during on-site monitoring visits. The return of all unused study drugs to Medicago (or its 
designee) for destruction will be documented on the Drug Return Form. When the site is 

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authorized by Medicago (or its designee) to destroy study drug supplies on site, this must also be 
documented. 
The study drug should be dispensed under the supervision of the Investigator (or a qualified 
member of the investigational staff), who remains blinded as to which treatment is administered. 
The study drug will be supplied only to subjects participating in the study. Returned study drugs 
may not be relabeled or reassigned for use for other subjects. The Investigator agrees neither to 
dispense the study drug from, nor to store it at, any site other than the study centers agreed upon 
with Medicago (or its designee). 
15 
STUDY-SPECIFIC MATERIALS 
The Investigator will be provided with the following: 
• eCRF; 
• Source documents (when applicable); 
• Forms and questionnaires for special assessments; 
• Thermometers and measurements template; 
• Study manuals. 
16 
ETHICAL ASPECTS 
16.1 
Study-Specific Design Considerations 
On-going medical review will be performed by Medicago (or its designee) throughout the 
duration of the study; subjects will be given any new information that may affect their decision 
to continue participation in the study. 
Since the use of a placebo would raise ethical concerns for individuals of this age group (65 
years of age and older), who are considered at risk of complications from seasonal influenza, the 
control selected for this study is an active comparator. 
Blood samples will be collected from a subset of subjects for immunogenicity analysis, although 
not all may be analysed (sample analyses may be restricted to those subjects who present with 
influenza during the surveillance period). Since blood sample collection is a minimally invasive 
procedure and the amount of blood collected will be a relatively small amount (Table 5), the 
benefits of obtaining this data outweigh the small level of risk associated with the collection of 
samples that may not require analysis. 
16.2 
Regulatory Ethics Compliance 
16.2.1 Investigator Responsibilities 
The Investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Conference on Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and applicable regulatory and country-specific requirements. 

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GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are reliable. 
16.2.2 Independent Ethics Committee or Institutional Review Board 
Before the start of the study, the Investigator (or Medicago, where required) will provide the 
independent ethics committee (IEC)/IRB with current and complete copies of the following 
documents (as required by local regulations): 
• Final protocol and, if applicable, amendments to the protocol; 
• Sponsor-approved ICF (and any other written materials to be provided to the subjects); 
• IB (or equivalent information) and amendments/addenda; 
• Sponsor-approved subject recruiting materials; 
• Information on compensation for study-related injuries or payments to subjects for 
participation in the study, if applicable; 
• Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB); 
• Information regarding funding, name of the sponsor, institutional affiliations, other 
potential conflicts of interest, and incentives for subjects; 
• Any other documents that the IEC/IRB requests to fulfill its obligation. 
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative in nature, with 
no consequences for subjects, data, or study conduct), the ICF, applicable recruiting materials, 
and subject compensation programs, and Medicago (or its designee) has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. In addition, the Investigator must wait for written confirmation from 
Medicago (or its designee) that the study can be started. 
During the study, the Investigator (or Medicago [or its designee], where required) will send the 
following documents and updates to the IEC/IRB for their review and approval, where 
appropriate: 
• Protocol amendments; 
• Revision(s) to ICF and any other written materials to be provided to subjects; 
• If applicable, new or revised subject recruiting materials approved by Medicago; 
• Revisions to compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable; 
• New edition(s) of the IB and amendments/addenda; 

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• Summaries of the study at intervals stipulated in guidelines of the IEC/IRB (at a minimum, 
annually); 
• Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug 
(when applicable); 
• New information that may adversely affect the safety of the subjects or the conduct of the 
study; 
• Deviations from or changes to the protocol to eliminate immediate hazards to subjects; 
• Reports of deaths of subjects under the Investigator’s care; 
• Notification if a new Investigator is responsible for the study at any of the sites; 
• Development Safety Update Report and Line Listings, where applicable; 
• Any other requirements of the IEC/IRB. 
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing. At the end of the study, the Investigator (or 
Medicago [or its designee], where required) will notify the IEC/IRB of study completion. 
16.2.3 Informed Consent 
Each subject who participates in the study must first give written consent according to local 
requirements after the nature of the study has been fully explained, including the risks and 
requirements of the study. The consent form must be signed before performing any study-related 
activity. The consent form that is used must have been approved by regulatory authorities, 
Medicago, and the reviewing IEC/IRB. The informed consent should be in accordance with 
principles that originated in the Declaration of Helsinki, current ICH and GCP guidelines, 
applicable regulatory requirements, and Medicago policy. During the study, subjects will be 
given any new information that may affect their decision to continue their participation in the 
study. They will be told that their consent to participate is voluntary and that it may be 
withdrawn at any time, with no reason given, and without penalty or loss of benefits to which 
they would otherwise be entitled. Only subjects who are fully able to understand the risks, 
benefits, and potential AEs of the study and who provide their consent voluntarily will be 
enrolled. 
16.2.4 Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to support the development, registration, and future 
marketing of the investigational product. The data must be collected and processed with adequate 
precautions to ensure confidentiality and compliance with applicable data privacy protection 
laws and regulations. Appropriate technical and organizational measures to protect the personal 
data against unauthorized disclosures or access, accidental or unlawful destruction, or accidental 
loss or alteration must be in place. Medicago (or its designee) personnel whose responsibilities 
require access to personal data agree to keep the identity of study subjects confidential. 

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17 
ADMINISTRATIVE REQUIREMENTS 
17.1 
Protocol Amendments 
Neither the Investigator nor Medicago will modify this protocol without a formal amendment. 
All protocol amendments must be issued and approved by Medicago, and signed and dated by 
the Investigator. Protocol amendments must not be implemented without prior IEC/IRB approval 
or when the relevant competent authority has raised any grounds for non-acceptance, except 
when necessary in order to eliminate an immediate hazard to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the Investigator and IEC/IRB must be provided to 
Medicago or its designee. 
Note that administrative changes may be implemented without prior IRB approval; however, 
the Investigator or Medicago, as applicable, must notify the IRB of any administrative change 
and ensure that the IRB acknowledges receipt of the administrative changes. 
The Investigator is responsible for notifying the IRB of all protocol amendments and ensuring 
that the IRB has approved any amendments when local IRBs are used. When a central IRB is 
used, Medicago or its designee will inform the IRB on behalf of the sites. 
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the Investigator or other physician in attendance will contact the appropriate Medicago 
representative or its designee (see Contact Information pages provided separately). Except in 
emergency situations, this contact should be made before implementing any departure from the 
protocol. In all cases, contact with Medicago or its designee must be made as soon as possible to 
discuss the situation and to agree on an appropriate course of action. The data recorded in the 
eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances that made a deviation necessary. 
17.2 
Regulatory Documentation 
17.2.1 Regulatory Approval/Notification 
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, as applicable. A study may not be initiated until all local regulatory 
requirements are met. 
17.3 
Source Documentation 
At a minimum, source documentation must be available for the following information: 
• Subject identification, eligibility, and study identification; 
• ICF discussion and date of informed consent; 
• Dates of visits; 
• Results of safety and study procedures as required by the protocol; 
• Record of all reactions, AEs, respiratory illnesses, ILIs, and associated follow ups; 

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• Concomitant medication; 
• Drug receipt, dispensing, and return records; 
• Study drug administration information; 
• Date of study completion and reason for early discontinuation of study drug or withdrawal 
from the study, if applicable. 
It is recommended that the author of an entry in the source documents be identifiable. 
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. If 
Investigator judgement was used in the determination of eligibility, an explanation for inclusion 
of the subject in the study must be provided in the source documents. Specific details required as 
source data for the study will be reviewed with the Investigator before the study and will be 
described in the monitoring guidelines (or other equivalent document). 
17.3.1 Diary and Memory Aid 
Subjects will be provided with a diary in which to record reactions and other safety information. 
Subject diaries are considered source documents; the diary will be returned by the subject to the 
site after Day 21 (the method of return will be defined in the study-specific documentation) and 
kept with each subject’s study chart. In the event the diary is lost by the subject, information 
collected by the coordinator or designee and information recalled by the subject will serve as the 
source data for this subject. The recalled information will be captured in the source documents. 
Corrections to data entered by the subject in the diary should only be performed by the subject 
him/herself, when possible. Clarifications can be made in the comment section of the diary by 
the study personnel if the subject is not present onsite to make the correction him/herself. 
Subjects will be provided with a memory aid to record information on respiratory illnesses and 
ILIs, and to record information on SAEs, NOCDs, AEs leading to withdrawal, and reportable 
concomitant medications from the Day 21 visit to the end of the study. These memory aids will 
not be collected by the site and are intended to be used by the subject to help them in reporting 
this information to site staff. 
17.4 
Case Report Form Completion 
An eCRF will be provided for each subject who is randomized and receives a dose of study drug. 
Screening failures will also be entered in an eCRF; data entered should include date of birth and 
reason for screening failure. 
Data must be entered into the eCRFs in English. The Investigator must verify that all data entries 
in the eCRFs are accurate and correct. All eCRF entries, corrections, and alterations must be 
made by the Investigator or other authorized study-site personnel. 

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17.5 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Medicago (or its designee) procedures, the 
site will be contacted prior to the study start to review the protocol and study requirements with 
the clinical study staff. Medicago (or its designee) will review their responsibilities to satisfy 
regulatory, ethical, and company (Medicago) requirements. 
The Investigator or institution, if applicable, will authorize and provide direct access to all 
relevant documents to allow review of the appropriate conduct of the study by Medicago’s (or its 
designee’s) monitor. The Investigator(s) must allocate their time and the time of their staff to the 
monitors, discuss any findings or issues, and take appropriate actions to maintain the quality and 
integrity of the study data and conduct. 
Protocol deviations will be reviewed by Medicago (or its designee) to identify any non-
compliances likely to have a significant effect on the safety and rights of a subject or the 
reliability and robustness of the data generated. These deviations will be included in the clinical 
study report. 
17.6 
Quality Assurance 
To ensure compliance with GCP and all other applicable regulatory requirements, Medicago (or 
its designee) may conduct quality assurance assessments and/or an audit of the site. Regulatory 
agencies may conduct regulatory inspections at any time during or after completion of the study. 
If an audit or an inspection is conducted, the Investigator and/or institution (if applicable) must 
agree to grant auditors or inspectors direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss the conduct of the study and any findings or issues, and 
to implement corrective and/or preventative actions to address any findings or issues identified. 
17.7 
Record Retention 
Following closure of the study, the Investigator must maintain all site study records in a safe and 
secure location. The records must be easily accessible when needed (e.g. for a Medicago [or its 
designee] audit or regulatory inspection) and must be available for review in conjunction with 
assessment of the facility, supporting systems, and relevant site staff. 
When permitted by local laws and regulations or institutional policy, some or all of the records 
may be maintained in a format other than a hard copy (e.g. scanned electronic). The Investigator 
must ensure that all reproductions are legible and are a true and accurate copy of the original. 
The Investigator must follow the time period for retaining the site records in order to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to a particular site, as dictated by local laws and regulations, Medicago (or its 
designee) standard operating procedures (SOPs), and/or institutional requirements. The 
Investigator must contact Medicago (or its designee) prior to the disposal of any study 
documents at the end of the retention period. 
If the responsible Investigator retires, relocates, or, for any other reason, withdraws from the 
responsibility of keeping the study records, custody must be transferred to another person who 

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will accept the responsibility. Medicago (or its designee) must be notified in writing of the name 
and address of the new custodian. Under no circumstance shall the Investigator relocate or 
dispose of any study documents without having obtained prior written approval from Medicago 
(or its designee). 
If it becomes necessary for Medicago or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such reports. 
17.8 
Study Completion/Termination 
17.8.1 Study Completion 
The study will be considered to be completed with the last contact with the last subject 
participating in the study. The final data from the investigational site will be sent to Medicago 
(or designee) after completion of the final subject visit at that site. Investigational sites will be 
closed after study completion. An investigational site is considered closed when all required 
documents and study supplies have been collected, all data have been entered, monitored, 
locked, and signed and a site closure visit has been performed. 
17.8.2 Study Termination 
Medicago (or its designee) reserves the right to close the investigational site or terminate the 
study at any time for any reason at the sole discretion of Medicago. Investigational sites will be 
closed after study termination once Medicago (or its designee) has completed all study related 
tasks. Reasons for the early closure of an investigational site by Medicago (or its designee) or the 
Investigator may include, but are not limited to: 
• Failure of the Investigator to comply with the protocol, Medicago’s (or its designee’s) 
procedures, or GCP guidelines; 
• Inadequate recruitment of subjects by the Investigator; 
• Discontinuation of further drug development. 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended closure. 
Site closure following an Investigator request can only be performed when all active study 
subjects have completed the study period, Medicago (or its designee) has collected all required 
documents and study supplies, and all data have been entered, monitored and locked. 
17.9 
Registration of Clinical Studies and Disclosure of Results 
Study information from this study will be posted on publicly available clinical trial registries in 
countries where applicable and will include information required by law. In addition, the results 
summary will be posted to the same clinical trial registries, to the extent specified by law, and 
will include information required by regulatory authorities. 

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18 
REFERENCES 
CDC. Seasonal Influenza (Flu): What You Should Know and Do this Flu Season If You Are 65 
Years and Older; cited 12 February 2018.. Available from 
https://www.cdc.gov/flu/about/disease/65over.htm 
DiazGranados C, Denis M, Plotkin S. Seasonal influenza vaccine efficacy and its determinants in 
children and non-elderly adults: a systematic review with meta-analyses of controlled 
trials. Vaccine. 2012;31(1):49-57.  
FDA. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. 
Jefferson T, Rivetti D, Rivetti A, Rudin W, DiPietrantonj C, Demicheli V. Efficacy and 
effectiveness of influenza vaccines in elderly people: a systematic review. The Lancet. 
2005;366(9492):1165-1174. 
McElhaney JE. Influenza Vaccine Responses in Older Adults. Ageing Res Rev. 2011;10(3):379-
388. 
Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, 
Bridges CB. The annual impact of seasonal influenza in the US: measuring disease 
burden and costs. Vaccine. 2007;25(27):5086-5096.  
Osterholm M, Kelley N, Sommer A, Belongia E. Efficacy and effectiveness of influenza 
vaccines: a systematic review and meta-analysis. The Lancet Infectious Diseases. 
2012;12(1):36-44.  
Palache A. Seasonal influenza vaccine provision in 157 countries (2004-2009) and the potential 
influence of national public health policies. Vaccine. 2011;29(51):9459-9466.  
Skowronski DM, Chambers C, Sabaiduc S, De Serres G, Dickinson JA, Winter AL, Drews SJ, 
Fonseca K, Charest H, Gubbay JB, Petric M, Krajden M, Kwindt TL, Martineau C, 
Eshaghi A, Bastien N, Li Y. Interim estimates of 2014/15 vaccine effectiveness against 
influenza A(H3N2) from Canada's Sentinel Physician Surveillance Network. 
2015;20(4):21022. 
Zost SJ, Parkhouse K, Gumina ME, Kim K, Perez SD, Wilson PC, Treanor JJ, Sant AJ, Cobey S, 
Hensley SE. Contemporary H3N2 influenza viruses have a glycosylation site that alters 
binding of antibodies elicited by egg-adapted vaccine strains. PNAS. 
2017;114(47):12578-12583. 
 
 

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19 
APPENDICES 
The clinical documents included in the appendices are meant as examples only; the actual 
documents used during the trial may differ slightly. 
19.1 
Appendix 1 – Sample Ruler to Measure Local Reactions