A Randomized, Observer-blind, Multicenter, Phase 3 Study to Evaluate the Lot Consistency, Immunogenicity, and Safety of a Plant-Derived Quadrivalent VLP Influenza Vaccine in Healthy Adults 18-49 Years of Age
Phase: PHASE3
Conditions: Virus Diseases, RNA Virus Infections, Respiratory Tract Infections, Respiratory Tract Disease, Influenza
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, Multicenter, Phase 3 Study to Evaluate the Lot 
Consistency, Immunogenicity, and Safety of a Plant-Derived Quadrivalent VLP 
Influenza Vaccine in Healthy Adults 18-49 Years of Age 
CP-PRO-QVLP-011; 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 1.3 
Date: 
08 August 2017 

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INVESTIGATOR AGREEMENT 
I have read the version 1.3 (dated 08 August, 2017) Protocol No. CP-PRO-QVLP-011 titled, “A 
Randomized, Observer-blind, Multicenter, Phase 3 Study to Evaluate the Lot Consistency, 
Immunogenicity, and Safety of a Plant-Derived Quadrivalent VLP Influenza Vaccine in Healthy 
Adults 18-49 Years of Age”. 
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), 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 
SIGNATURE .................................................................................................................................. 2 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 7 
SYNOPSIS ...................................................................................................................................... 8 
ABBREVIATIONS ...................................................................................................................... 13 
1 
INTRODUCTION ................................................................................................................. 14 
1.1 
Background .................................................................................................................... 15 
1.2 
Pre-clinical Studies ......................................................................................................... 15 
1.3 
Clinical Studies .............................................................................................................. 15 
1.3.1 
Safety Overview...................................................................................................... 16 
1.3.2 
Immunogenicity Overview ..................................................................................... 17 
1.4 
Overall Rationale for the Study ...................................................................................... 18 
2 
OBJECTIVES ........................................................................................................................ 19 
2.1 
Primary Objectives ......................................................................................................... 19 
2.2 
Secondary Objectives ..................................................................................................... 19 
3 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ............................ 19 
4 
STUDY DESIGN AND RATIONALE ................................................................................. 19 
4.1 
Overview of Study Design ............................................................................................. 19 
4.2 
Rationale of Study Design.............................................................................................. 20 
4.2.1 
Randomization ........................................................................................................ 20 
4.2.2 
Observer-blinding ................................................................................................... 20 
4.2.3 
Dose Selection ........................................................................................................ 20 
4.2.4 
Study Duration ........................................................................................................ 20 
4.2.5 
Immunogenicity Assessments ................................................................................. 20 
5 
STUDY POPULATION ........................................................................................................ 21 
5.1 
Inclusion Criteria ............................................................................................................ 21 
5.2 
Exclusion Criteria ........................................................................................................... 22 
5.3 
Prior and Concomitant Therapy ..................................................................................... 24 
5.4 
Prohibited Therapy ......................................................................................................... 24 
6 
TREATMENT ALLOCATION AND BLINDING .............................................................. 24 

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6.1 
Randomization ............................................................................................................... 24 
6.2 
Blinding .......................................................................................................................... 25 
7 
DOSAGE AND ADMINISTRATION .................................................................................. 25 
8 
SPECIMENS AND CLINICAL SUPPLIES ......................................................................... 25 
8.1 
Management of Samples ................................................................................................ 25 
8.2 
Clinical Supplies ............................................................................................................ 26 
9 
TREATMENT COMPLIANCE ............................................................................................ 26 
10 STUDY EVALUATIONS ..................................................................................................... 26 
10.1 Study Procedures ............................................................................................................ 26 
10.1.1 
Overview ................................................................................................................. 26 
10.1.2 
Screening/Vaccination (Visit 1) .............................................................................. 26 
10.1.3 
Day 1 and Day 8 (Telephone Contact) ................................................................... 30 
10.1.4 
Day 21 (Visit 2) ...................................................................................................... 30 
10.2 Immunogenicity ............................................................................................................. 31 
10.2.1 
Evaluations .............................................................................................................. 31 
10.2.2 
Immunogenicity Endpoints ..................................................................................... 31 
10.3 Safety .............................................................................................................................. 32 
10.3.1 
Evaluations .............................................................................................................. 32 
10.3.2 
Pregnancy ................................................................................................................ 34 
10.3.3 
Safety Endpoints ..................................................................................................... 34 
10.3.4 
Memory Aid ............................................................................................................ 35 
11 SUBJECT COMPLETION / WITHDRAWAL .................................................................... 35 
11.1 Temporary Contraindications ......................................................................................... 35 
11.2 Screening Failures .......................................................................................................... 35 
11.3 Removal of Subjects from Assessment .......................................................................... 36 
11.3.1 
Follow-up of Discontinuations ............................................................................... 36 
11.3.2 
Lost to Follow-up Procedures ................................................................................. 36 
11.4 Interruption of the Study ................................................................................................ 36 
12 STATISTICAL METHODS.................................................................................................. 37 
12.1 Analysis Populations ...................................................................................................... 37 
12.1.1 
Safety Analysis Set ................................................................................................. 37 
12.1.2 
Full Analysis Set ..................................................................................................... 37 

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12.1.3 
Per Protocol Set....................................................................................................... 37 
12.2 Sample Size Determination ............................................................................................ 37 
12.3 Immunogenicity Analyses .............................................................................................. 37 
12.3.1 
Analysis of Primary Endpoints ............................................................................... 38 
12.3.2 
Analysis of Secondary Endpoints ........................................................................... 38 
12.4 Baseline and Subject Disposition ................................................................................... 38 
12.5 Safety Analyses .............................................................................................................. 38 
13 ADVERSE EVENT REPORTING ....................................................................................... 39 
13.1 Definitions ...................................................................................................................... 39 
13.1.1 
Serious Adverse Events .......................................................................................... 39 
13.1.2 
Adverse Events ....................................................................................................... 40 
13.1.3 
Adverse Events of Special Interest ......................................................................... 41 
13.1.4 
New Onset of Chronic Disease ............................................................................... 41 
13.1.5 
Expectedness of an Adverse Drug Reaction ........................................................... 41 
13.1.6 
Initial SAE Reporting by the Investigator .............................................................. 41 
13.1.7 
Follow-up Reporting by the Investigator ................................................................ 42 
13.1.8 
Reporting of SAEs Occurring after Detection Period or Study Termination ......... 42 
13.1.9 
Causal Relationship ................................................................................................ 42 
13.1.10 Reporting of SAEs to Health Authorities and IRB ................................................. 43 
14 INVESTIGATIONAL PRODUCT INFORMATION .......................................................... 43 
14.1 Identity of Investigational Product ................................................................................. 43 
14.1.1 
Study Vaccine Composition ................................................................................... 44 
14.1.2 
Independence between Vaccine Lots ...................................................................... 44 
14.1.3 
Preparation and Administration of Study Vaccine ................................................. 44 
14.1.4 
Preparation, Handling, Storage, and Precautions for Use ....................................... 45 
14.2 Packaging ....................................................................................................................... 45 
14.3 Labeling .......................................................................................................................... 45 
14.4 Drug Accountability ....................................................................................................... 45 
15 STUDY-SPECIFIC MATERIALS........................................................................................ 46 
16 ETHICAL ASPECTS ............................................................................................................ 46 
16.1 Study-Specific Design Considerations ........................................................................... 46 
16.2 Regulatory Ethics Compliance ....................................................................................... 46 

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16.2.1 
Investigator Responsibilities ................................................................................... 46 
16.2.2 
Independent Ethics Committee or Institutional Review Board .............................. 46 
16.2.3 
Informed Consent.................................................................................................... 48 
16.2.4 
Privacy of Personal Data ......................................................................................... 48 
17 ADMINISTRATIVE REQUIREMENTS ............................................................................. 48 
17.1 Protocol Amendments .................................................................................................... 48 
17.2 Regulatory Documentation ............................................................................................ 49 
17.2.1 
Regulatory Approval / Notification ........................................................................ 49 
17.3 Source Documentation ................................................................................................... 49 
17.4 Case Report Form Completion ....................................................................................... 50 
17.5 Quality Control (Study Monitoring) .............................................................................. 50 
17.6 Quality Assurance .......................................................................................................... 50 
17.7 Record Retention ............................................................................................................ 50 
17.8 Study Completion / Termination .................................................................................... 51 
17.8.1 
Study Completion ................................................................................................... 51 
17.8.2 
Study Termination .................................................................................................. 51 
17.9 Registration of Clinical Studies and Disclosure of Results............................................ 52 
18 References ............................................................................................................................. 53 
19 APPENDICES ....................................................................................................................... 54 
19.1 Appendix 1 – Sample Memory Aid Diary (Day 0 to Day 21) ....................................... 54 
19.2 Appendix 2 – Sample Ruler to Measure Local Reactions ............................................. 61 
 
LIST OF TABLES 
Table 1 Time and Events Schedule ............................................................................................... 12 
Table 2 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent VLP 
Influenza Vaccine ............................................................................................................. 16 
Table 3 Study Administrative Structure ....................................................................................... 19 
Table 4 Estimated Blood Volume Drawn ..................................................................................... 26 
Table 5 Severity Grades for Solicited Local and Systemic Reactions .......................................... 32 
 
 
 

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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 proteins (hemagglutinin) 
expressed as virus-like particles (VLPs) for the 2016-2017 
influenza virus strains in the Northern hemisphere. 
Protocol Title: 
A Randomized, Observer-blind, Multicenter, Phase 3 Study to 
Evaluate the Lot Consistency, Immunogenicity, and Safety of a 
Plant-Derived Quadrivalent VLP Influenza Vaccine in Healthy 
Adults 18-49 Years of Age 
Protocol Number: 
CP-PRO-QVLP-011 
Development Phase: 
Phase 3 
Study Center(s): 
Multiple sites in Canada 
Study Rationale: 
This Phase 3 study is intended to assess the clinical lot-to-lot 
consistency in manufacturing by evaluating and comparing the 
immunogenicity of three consecutively manufactured lots of the 
Quadrivalent VLP Influenza Vaccine, during the 2016-2017 
influenza season, in healthy adults 18-49 years of age. A single 
dose of one of three consecutive lots of Quadrivalent VLP 
Influenza Vaccine (30 µg/strain) will be administered to 1,200 
subjects. The study is intended to support consistency of the 
manufacturing process and therefore support the licensure of the 
vaccine in Canada, the United States (USA), and Europe. 
Planned Study Period: 
The Day 0 (Screening/Vaccination) visit will occur between 
September and October 2017. 
The last study blood sample (Day 21) will be collected in 
November 2017. 
Study Objectives 
  Primary Objective: 
• To assess the consistency of three consecutive manufacturing 
lots of the Quadrivalent VLP Influenza Vaccine given at a dose 
of 30 µg/strain, as measured by the serum hemagglutination 
inhibition (HI) antibody titers on Day 0 and Day 21. 

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  Secondary Objectives: 
Safety: 
• To assess the safety and tolerability of a single dose of the 
Quadrivalent VLP Influenza Vaccine given at a dose of 
30 µg/strain. 
Immunogenicity: 
• To assess the immunogenicity of a single dose of Quadrivalent 
VLP Influenza Vaccine given at a dose of 30 µg/strain against 
homologous influenza strains. 
Number of Planned 
Subjects: 
Approximately 1,200 subjects are planned for randomization in a 
1:1:1 ratio to receive one of three lots of Quadrivalent VLP 
Influenza Vaccine at a dose of 30 µg/strain. 
Sample Size 
Determination: 
Based on data from the CP-Q14VLP-009 study, a sample size of 
400 subjects per lot (a total of 1,200 subjects) will have a greater 
than 90 % power to detect consistency between the lots (i.e. to 
test that the pairwise comparisons of the two-sided 95 % 
confidence interval (CI) for adjusted geometric mean titer (GMT) 
ratios of the three lots being tested [lot 1/lot 2, lot 1/lot 3, lot 2/lot 
3] fall within the equivalence range of 0.67 to 1.5 for all four 
homologous strains). 
A drop-out rate and exclusion from the per protocol (PP) 
population of approximately 10 % was assumed in the sample 
size calculation. 
Study Population: 
Healthy male and female subjects 18 to 49 years of age and with 
no clinically significant disease at the time of vaccination are to 
be included in this study. The subjects must understand and agree 
to comply with study procedures and be available throughout the 
study. Subjects must not have received any influenza vaccine in 
the last 24 months. 
Dosage and 
Administration: 
On Day 0, subjects will receive one intramuscular (IM) injection 
of 0.5 mL of their assigned vaccine lot (lot 1 or 2 or 3) of 
30 µg/strain Quadrivalent VLP Influenza Vaccine. 
Study Design: 
This is a randomized, observer-blind, multicenter, Phase 3 lot 
consistency study. 
Subjects will participate in this study for approximately 21 days, 
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 memory aid (MA), 
concomitant medications, and medical history; a visit will occur 

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on Day 21 for blood sample collection for immunogenicity 
assessment. 
Primary Evaluations 
and Endpoints: 
Immunogenicity: 
Immunogenicity will be evaluated by the immune response, as 
measured by the serum HI antibody titers on Day 0 and Day 21: 
• GMTs of the three vaccine lots (21 days after vaccination) for 
all four vaccine strains. 
Secondary Endpoints: 
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 treatment-emergent 
adverse events (TEAEs) for 21 days following study vaccine 
administration; 
• Occurrences of deaths, serious adverse events (SAEs), adverse 
events (AEs) leading to withdrawal, and new onset of chronic 
disease (NOCD) up to Day 21. 
Immunogenicity: 
• HI antibody response induced by the Quadrivalent VLP 
Influenza Vaccine (pooled data from the three lots) against the 
homologous influenza strains on Days 0 and 21; HI antibody 
titers will be analyzed using the following parameters: 
seroconversion (SC) rate, seroprotection (SP) rate, and 
geometric mean fold rise (GMFR). 
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 PP set) according to the statistical analysis plan (SAP). 
The analyses of the primary endpoint (Day 21 GMT), as well as 
the analyses of the secondary endpoints (SC rate, SP rate, and 
GMFR) for each strain will be performed using the PP set. The 
primary immunogenicity endpoint analyses will also be 
performed on the FAS to support results from the PP set. 
All safety analyses will be performed using the SAS. 

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Statistical Analyses: 
In general, continuous data will be summarized using descriptive 
statistics (i.e. mean or geometric mean, median, standard 
deviation, minimum, and maximum). Categorical data will be 
summarized using the number and percent of subjects in each 
category. 
Immunogenicity Analyses: 
The immunologic equivalence of three separate production lots of 
the Quadrivalent VLP Influenza Vaccine will be measured in 
terms of GMTs, as measured by HI assay, against all vaccine 
influenza strains. Lot-to-lot consistency is based on adjusted Day 
21 GMT ratios for pairwise comparisons of the lots (lot 1/lot 2, 
lot 1/lot 3, and lot 2/lot 3). For each pairwise comparison of the 
lots, the lot-to-lot consistency will be demonstrated if the two-
sided 95 % CIs on the adjusted Day 21 GMT ratios fall within the 
equivalence range of 0.67 to 1.5 for all four strains. 
For the secondary immunogenicity analysis (conducted on the 
pooled data of the three lots), the point estimates and the 
corresponding two-sided 95 % CI will be calculated to determine 
if the CI meets the USA Center for Biologics Evaluation and 
Research (CBER) criteria for SC rate and SP rate. The 
immunogenicity endpoints for all four homologous influenza 
antigens will be evaluated according to the CBER) criteria for SC 
rate and SP rate. 
Safety Analyses: 
Safety data will be summarized using descriptive statistics as 
pooled data of all three lots: 
•  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 study (Day 21). 
 
 
 

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Table 1 Time and Events Schedule 
Visit Type 
Screening/ Vaccination 
Post-vaccination Visits/Contacts 
Study Day 
Day 0 
Day 1 (+ 1) 
Day 8 
(- 1/+ 1) 
Day 21 
(- 2/+ 3) 
Visit Number 
1 
Phone 
Phone 
2 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history/prior medication 
X 
 
 
 
Vaccination history1 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Randomization 
X 
 
 
 
Vaccine administration 
X 
 
 
 
Immediate surveillance (15 min) 
X 
 
 
 
Serology for HI titers 
X 
 
 
X 
Vital Signs (blood pressure [BP], heart 
rate [HR], oral temperature [OT]) 
X 
 
 
 
Height, weight, and body mass index 
(BMI) 
X 
 
 
 
History/symptom-directed physical 
examination 
X 
 
 
X2 
Urine (dipstick) pregnancy test 
X 
 
 
X 
Memory aid (MA)3 and digital 
thermometer instructions 
X 
 
 
 
Collection of solicited local/ systemic 
reactions 
X 
X 
X 
 
Concomitant medications 
At any time during the study period 
AEs, SAEs, and NOCDs 
X 
X 
X 
X 
1 Information on past influenza vaccinations for two years prior to study entry; subjects who received an 
influenza vaccine within 24 months prior to study start are to be excluded from the study. 
2 History/symptom-directed physical examinations will be performed on Day 21 if deemed necessary by the 
Investigator. If a subject complains of arm and/or shoulder pain of the vaccinated arm or neck pain on the day of 
the visit, a direct examination of the lymph nodes for swelling (neck and axilla) will be performed by the 
Investigator. 
3 The MA must be verified with the subject for completeness. All corrections must be made by the subjects 
before leaving the clinic. 
 
 

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ABBREVIATIONS 
AE 
adverse event 
BMI 
body mass index 
BP 
blood pressure 
CBER 
Center for Biologics Evaluation and Research 
CI 
confidence interval 
DP 
drug product 
DS 
drug substance 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
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 Council for Harmonisation 
IEC 
independent ethics committee 
IM 
intramuscular 
IRB 
institutional review board 
IRT 
interactive voice response system 
MA 
memory aid 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOCD 
new onset of chronic disease 
OT 
oral temperature 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SAS® 
Statistical Analysis System® 
SC 
seroconversion 
SP 
seroprotection 
TEAE 
treatment-emergent adverse event 
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 (H) and neuraminidase (N) antigens that 
play an essential role in virus infectivity. At present, 17 H and ten N 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. In the 
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 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. 
For the 2012-2013 influenza season, vaccine efficacy numbers were particularly discouraging. 
When stratified by age group, the overall vaccine efficacy against influenza A and B viruses 
ranged from 27 % in persons 65 and older to 64 % in children (aged six months to 17 years old). 
When specific strains and age groups were examined (e.g. H3N2 in the elderly), efficacy 
estimates could be as low as 9 % (95 % CI: -84 % to 55 %). Preliminary efficacy estimates for 
the H3N2 strain in 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). 

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1.1 
Background 
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 viruses contained in the vaccine. This 
vaccine may be able to address some limitations of the currently licensed vaccines: 
• The hemagglutinin proteins in each monovalent 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-made 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. 
For more comprehensive preclinical information regarding the safety and toxicity of the 
Quadrivalent VLP Influenza Vaccine, refer to the current version of the investigator’s brochure 
(IB). 
1.3 
Clinical Studies  
Under the clinical development program for the Quadrivalent VLP Influenza Vaccine, Medicago 
has conducted five clinical trials to date (CP-Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, 
CP-Q14VLP-009, and CP-Q14VLP-010). Study designs and statuses are summarized in Table 2. 

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Table 2 Summary of Design of Clinical Studies Performed to Date with the Quadrivalent 
VLP Influenza 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-
49 years of age, 
both genders 
90 (active; 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-
49 years of age, 
both genders 
225 (active; 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 (active; 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 / 
Clinic portion 
completed 
2 
Multicenter, observer-
blind, randomized, dose 
ranging, active-
comparator clinical study 
Healthy adults aged 
18 - 64 years, both 
genders 
604 (active; ratio 
1:1); 
296 (active 
comparator) 
15 µg VLP; 
30 µg VLP; 
15 µg/strain dose of 
FluLaval® Tetra 
CP-Q14VLP-010 / 
Clinic portion 
completed 
2 
Multicenter, observer-
blind, randomized, dose 
ranging, active-
comparator clinical study 
Healthy subjects of 
65 years of age or 
older, both genders 
499 (active; 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 
Overall, a total of 1,793 normal healthy subjects have received a single dose of the Quadrivalent 
VLP Influenza Vaccine: 1,106 subjects aged from 18 to 64 years and 687 subjects 65 years of 
age and older. 
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 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 2 for a description of the basic design, status, and exposure for these studies. 
No deaths were reported for either the adults (N = 1,106) or the elderly subjects (N = 687) 
administered the Quadrivalent VLP Influenza Vaccine. A total of 21 SAEs were reported for 
subjects who received the Quadrivalent VLP Influenza Vaccine: 18 for subjects who received a 
single dose of VLP vaccine (all dose levels without adjuvant combined, N = 1,642) and three for 
subjects who received a single dose of adjuvanted VLP vaccine (both dose levels combined, 
N = 151). None of these SAEs were considered to be vaccine-related by the Investigator. No 
subject withdrew from any of the studies due to a TEAE and none of the NOCDs reported for 

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subjects who received the VLP vaccine (with and without adjuvant) were considered to be 
vaccine-related. 
The incidence of local and systemic reactions observed within seven days post-vaccination in the 
five 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, 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. 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. Few 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 biotherapeutics 
may induce hypersensitivity), the Sponsor will continue to require that appropriate medical 
treatment and supervision be 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 clinical trials 
conducted to date (CP-Q12VLP-004, CP-Q13VLP-007, CP-Q13VLP-008, CP-Q14VLP-009, 
and CP-Q14VLP-010). Studies CP-Q12VLP-004, CP-Q13VLP-007, and CP-Q14VLP-009 were 
conducted in an adult 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 population (65 years and 
older). See Table 2 for a description of the basic design, status, and exposure of these studies. 
1.3.2.1 
Antibody Response 
Overall, the immunogenicity data from the studies conducted to date show that the Quadrivalent 
VLP Influenza Vaccine induced a strong antibody response in healthy adults (18 to 64 years). 
The 30 μg/strain dose level appeared to be the lowest dose to consistently meet the CBER 
criteria. As a result, the 30 μg/strain dose level has been selected for the lot-to-lot consistency 
evaluation study to be conducted in an adult population. 

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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) studies, the 30 μg/strain dose level met the CHMP 
criteria for SC rate, SP rate, and GMFR against all four homologous strains and the CBER 
criteria for both SC rate and SP rate against all four homologous strains; 
• In study CP-Q14VLP-009, conducted in adults aged from 18 to 64 years, the 30 μg/strain 
VLP vaccine met the CBER criteria for both SC rate and SP rate, as well as the CHMP 
criterion for GMFR against all four homologous strains tested. 
For all of these studies, the HI response may have been underestimated due to the limited 
availability of assay reagents unbiased by the use of eggs for production (even when cell-based 
reagents are available, their history includes an initial expansion in embryonic-eggs). These 
reagents often include mutations of a 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 in these studies. 
Further assessment of the humoral immune response induced by the VLP vaccine included MN 
and SRH assays. No correlates of protection are currently available for these two assays and, as a 
result, data interpretation is limited. However, for both assays, the VLP vaccine showed notable 
Day 0 to Day 21 increases in GMT against all four of the homologous strains, and the overall 
pattern of responses confirms the 30 μg/strain dose selection 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-protective antibodies against 
heterologous influenza strains (reference: current IB version). 
1.3.2.2 
Plant Glycans 
Plant glycoproteins contain structural motifs not found on human glycoproteins (e.g. core β1-2 
xylose and α1-3fucose). Since some of these motifs occur on known plant allergens, one 
theoretical risk of using plants for production of biotherapeutics was the induction of 
hypersensitivity. Medicago monitored allergic symptoms and the humoral response to plant 
glycans in the clinical trials conducted to date; based on the results obtained from these studies, 
in which there were no observed trends suggestive of safety concerns (reference: current IB 
version), there is no need to include assessment of plant glycans in this study. 
1.4 
Overall Rationale for the Study 
This Phase 3 study is intended to assess the clinical lot-to-lot consistency in manufacturing by 
comparing the immunogenicity of three separately manufactured lots of the Quadrivalent VLP 
Influenza Vaccine, during the 2017-2018 Influenza season, in healthy adults 18 to 49 years of 
age. One dose of Quadrivalent VLP Influenza Vaccine (30 µg/strain) will be administered 
according to the randomization code to each of the 1,200 trial participants. The study is intended 
to support consistency of the manufacturing process. 

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2 
OBJECTIVES 
2.1 
Primary Objectives 
• To assess the consistency of three consecutive manufacturing lots of the Quadrivalent VLP 
Influenza Vaccine given at a dose of 30 µg/strain, as measured by the serum 
hemagglutination inhibition (HI) antibody titers on Day 21. 
2.2 
Secondary Objectives 
Safety: 
• To assess the safety and tolerability of a single dose of the Quadrivalent VLP Influenza 
Vaccine given at a dose of 30 µg/strain. 
Immunogenicity: 
•  To assess the immunogenicity of a single dose of Quadrivalent VLP Influenza Vaccine 
given at a dose of 30 µg/strain against homologous influenza strains. 
3 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Table 3 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 
 
 
 
Analytical Laboratories 
 
 
 
Serology (Immunogenicity): 
Medicago Inc., 
1020, route de l’Église, bureau 600, 
Sainte-Foy (Qc) Canada G1V 3V9 
 
 
Contract Research Organisation 
 
 
4 
STUDY DESIGN AND RATIONALE 
4.1 
Overview of Study Design 
This randomized, observer-blind, multicenter, Phase 3 lot consistency study will be conducted at 
multiple sites in Canada. 
CCI
PPD
PPD

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The composition of the Quadrivalent VLP Influenza Vaccine used in this study includes two 
influenza A virus strains and two influenza B virus strains based on the 2016-2017 recommended 
WHO strains for vaccination in the Northern hemisphere. 
Subjects will participate in this study for approximately 21 days, during which a first visit will be 
scheduled on Day 0 for screening, eligibility assessment, and vaccine administration; a phone 
contact will be made on Days 1 and 8 specifically for review of the MA, concomitant 
medications, and health status; a visit will occur on Day 21 for blood sample collection for 
immunogenicity assessment. 
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 any potential bias that could arise during data 
collection and the evaluation of the clinical endpoints. 
4.2.3 Dose Selection 
The dose of 30 µg/strain was selected based on data from previous studies. 
4.2.4 Study Duration 
The study duration of 21 days will allow for collection of immunogenicity data and the standard 
evaluation of immediate complaints, local and systemic reactions, and TEAEs. Given the modest 
sample size of this study compared to the planned phase 3 study, it was considered that 
monitoring of SAEs and NOCDs past Day 21 would not provide significant additional safety 
information on this vaccine in this subject population. 
4.2.5 Immunogenicity Assessments 
The primary immunogenicity assessment (Day 21 GMT measured by HI assay), is standard for 
this type of study. The secondary immunogenicity assessments (SC rate, SP rate, and GMFR 
measured by HI assay) are standard for immunogenicity evaluation in vaccine development. 

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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 be able to read, understand, and sign the informed consent form (ICF); 
complete study-related procedures; and communicate with the study staff at visits and by 
phone; 
2. Subjects must be considered by the Investigator to be reliable and likely to cooperate with 
the assessment procedures and be available for the duration of the study; 
3. Male and female subjects must be 18 to 49 years of age, inclusive, at the 
Screening/Vaccination visit (Visit 1); 
4. Subjects have a body mass index (BMI) ≤ 40.0 kg/m2 on Day 0 pre-vaccination; 
5. Subjects must be in good general health prior to study participation with 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 six months prior to vaccination. Based on the Investigator's 
judgment, a subject with a more recent stabilization of a disease could also be eligible. 
6. Female subjects must have a negative urine pregnancy test result at the 
Screening/Vaccination visit (Visit 1); 
7. Female subjects of childbearing potential must use an effective method of contraception for 
one month prior to vaccination and agree to continue employing adequate birth control 
measures for the duration of the study. Abstinent subjects should be asked what method(s) 
they would use, should their circumstances change, and subjects without a well-defined 
plan should be excluded. The following relationship or methods of contraception are 
considered to be effective: 
• 
Hormonal contraceptives (e.g. oral, injectable, topical [patch], or estrogenic vaginal 
ring); 
• 
Intra-uterine device with or without hormonal release; 
• 
Male partner using a condom plus spermicide or a sterilized partner (at least one year 
prior to vaccination); 
• 
Credible self-reported history of heterosexual vaginal intercourse abstinence until at 
least the Day 21 visit; 
• 
Female partner. 

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8. Non-childbearing females are defined as: 
• 
Surgically-sterile (defined as bilateral tubal ligation, hysterectomy, or bilateral 
oophorectomy performed more than one month prior to vaccination); or 
• 
Post-menopausal (absence of menses for 24 consecutive months and age consistent with 
natural cessation of ovulation). 
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 significant acute or chronic, uncontrolled 
medical or neuropsychiatric illness. ‘Uncontrolled’ is defined as: 
• 
Requiring a new medical or surgical treatment during the six 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 
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 which, in the Investigator’s opinion, would render the subject unable to provide 
informed consent or unable to provide valid safety observations and reporting; 
3. Any autoimmune disease other than hypothyroidism with stable replacement therapy; or 
any confirmed or suspected immunosuppressive condition or immunodeficiency including 
known or suspected human immunodeficiency virus (HIV), hepatitis B or C infection, or 
the presence of lymphoproliferative disease; 
4. Administration or planned administration of any non-influenza vaccine within 30 days prior 
to randomization and up to blood sampling on Day 21. Immunization on an emergency 
basis will be evaluated case-by-case by the Investigator; 
5. Administration of any adjuvanted or investigational influenza vaccine within 24 months 
prior to randomization or planned administration prior to the completion of Day 21; 
6. Administration of any “standard”, non-adjuvanted influenza vaccine (e.g. live attenuated 
trivalent/quadrivalent inactivated influenza vaccine intranasal or split trivalent/quadrivalent 
inactivated influenza vaccine by either intradermal or IM route) within 24 months prior to 
randomization and up to completion of the Day 21 visit; 
7. Use of any investigational or non-registered product within 30 days 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 the Day 21 
visit. Participation in observational studies is permitted; 

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8. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or the 
equivalent) per day for more than seven consecutive days or for ten or more days in total, 
within one month of study vaccine administration; or any other cytotoxic or 
immunosuppressant drug, or any immunoglobulin preparation within three months of 
vaccination and until the completion of the Day 21 visit. Low doses of nasal or inhaled 
glucocorticoids and topical steroids are permitted; 
9. 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 325 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. 
10. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine or a 
tobacco allergy; 
11. History of anaphylactic allergic reactions to plants or plants components; 
12. Any history of serious asthma (e.g. status asthmaticus, hospitalization for asthma control) in 
the last three years; 
13. Use of antihistamines 48 hours prior to study vaccination; 
14. The 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. Subjects discovered to have taken a prophylactic medication to prevent or 
pre-empt symptoms due to vaccination within the 24 hours prior to planned randomization 
must be delayed until at least the 24-hour period is met; 
15. Subjects who have a dermatological condition at the injection site that may interfere with 
injection site reaction rating; 
16. Subjects who have received a blood transfusion within 90 days prior to study vaccination; 
17. Any female subject who has a positive or doubtful pregnancy test result prior to vaccination 
or who is lactating; 
18. Presence of any febrile illness (including oral temperature [OT] ≥ 38.0 ˚C within 24 hours 
prior to vaccination). Such subjects may be re-evaluated for enrolment after resolution of 
illness; 
19. Cancer or treatment for cancer within three years of study vaccine administration. Persons 
with a history of cancer who are disease-free without treatment for three years or more are 
eligible. Individuals with treated and uncomplicated basal cell carcinoma of the skin or with 
non-treated, non-disseminated local prostate cancer are eligible; 
20. 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, natural or adopted child) of the Investigator or employee with direct 
involvement in the proposed study or any employee of Medicago. Immediate family 
members of the Investigator or employees of a clinical site can participate in the study at 

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another clinical site, as long as the Investigator or employees are not involved in the study 
at that site; 
21. Subject with a history of Guillain-Barré syndrome. 
5.3 
Prior and Concomitant Therapy 
Any new or changed medications reported by the subject post-vaccination and through to the end 
of the study will be recorded in the electronic case report form (eCRF) as a concomitant 
medication. Any AEs associated with the new or changed medication use must also be 
documented. 
Concomitant medications must be reported in the eCRF (reason for use, dates of administration, 
dosage, frequency, and route) if the use meets the following conditions: 
• 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; 
• Any concomitant medication use to treat conditions reported as medical history; 
• Any investigational medication or vaccine; 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 
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. 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.). 
Please refer to Section 5.2 (exclusion criteria numbers 3, 4, 5, 6, 7, 8, 9, 13, 14, and 19) for 
details on medications or therapies prohibited prior to randomization and/or during the conduct 
of this study. 
6 
TREATMENT ALLOCATION AND BLINDING 
6.1 
Randomization 
Randomization will be stratified by site. Subjects will be randomized to one of three treatment 
groups, based on a computer-generated randomization schedule prepared by or under the 
supervision of Medicago before the study. The randomization system will assign the treatment 
group. 

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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. 
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. 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. 
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 or designee as soon as possible 
after the unblinding to discuss the case. 
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 AEs or 
reactogenicity of the subjects following vaccination. 
This study is blinded through to the end of the study. 
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 (one of three lots of 30 μg/strain of Quadrivalent 
VLP Influenza Vaccine). The volume of injection will be 0.5 mL for all treatments. 
8 
SPECIMENS AND CLINICAL SUPPLIES 
8.1 
Management of Samples 
A urine sample will be collected during the Screening/Vaccination visit for a dipstick pregnancy 
test to be performed during the same visit. 
On Days 0 and 21, a serology sample for HI response analysis will be collected for all subjects. 

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Refer to the Study Procedure Manual for complete information on the handling, storage, and 
shipment of all laboratory samples. 
8.2 
Clinical Supplies 
Each study center will be provided with supplies for serologic measures (e.g. aliquot tubes, 
aliquot labels, aliquot storage, shipping boxes, and accompanying manifests). Sites will be 
authorized to use their own materials if agreed to by Medicago. 
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. 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 (refer to 
Investigational Product Management Manual for details). 
10 STUDY EVALUATIONS 
10.1 Study Procedures 
10.1.1 Overview 
The Time and Events Schedule (see Table 1) summarizes the frequency and timing of scheduled 
assessments applicable to this study. 
Subjects who complete the study will have blood volumes of 20 mL drawn (Table 4). 
Table 4 Estimated Blood Volume Drawn 
Type of Sample 
Volume per Sample 
(mL) 
Number of Samples per 
Subject 
Total Volume of Blood 
per Subject (mL) 
HI titers 
10 
2 
20 
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 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 

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benefits of participation, and the study procedures involved. They 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 must be 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, and height) data in metric units. 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. The 
medical history should include significant problems active at the time of Screening and 
present within the preceding year. Problems that have been clinically inactive for more than 
one year preceding Screening, but which might alter the subject’s current or 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 blood pressure (BP), heart rate (HR), 
and OT. The OT will be collected in degrees Celsius using a digital thermometer and 
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). The 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. The physical exam will be 
performed by an Investigator; 
• Collect a urine sample for all female subjects and a perform urine dipstick pregnancy test. 
No study vaccine must be administered until a negative result is obtained and documented; 
• 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; 
• Register the subject in the interactive voice response system (IRT); the subject’s treatment 
group will be automatically assigned by this system; 
• Collect a baseline blood sample for HI assessment and prepare and store the sample until 
shipment to the analytical laboratory. 

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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, using a 25 gauge needle of sufficient length to reach the substance of the muscle 
(at least 1 inch or 2.5 cm or longer). Needle length will be based on the subject’s BMI: for 
subjects with a BMI > 30 kg/m2, the use of a 1.5 inch or 3.8 cm needle is recommended. 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 arm used for 
vaccination will be documented in the source documents. 
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 in the source 
documents 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 an MA, a measurement 
device template for measuring (in mm) solicited local reactions of erythema (redness) and 
swelling, and a digital thermometer for recording daily temperature (in degrees Celsius). 
Each subject will be provided with the following instructions: 
• 
How to collect his/her OT in degrees Celsius with the provided digital thermometer (the 
preferred route for temperature measurement is oral): 
• 
From Day 0 to Day 7, the subject will measure his/her OT at approximately the same 
time (preferably in the evening) and will record the results in the MA; 
• 
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 MA. In the event that a temperature ≥ 38.0 °C 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). The subject 
is to document medication intake in the MA, which will be reviewed by the site 
personnel; 

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• 
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 from Day 0 to Day 7 (preferably in the evening); the results will be 
recorded in the MA. 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 5; 
• 
How to grade, on a daily basis from the Day 0 to Day 7 (preferably in the evening), each 
of the solicited systemic reactions and their severity (as per the same guidance used for 
solicited local reactions; see Table 5) (FDA, 2007) and to record the worst grade of the 
day for each of these solicited systemic reaction in the MA. The instructions will include 
how to examine and grade swelling in the neck and axilla and to record any unusual 
feeling and/or swelling in the MA; 
• 
To use their MA to support their recall in providing information during the scheduled 
phone interview conducted on Days 1 and 8 and to bring their MA with them to the Day 
21 clinic visit. The staff will review the MA entries and grade these entries with the 
subject; 
• 
To record new use of medication in their MA, in addition to each intake of PRN drugs; 
• 
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; 
• 
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 at least 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 (preferably in the evening) each day from Day 0 to Day 7; 
• Provide appointments (date and time) for the next planned visit to the clinical site (Day 21) 
and also for the Days 1 and 8 phone contacts; 

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• 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 Day 1 (+ 1 day) and Day 8 (- 1 day/+ 1 
days) phone contact: 
• Ask the subjects to use their MA to support their recall in providing information during the 
scheduled phone interview; 
• Ask the subjects about any difficulties in completing the MA, 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; 
• 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 and to record this information on the appropriate MA 
pages. Remind the subjects to record PRN intake; 
• 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 bring back the MA for their Day 21 
visit; 
In the event that a subject cannot be reached via phone, he/she may be contacted by text message 
or via email (if these contacts are available). However, the phone should be the initial and 
preferred means of communication. 
10.1.4 Day 21 (Visit 2) 
The following procedures will be performed during the Day 21 (-2/+3 days) visit: 
• Collect and review the MA content with the subject to ensure appropriate completion. 
Corrections must be made by the subject him/herself and all corrections must be initialed 
and dated. In the event that a subject is not able to make the correction him/herself, the site 
personnel will be authorized to enter a clarification in the comments section of the MA with 
a proper explanation. The original MA will be kept in subject’s chart; 
• Record any changes in the subject’s health, any complaints of lymphadenopathy, any visits 
to health care facilities and/or medical practitioners, and any concomitant medication use 

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(including any vaccines received) since the Day 8 phone contact and confirm that the 
subject has continued to comply with the protocol requirements (e.g. no use of prohibited 
concomitant medications, use of an adequate contraceptive method); 
• Perform a lymphadenopathy examination if the subject complains of arm or shoulder pain 
of the vaccinated arm or neck pain at the time of the visit (a directed exam for lymph node 
swelling of the neck and axilla). In addition, a history/symptom-directed physical 
examination can also be performed, based on the Investigator’s opinion. These 
examinations should be performed by the Investigator; 
• Collect a blood sample for HI assessment and prepare and store the sample until shipment 
to the analytical laboratory; 
• Collect a urine sample for all female subjects and a perform urine dipstick pregnancy test. 
Any subject who withdraws consent from the study prior to completion of the Day 21 visit will 
be asked to return their MA to the clinic site and to provide an update on their health status and 
concomitant medication usage (if the subject agrees). 
10.2 Immunogenicity 
10.2.1 Evaluations 
Immunogenicity will be evaluated by the humoral immune response (HI assay) induced in 
subjects on Day 0 and Day 21. 
10.2.2 Immunogenicity Endpoints 
10.2.2.1 Primary Immunogenicity Endpoints 
• GMTs of the three vaccine lots (21 days after vaccination) for all four vaccine strains: 
• 
Lot-to-lot consistency is based on adjusted GMT ratios for pairwise comparisons of the 
lots (lot 1/lot 2, lot 1/lot 3, and lot 2/lot 3). Lot-to-lot consistency will be demonstrated if 
the two-sided 95 % CI limit falls between 0.67 and 1.5 for all four strains. 
10.2.2.2 Secondary Immunogenicity Endpoints 
• HI antibody response induced by the Quadrivalent VLP Influenza Vaccine (pooled data 
from the three lots) against the homologous influenza strains on Days 0 and 21; HI 
antibody titers will be analyzed as follows: 
• 
SC rate: the proportion of subjects 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 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); 
• 
GMFR: geometric mean of the ratio of GMTs (Day 21/Day 0). 

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The immunogenicity endpoints for all four homologous influenza antigens will be evaluated 
according to the CBER criteria for SC rate and SP rate. 
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 reactions up to seven days post-vaccination), 
and unsolicited SAEs, NOCDs, and AEs up to 21 days post-vaccination. 
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 Day 0 to Day 7 (preferably in the evening), subjects will measure 
and record their local and systemic reactions in their MA. 
The intensity of the solicited local and systemic reactions will be graded as: mild (1), moderate 
(2), severe (3) or potentially life threatening (4), as defined below in Table 5. 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. 
Table 5 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 

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Symptoms 
Severity 
None 
Grade 1  
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially life-
threatening) 
Solicited Systemic Reactions 
Fever (ºC) 
< 38.0 ºC 
38.0 - 38.4 ºC 
38.5 - 38.9 ºC 
39.0 - 40.0 ºC 
 > 40.0 ºC 
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 AEs occurring within 21 days after vaccination will be recorded in the source documents or 
MA and reported in the “Adverse Event” form in the subject’s eCRF, irrespective of intensity or 
whether or not they are considered to be vaccination-related. 
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. 
Oral temperature should be collected in degrees Celsius using a digital thermometer. The OT 
measurement should not be collected immediately following consumption of a hot or cold 
beverage or after smoking. 

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Blood pressure will be taken after the subject has been in a seated position as per the site’s 
standard procedure. The BP measurement should be taken by cuff (manual or automated are both 
acceptable). Both 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 
A history/symptom-directed physical examination will be performed by the Investigator as part 
of screening procedures (prior to eligibility assessment on Day 0) and on Day 21 (if deemed 
necessary by the Investigator). In addition, on Day 21, a lymphadenopathy examination (a 
directed exam for lymph node swelling of the neck and axilla) will be performed for subjects 
who complain of arm or shoulder pain of the vaccinated arm or neck pain at the time of the visit. 
10.3.2 Pregnancy 
A urine dipstick pregnancy test will be performed prior to vaccination and during the Day 21 
visit. Female subjects who become pregnant during the study will be followed for safety. The 
Investigator or his/her designee will collect pregnancy information on any subject who becomes 
pregnant while participating in this study. The Investigator or his/her designee will record 
pregnancy information on the Pregnancy Report Form (for the template of the form, refer to 
Study Procedures Manual) and submit it to the Sponsor Safety Contact (see Section 13.1.6) 
within 24 hours of learning of a subject's pregnancy. The subject will be followed to determine 
the outcome of the pregnancy. At the end of the pregnancy, whether full-term or premature, 
information on the status of the mother and child will be forwarded to the Sponsor Safety 
Contact, if available. Generally, follow-up will be no longer than six to eight weeks following 
the estimated delivery date. 
While pregnancy itself or elective termination of a pregnancy for non-medical reasons are not 
considered to be an AE or SAE, any pregnancy complication or elective termination of a 
pregnancy for medical reasons will be recorded in the Pregnancy Report Form or as an SAE and 
will be followed. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and considered to 
be reasonably related in time to receipt of the investigational product by the Investigator, will be 
reported to the Sponsor Safety Contact. While the Investigator is not obligated to actively seek 
this information from former study subjects, he/she may learn of a pregnancy through 
spontaneous reporting. Information on pregnancies identified during the Screening phase/prior to 
vaccine administration do not need to be collected; this information need not be communicated 
to Medicago (or its designee). 
10.3.3 Safety 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); 

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• 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 Day 21. 
10.3.4 Memory Aid 
The MA is considered to be a critical source document that facilitates and ensures accurate 
reporting of reactions and illnesses by subjects through the inclusion of both the space for 
subjects to record data and instructions on what and how to record information. These documents 
will be collected by the clinical sites on Day 21 and kept with each subject’s study chart. Review 
of the MA will be done by clinic site staff. Any required corrections noted at the time of the 
Day 21 visit may be made by the subjects; otherwise clinic staff will make corrections after 
confirmation by the subject (when appropriate). In the event the MA 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. 
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 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. 
Following the resolution of such conditions, a subject may be considered eligible by the 
Investigator and be enrolled in the study. 
11.2 Screening Failures 
Screening failures are subjects who have signed the study-specific ICF but who are not eligible 
for enrolment (subjects who were not randomized), 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 who have signed the ICF and are eligible for enrolment, 
but who were either not randomized or randomized and not treated. 
Tracking 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. 
A screening failure subject can be rescreened once, with prior authorization from Medicago or its 
designee. If the subject is rescreened, a new subject number will be allocated. 

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11.3 Removal of Subjects from 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 the 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 prior to completion of the Day 21 visit, 
for whatever reason. Withdrawal subjects will not be replaced. Withdrawal subjects who 
received the study medication will be asked to return to the clinical site for a final assessment. 
The procedures performed for the final assessment will comprise those of the Day 21 visit, 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. 
11.3.1 Follow-up of Discontinuations 
All subjects who receive a study vaccine will be followed for safety until the end of the Day 21 
visit, 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 regulatory agencies within the 
appropriate timeframe, providing them with the reasons for the discontinuance, and advising 

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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 immunogenicity and safety 
data is outlined below. Complete details will be provided in the SAP. 
12.1 Analysis Populations 
12.1.1 Safety Analysis Set 
The SAS is defined as all subjects who received one of the study treatments. All safety analyses 
will be performed using the SAS, according to the treatment the subjects actually received (when 
applicable). 
12.1.2 Full Analysis Set 
The FAS will consist of the subset of subjects in the SAS with Day 0 and Day 21 
immunogenicity assessments. 
Subjects who receive the wrong treatment will be analyzed as randomized. 
12.1.3 Per Protocol Set 
The PP set will consist of the subjects with no major deviations related to the analyses and with 
Day 0 and Day 21 immunogenicity assessments. Subjects who had blood samples for 
immunogenicity collected outside of the time window are to be excluded from the PP set. 
Subjects who received the wrong vaccine, but for whom the treatment received can be 
unequivocally confirmed, will be analyzed in the PP set as treated, provided they have no other 
deviations that could compromise their data. The PP set will be the primary analysis population 
for the primary immunogenicity endpoint. 
12.2 Sample Size Determination 
Based on data from the CP-Q14VLP-009 study, a sample size of 400 subjects per lot (a total of 
1,200 subjects) will have a greater than 90 % power to test the consistency criterion between the 
lots (i.e. to test that the pairwise comparisons of the two-sided 95 % CI limit for adjusted GMT 
ratios of the three lots being tested [lot 1/lot 2, lot 1/lot 3, lot 2/lot 3] fall within the equivalence 
range of 0.67 to 1.5 for all four vaccine strains). 
A drop-out rate and exclusion from the PP set of approximately 10 % was assumed in the sample 
size calculation. 
12.3 Immunogenicity Analyses 
Immunogenicity endpoints are described in Section 10.2.2. 

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All descriptive and inferential statistical analyses will be performed using Statistical Analysis 
System® (SAS®) software (version 9.3 or higher). In general, continuous data will be 
summarized using descriptive statistics (i.e. mean or geometric mean, CI, median, standard 
deviation, minimum, and maximum). Categorical data will be summarized using the number and 
percent of subjects in each category. 
12.3.1 Analysis of Primary Endpoints 
The primary immunogenicity endpoint is defined in Section 10.2.2.1. 
The immunologic equivalence of three consecutive production lots of the Quadrivalent VLP 
Influenza Vaccine will be measured in terms of GMTs, as measured by HI assay, for all vaccine 
influenza strains. Lot-to-lot consistency is based on adjusted Day 21 GMT ratios for pairwise 
comparisons of the lots (lot 1/lot 2, lot 1/lot 3, lot 2/lot 3); for each pairwise comparison of the 
lots, the lot-to-lot consistency will be demonstrated if the two-sided 95% CIs on the adjusted 
Day 21 GMT ratios fall within the equivalence range of 0.67 to 1.5 for all four vaccine strains in 
the investigational product. The adjusted Day 21 GMT ratios and the 95 % CI of the ratios will 
be calculated via an analysis of covariance (ANCOVA) model and back-transformation. 
12.3.2 Analysis of Secondary Endpoints 
The secondary immunogenicity endpoints are defined in Section 10.2.2.2. 
The secondary immunogenicity analysis will be conducted on the pooled data of the three lots. 
The point estimates and the corresponding two-sided 95 % CI will be calculated to determine if 
the CI meets the CBER criteria for SC rate and SP rate. 
12.4 Baseline and Subject Disposition 
Demographic data will be presented in listings and summarized by vaccine lot (treatment group). 
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, and ethnicity. 
The frequency of subjects for 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 10.3.3.  
Safety and tolerability endpoints (immediate complaints, solicited local and systemic reactions, 
and TEAEs, SAEs, and NOCDs) will be summarized using descriptive statistics by individual 
vaccine lot and as pooled data of all three lots. Listings of safety data will be provided. 

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The original terms used in the eCRFs by Investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All eCRF-reported AEs with a post-
vaccination onset will be included in the safety analyses. 
Additional attention will be given to the safety data from those subjects who die, who 
discontinue from the study due to an AE, who experience a severe AE or 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). 
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. 
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 puts 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 (e.g. any cases of newly diagnosed cancer). 
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. 

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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, 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) 
and the following definitions: 
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 recorded in the source documents or 
MA and reported in the “Adverse Event” form in the subject’s eCRF, irrespective of intensity or 
whether or not they are considered to be vaccination-related. 
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 study period will 
continue under the discretion of the Investigator. 

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13.1.3 Adverse Events of Special Interest 
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. Few 
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 
biotherapeutics may induce hypersensitivity), the Sponsor will continue to require that 
appropriate medical treatment and supervision be 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 
Procedure Manual. 
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. 
Any NOCDs will be collected from vaccination on Day 0 to the end of the Day 21 visit 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 
Any 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 Day 21 visit. The Investigator (or 
designee) must report, by phone or email, all SAEs, whether considered related to the study 
vaccine or not, and whether considered unexpected or expected (as defined in Section 13.1.1), to 
Medicago (or designee) within 24 hours of the Investigator learning of the event. The 

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Investigator must also complete, sign, and date the SAE report form, and send, via e-mail, a copy 
to the safety e-mail address: 
 
Medicago-Safety@medicago.com 
 
 
Sponsor Safety Contact: 
 
 
 
 
13.1.7 Follow-up Reporting by the Investigator 
All SAEs, regardless of relationship to study vaccination, 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 Detection Period or Study Termination 
All SAEs occurring during the study will be followed until resolution or for a period of 30 days 
from the final subject’s visit, regardless of conclusion of the study. 
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection 
period (after the Day 21 visit). 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 
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underlying medical condition or concomitant therapy or lacks a 
plausible temporal relationship to the study vaccine. 
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. 
All AE outcomes will be classified as recovered/resolved, not recovered/not resolved, 
recovered/resolved with sequelae, recovering/resolving, or death. 
13.1.10 Reporting of SAEs to Health Authorities and IRB 
Medicago 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 IRB as soon as possible, and will also provide the IRB with any safety 
reports prepared by Medicago. 
All SAEs that are suspected, unexpected serious adverse reactions (SUSARs) should be reported 
to regulatory authorities by phone or by facsimile transmission as soon as possible but, in no 
event, later than seven calendar days for deaths and 15 calendar days for other SAEs after 
Medicago'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 for the 2016-2017 influenza virus strains 
in the Northern hemisphere, assembled into VLPs, and produced in a plant-based (Nicotiana 
benthamiana) transient expression system. The transfer vector used to insert the plasmids 
(containing the constructs for proteins of interest) into the plant for expression is a bacterium, 
Agrobacterium tumefaciens. The hemagglutinin protein sequences utilized in the expression 
constructs are all obtained from viruses isolated from humans, not from egg- or cell-grown 
viruses. 

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14.1.1 Study Vaccine Composition 
The Quadrivalent VLP Influenza Vaccine is a sterile transparent to opalescent colorless to 
slightly yellowish liquid suspension consisting of a mix of VLPs from four strains, each bearing 
the hemagglutinin of one of the indicated virus strains, in a phosphate buffered saline 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 one-millilitre borosilicate pre-filled 
syringes (type 1). The hemagglutinin protein concentration in the provided syringes will be 
60 μg/strain/mL in a volume of approximately 0.6 mL for a final dose of 30 μg/strain. 
14.1.2 Independence between Vaccine Lots 
Three lots of the quadrivalent VLP drug product (DP) will be used in this study. Each DP lot will 
be manufactured separately and will be obtained by mixing four strains of monovalent VLP drug 
substance (DS). Each DS lot within a DP lot represents the recombinant hemagglutinin proteins 
expressed as VLPs of one of the four influenza virus strains recommended by WHO for the 
2016-2017 season in the Northern hemisphere. Each DS lot will be manufactured separately. 
14.1.3 Preparation and Administration of Study Vaccine 
The study treatments will be prepared by staff members at the clinical site as described in the 
Investigational Product Management Manual. The study treatment will subsequently be 
administered to subjects by a staff member at the clinic site. 
The pre-filled syringes 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 individual 30 μg/strain vaccine dose lots, the site will use a 
pre-filled syringe labelled with study protocol CP-PRO-QVLP-011, the lot 
number/treatment number identification, an indication that the product is for clinical use 
only, the concentration of 60 μg/strain/mL, and with the dose of 0.5 mL (30 μg/strain). 
The study treatments will be administered IM. 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 one of the three lots of Quadrivalent VLP Influenza Vaccine (30 μg/strain) 
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. 
The dose 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 is completed by Medicago (or its designee), all study treatments 
(used and unused syringes) will be returned to Medicago in accordance with instructions 
provided in the Investigational Product Management Manual. When the site is authorized by 
Medicago to destroy study drug supplies on site, this must be documented. Instructions will be 
provided by Medicago, when applicable. 

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Further specific information relating to treatment preparation, storage, and shipment will be 
provided in the Investigational Product Management Manual. 
14.1.4 Preparation, Handling, Storage, and Precautions for Use 
The study treatment should be stored in an access-restricted area between 2 ºC and 8 ºC; the 
vaccine should, however, be at room temperature before administration (i.e. the vaccine should 
not be administered cold). 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. 
14.2 Packaging 
The study drug will be packaged in boxes containing syringes of the same treatment. 
14.3 Labeling 
The pre-filled syringes will have a product and study-specific label containing information that 
meets the applicable regulatory requirements. The study dispensing labels will contain dosing 
instructions, treatment, storage conditions, and a unique subject-specific treatment number. 
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. 
14.4 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 label and will be stored in a limited-access area or 
in a locked cabinet under appropriate environmental conditions. All 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 used and unused study drugs to Medicago (or its designee) for 
destruction will be documented on the Drug Return Form. When the site is authorized by 
Medicago (or its designee) to destroy study drug supplies on site, this must also be documented. 

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The study drug should be dispensed under the supervision of the Investigator or a qualified 
member of the investigational staff. 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 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. 
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. 
The GCP standard 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) or 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); 

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• 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; 
• 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. 

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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. 
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. 

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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 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 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 regulatory authority, as applicable. 
A study may not be initiated until all 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 and AEs and associated follow ups; 
• 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. 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). 

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17.4 Case Report Form Completion 
Electronic case report forms 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; the 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. 
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. 

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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 
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. 

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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 a 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 
DiazGranados, C., Denis, M., & Plotkin, S. (2012). Seasonal influenza vaccine efficacy and its 
determinants in children and non-elderly adults: a systematic review with meta-analyses 
of controlled trials. Vaccine, 31(1), 49-57.  
FDA. (2007). Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
McElhaney, J.E. (2011). Influenza Vaccine Responses in Older Adults. Ageing Res Rev, 10(3), 
379-388. doi:10.1016/j.arr.2010.10.008 
Molinari, N. A., Ortega-Sanchez, I. R., Messonnier, M. L., Thompson, W. W, Wortley, P. M., 
Weintraub, E., & Bridges, C. B. (2007). The annual impact of seasonal influenza in the 
US: measuring disease burden and costs. Vaccine, 25(27), 5086-5096.  
Osterholm, M., Kelley, N., Sommer, A., & Belongia, E. (2012). Efficacy and effectiveness of 
influenza vaccines: a systematic review and meta-analysis. The Lancet Infectious 
Diseases, 12(1), 36-44.  
Palache, A. (2011). Seasonal influenza vaccine provision in 157 countries (2004-2009) and the 
potential influence of national public health policies. Vaccine, 29(51), 9459-9466.  
Skowronski, D. M., Chambers, C., Sabaiduc, S., De Serres, G., Dickinson, J. A., Winter, A. L., 
Drews, S. J. , Fonseca, K., Charest, H., Gubbay, J. B., Petric, M., Krajden, M., Kwindt, T. 
L., Martineau, C., Eshaghi, A., Bastien, N., & Li, Y. (2015). Interim estimates of 2014/15 
vaccine effectiveness against influenza A(H3N2) from Canada's Sentinel Physician 
Surveillance Network (Vol. 20(4), pp. pii=21022). 
 

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19.2 Appendix 2 – Sample Ruler to Measure Local Reactions