Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Adults Age 56 Years and Older
Phase: PHASE3
Conditions: Meningitis, Meningococcal Meningitis, Meningococcal Infections
Sponsor: Sanofi Pasteur, a Sanofi Company

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Immunogenicity and Safety of an Investigational Quadrivalent 
Meningococcal Conjugate Vaccine in Adults Age 56 Years and 
Older 
Phase III, modified double-blind, randomized, parallel-group, active-controlled, multi-center 
trial to compare the immunogenicity and safety of MenACYW conjugate vaccine to 
Menomune® – A/C/Y/W-135 in adults ≥ 56 years of age in the United States. 
Clinical Trial Protocol, Amendment 1 
Health Authority File Number(s): BB-IND #: 14171 
WHO Universal Trial Number 
(UTN): 
U1111-1124-7760 
Trial Code: 
MET49 
Development Phase: 
Phase III 
Sponsor: 
Sanofi Pasteur Inc. 
Discovery Drive, Swiftwater, PA 18370-0187, USA 
Investigational Product: 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups 
A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine 
Form / Route: 
Liquid Solution / Intramuscular (IM) 
Indication For This Study: 
MenACYW conjugate vaccine as a single dose for adults 56 years of age 
and older 
Manufacturer: 
Same as Sponsor 
Coordinating Investigator: 
 
 
Sponsor’s Responsible Medical 
Officer: 
 
 
, Sanofi Pasteur Inc. 
Tel:  
 
Fax: 
 
Product Safety Officer: 
 
, Sanofi Pasteur Inc. 
Tel:  
 
Fax: 
 
Clinical Trial Manager: 
 
, Sanofi Pasteur Inc. 
Tel:  
 
Version and Date of the Protocol: Version 3.0 dated 20 May 2016 
This protocol version 3.0 is the first amendment to the initial trial protocol version 2.0, dated 22 December 2015. 
Information contained in this publication is the property of Sanofi Pasteur and is confidential. This information may not be 
disclosed to third parties without written authorization from Sanofi Pasteur. This document may not be reproduced, stored in a 
retrieval system, or transmitted in any form or by any means–electronic, mechanical recording, or otherwise–without prior 
authorization from Sanofi Pasteur. This document must be returned to Sanofi Pasteur upon request. 
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NCT Number: NCT02842866

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Table of Contents 
List of Tables 
................................................................................................................................... 7 
Synopsis 
................................................................................................
............................................ 8 
Table of Study Procedures 
............................................................................................................ 16
 
List of Abbreviations 
..................................................................................................................... 18
 
1 
Introduction 
..................................................................................................................... 20
 
1.1 
Background 
..................................................................................................................... 20 
1.2 
Background of the Investigational Product 
..................................................................... 21 
1.2.1 
Non-clinical Safety 
....................................................................................................... 21
 
1.2.2 
Clinical ......................................................................................................................... 21
 
1.3 
Potential Benefits and Risks 
........................................................................................... 23 
1.3.1 
Potential Benefits to Subjects 
....................................................................................... 23
 
1.3.2 
Potential Risks to Subjects ........................................................................................... 24 
1.4 
Rationale for the Trial 
..................................................................................................... 25
 
2 
Trial Objectives 
............................................................................................................... 25
 
2.1 
Primary Objectives 
.......................................................................................................... 25
 
2.2 
Secondary Objectives 
...................................................................................................... 26
 
2.3 
Observational Objectives 
................................................................................................ 26
 
3 
Investigators and Trial Organization 
............................................................................ 26 
4 
Independent Ethics Committee / Institutional Review Board .................................... 26
 
5 
Investigational Plan 
......................................................................................................... 27
 
5.1 
Description of the Overall Trial Design and Plan 
........................................................... 27 
5.1.1 
Trial Design 
.................................................................................................................. 27
 
5.1.2 
Justification of the Trial Design 
................................................................................... 28
 
5.1.3 
Trial Plan 
...................................................................................................................... 29
 
5.1.4 
Visit Procedures 
............................................................................................................ 30
 
5.1.5 
Planned Trial Calendar 
................................................................................................. 32 
5.1.6 
Early Safety Data Review............................................................................................. 
32 
5.2 
Enrollment and Retention of Trial Population 
................................................................ 32 
5.2.1 
Recruitment Procedures 
................................................................................................ 32
 
5.2.2 
Informed Consent Procedures ...................................................................................... 33 
5.2.3 
Screening Criteria 
......................................................................................................... 33
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5.2.4 
Inclusion Criteria 
.......................................................................................................... 33
 
5.2.5 
Exclusion Criteria 
......................................................................................................... 34
 
5.2.6 
Medical History 
............................................................................................................ 35
 
5.2.7 
Contraindications for Subsequent Vaccinations 
........................................................... 36 
5.2.8 
Contraindications for Subsequent Blood Samples 
....................................................... 36 
5.2.9 
Conditions for Withdrawal 
........................................................................................... 36 
5.2.10 
Lost to Follow-up Procedures....................................................................................... 36 
5.2.11 
Classification of Subjects Who Discontinue the Trial.................................................. 37
 
5.2.12 
Follow-up of Discontinuations 
..................................................................................... 37 
5.2.13 
Follow-up and Reporting of Pregnancies 
..................................................................... 37 
5.3 
Safety Emergency Call ................................................................................................... 38
 
5.4 
Modification of the Trial and Protocol 
........................................................................... 38 
5.5 
Interruption of the Trial .................................................................................................. 39
 
6 
Vaccines Administered ................................................................................................... 39
 
6.1 
Identity of the Investigational Product 
............................................................................ 39 
6.1.1 
Identity of Trial Product 
............................................................................................... 39 
6.1.1.1 
Composition 
............................................................................................................... 39
 
6.1.1.2 
Preparation and Administration ................................................................................. 39
 
6.1.1.3 
Dose Selection and Timing 
........................................................................................ 40 
6.1.2 
Identity of Control Product 
........................................................................................... 40 
6.1.2.1 
Composition 
............................................................................................................... 40
 
6.1.2.2 
Preparation and Administration ................................................................................. 40
 
6.1.2.3 
Dose Selection and Timing 
........................................................................................ 41 
6.2 
Identity of Other Products 
............................................................................................... 41 
6.3 
Product Logistics ............................................................................................................ 41 
6.3.1 
Labeling and Packaging ............................................................................................... 41 
6.3.2 
Product Shipment, Storage, and Accountability 
........................................................... 41 
6.3.2.1 
Product Shipment 
....................................................................................................... 41 
6.3.2.2 
Product Storage 
.......................................................................................................... 42 
6.3.2.3 
Product Accountability 
............................................................................................... 42 
6.3.3 
Replacement Doses....................................................................................................... 
42 
6.3.4 
Disposal of Unused Products 
........................................................................................ 42 
6.3.5 
Recall of Products 
......................................................................................................... 42 
6.4 
Blinding and Code-breaking Procedures 
........................................................................ 43 
6.5 
Randomization and Allocation Procedures 
..................................................................... 43 
6.6 
Treatment Compliance 
.................................................................................................... 44
 
6.7 
Concomitant Medications and Other Therapies ............................................................. 44
 
7 
Management of Samples 
................................................................................................ 45
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7.1 
Sample Collection 
........................................................................................................... 45
 
7.2 
Sample Preparation 
......................................................................................................... 45
 
7.3 
Sample Storage and Shipment 
........................................................................................ 46 
7.4 
Future Use of Stored Serum Samples for Research 
........................................................ 46
 
8 
Clinical Supplies 
.............................................................................................................. 46
 
9 
Endpoints and Assessment Methods ............................................................................. 47
 
9.1 
Primary Endpoints and Assessment Methods 
................................................................. 47 
9.1.1 
Immunogenicity 
............................................................................................................ 47 
9.1.1.1 
Immunogenicity Endpoints 
........................................................................................ 47 
9.1.1.2 
Immunogenicity Assessment Methods ...................................................................... 47 
9.1.2 
Safety 
............................................................................................................................ 48
 
9.1.3 
Efficacy 
......................................................................................................................... 48
 
9.2 
Secondary Endpoints and Assessment Methods 
............................................................. 48 
9.2.1 
Immunogenicity 
............................................................................................................ 48 
9.2.1.1 
Immunogenicity Endpoints 
........................................................................................ 48 
9.2.1.2 
Immunogenicity Assessment Methods ...................................................................... 48 
9.2.2 
Safety 
............................................................................................................................ 48
 
9.2.3 
Efficacy 
......................................................................................................................... 48
 
9.3 
Observational Endpoints and Assessment Methods 
....................................................... 48 
9.3.1 
Immunogenicity 
............................................................................................................ 48 
9.3.1.1 
Immunogenicity Endpoints 
........................................................................................ 48 
9.3.1.2 
Immunogenicity Assessment Methods ...................................................................... 49 
9.3.2 
Safety 
............................................................................................................................ 49
 
9.3.2.1 
Safety Definitions 
....................................................................................................... 49
 
9.3.2.2 
Safety Endpoints ........................................................................................................ 52 
9.3.2.3 
Safety Assessment Methods 
....................................................................................... 52
 
9.3.2.3.1 
Immediate Post-vaccination Surveillance Period 
.................................................... 53 
9.3.2.3.2 
Reactogenicity (Solicited Reactions from Day 0 to Day 7 after Vaccination) 
........ 53
 
9.3.2.3.3 
Unsolicited Non-serious Adverse Events from Day 0 to Day 30 after 
Vaccination 
.............................................................................................................. 57
 
9.3.2.3.4 
Serious Adverse Events 
........................................................................................... 58
 
9.3.2.3.5 
Adverse Events of Special Interest 
.......................................................................... 58 
9.3.2.3.6 
Medically-Attended Adverse Events 
....................................................................... 58
 
9.3.2.3.7 
Assessment of Causality 
.......................................................................................... 58
 
9.3.3 
Efficacy 
......................................................................................................................... 59
 
10 
Reporting of Serious Adverse Events 
............................................................................ 59
 
10.1 
Initial Reporting by the Investigator 
............................................................................... 59
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10.2 
Follow-up Reporting by the Investigator 
........................................................................ 60 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study 
...................... 60 
10.4 
Assessment of Causality 
................................................................................................. 60
 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 61
 
11 
Data Collection and Management ................................................................................. 61 
11.1 
Data Collection and CRF Completion 
............................................................................ 61 
11.2 
Data Management 
........................................................................................................... 62
 
11.3 
Data Review 
.................................................................................................................... 63
 
12 
Statistical Methods and Determination of Sample Size 
............................................... 63
 
12.1 
Statistical Methods 
.......................................................................................................... 63
 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective 
......................................... 63
 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives 
................................... 64
 
12.1.3 
Statistical Methods for Observational Objectives 
........................................................ 64
 
12.2 
Analysis Sets 
................................................................................................................... 65
 
12.2.1 
Full Analysis Set 
........................................................................................................... 65 
12.2.2 
Safety Analysis Set 
....................................................................................................... 66
 
12.2.3 
Per-Protocol Analysis Set 
............................................................................................. 66 
12.2.4 
Populations Used in Analyses 
...................................................................................... 66 
12.3 
Handling of Missing Data and Outliers 
.......................................................................... 66 
12.3.1 
Safety 
............................................................................................................................ 66
 
12.3.2 
Immunogenicity 
............................................................................................................ 66 
12.3.3 
Efficacy 
......................................................................................................................... 67
 
12.4 
Interim / Preliminary Analysis 
........................................................................................ 67
 
12.5 
Determination of Sample Size and Power Calculation 
................................................... 67
 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 68
 
13.1 
Ethical Conduct of the Trial / Good Clinical Practice 
.................................................... 68
 
13.2 
Source Data and Source Documents 
............................................................................... 68 
13.3 
Confidentiality of Data and Access to Subject Records 
................................................. 69 
13.4 
Monitoring, Auditing, and Archiving 
............................................................................. 69 
13.4.1 
Monitoring 
.................................................................................................................... 69 
13.4.2 
Audits and Inspections ................................................................................................. 70 
13.4.3 
Archiving 
...................................................................................................................... 70 
13.5 
Financial Contract and Insurance Coverage 
................................................................... 70 
13.6 
Stipends for Participation 
................................................................................................ 71
 
13.7 
Publication Policy 
........................................................................................................... 71
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14 
References List 
................................................................................................................. 72
 
15 
Signature Pages ............................................................................................................... 75
 
 
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List of Tables 
Table 5.1: Testing strategy for N. meningitidis serogroups ACYW 
...............................................28
 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
...........55
 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
.................56
 
Table 12.1: Power of the study based on the primary objective .....................................................68 
 
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Synopsis 
Company: 
Sanofi Pasteur 
Investigational Product: MenACYW conjugate vaccine 
Active Substances: 
Capsular polysaccharide from meningococcal serogroups A, C, Y, and W conjugated 
to tetanus toxoid 
 
 
Title of the Trial: 
Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal 
Conjugate Vaccine in Adults Age 56 Years and Older 
Development Phase: 
Phase III 
Coordinating 
Investigator: 
 
 
Trial Centers: 
This will be a multi-center trial conducted at approximately 35 sites in the United 
States. 
Investigators and sites will be listed in the “List of Investigators and Centers Involved 
in the Trial” document. 
Planned Trial Period: 
3Q 2016 to 2Q 2017 
Trial Design and 
Methodology: 
This will be a Phase III, modified double-blind, randomized, parallel-group, active-
controlled, multi-center trial to compare the immunogenicity and safety of MenACYW 
conjugate vaccine to Menomune
® - A/C/Y/W-135 in adults ≥ 56 years of age in the US. 
Approximately 900 healthy adults will be randomized in a 1:1 ratio to the following 
groups: 
•  Group 1: MenACYW conjugate vaccine 
•  Group 2: Menomune® - A/C/Y/W-135 
Enrollment will be stratified by age (see Table S1). For subjects 56 to 64 years of age, 
200 subjects will be enrolled in both Group 1 and Group 2. 
For subjects 65 years of age and older, 250 subjects will be enrolled in both Group 1 
and Group 2. These subjects will be further stratified into 2 groups as 65 to 74 years of 
age and 75 years and older. At least 25% of the 250 subjects will be enrolled in each of 
these age groups. 
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Table S1: Testing strategy for N. meningitidis serogroups ACYW 
 
ACYW serogroups 
tested by hSBA* 
(all subjects) 
ACYW serogroups 
tested by rSBA† 
(subset) 
Group 1 
 
 
56-64 years 
200 
50 
≥ 65 years: 
250 
50 
    65-74 years 
70-180 
15-35 
    ≥ 75 years 
70-180 
15-35 
Group 2 
 
 
56-64 years 
200 
50 
≥ 65 years: 
250 
50 
    65-74 years 
70-180 
15-35 
    ≥ 75 years 
70-180 
15-35 
* hSBA: serum bactericidal assay using human complement 
† rSBA: serum bactericidal assay using baby rabbit complement 
 
 
All subjects will provide pre-vaccination blood samples for immunogenicity assessment 
at baseline (Visit 1) and at Day (D)30 (+14-day window) post-vaccination (Visit 2). 
Solicited adverse event (AE) information will be collected for 7 days after vaccination, 
unsolicited AE information will be collected from Visit 1 to D30 (Visit 2), and serious 
adverse event (SAE) information will be collected from D0 through D180 (+14 days) 
after vaccination. Medically-attended adverse events (MAAEs) will be collected from 
Visit 1 through Visit 2 (as part of the collection of unsolicited AE information) and 
from Visit 2 through D180 (+14 days) (as MAAEs). 
Early Safety Data 
Review: 
This trial will not include an early review of safety data (i.e., no early safety review[s] 
of preliminary safety data occurring at pre-determined milestones defined in the 
protocol with pause in enrollment.) However, it may be interrupted at any time if new 
data about the investigational product become available, and/or on advice of the 
Sponsor, the Independent Ethics Committees (IECs) / Institutional Review Boards 
(IRBs), or the governing regulatory authorities in the country where the trial is taking 
place.  
If the trial is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators, the IECs/IRBs, and the regulatory authorities of the reason for 
termination or suspension. If the trial is prematurely terminated for any reason, the 
Investigator will promptly inform the trial subjects and should assure appropriate 
therapy and follow-up. 
Primary Objectives: 
To demonstrate the non-inferiority of the vaccine seroresponse to meningococcal 
serogroups A, C, Y, and W following the administration of a single dose of 
MenACYW conjugate vaccine compared to those observed following the 
administration of a single dose of Menomune® – A/C/Y/W-135. 
Primary Endpoints: 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by 
serum bactericidal assay using human complement (hSBA) assessed at baseline (D0, 
before vaccination) and 30 days after vaccination 
Secondary Objectives: 
1)  To compare the hSBA antibody geometric mean titers (GMTs) of meningococcal 
serogroups A, C, Y, and W following the administration of MenACYW 
conjugate vaccine to those observed following the administration of Menomune® 
– A/C/Y/W-135 
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Secondary Endpoints: 
1)  GMTs against meningococcal serogroups A, C, Y, and W measured by hSBA 
assessed at 30 days (+14 days) after vaccination with MenACYW conjugate 
vaccine and Menomune® – A/C/Y/W-135 
Observational 
Objectives: 
Immunogenicity 
•  To describe antibody titers against meningococcal serogroups A, C, Y, and W 
measured by hSBA at baseline (before vaccination) and 30 days after vaccination 
with MenACYW conjugate vaccine or Menomune® – A/C/Y/W-135 
•  To describe antibody titers against meningococcal serogroups A, C, Y, and W 
measured by serum bactericidal assay using baby rabbit complement (rSBA) at 
baseline (before vaccination) and 30 days after vaccination with MenACYW 
conjugate vaccine or Menomune® – A/C/Y/W-135 in a subset of 100 subjects per 
treatment group. 
Safety 
To describe the safety profile of MenACYW conjugated vaccine compared to that of 
the licensed Menomune
® – A/C/Y/W-135 after a single administration. 
Observational 
Endpoints: 
Immunogenicity 
Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA 
and rSBA before and 30 days (+14 days) after vaccination with MenACYW conjugate 
vaccine or Menomune® – A/C/Y/W-135 
Safety 
•  Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] 
preferred term), duration, intensity, and relationship to vaccination of any 
unsolicited systemic AEs reported in the 30 minutes after vaccination. 
•  Occurrence, time to onset, number of days of occurrence, intensity, action taken, 
and whether the reaction led to early termination from the study, of solicited 
(prelisted in the subject’s diary card (DC) and electronic case report form [CRF]) 
injection site reactions occurring up to 7 days after vaccination. 
•  Occurrence, time to onset, number of days of occurrence, intensity, action taken, 
and whether the reaction led to early termination from the study, of solicited 
(prelisted in the subject’s DC and CRF) systemic reactions occurring up to 7 days 
after vaccination. 
 
•  Occurrence, nature (MedDRA preferred term), time to onset, duration, intensity, 
action taken, relationship to vaccination (for systemic AEs only), and whether the 
event led to early termination from the study, of unsolicited AEs occurring up to 
Visit 2. 
 
•  Occurrence, nature (MedDRA preferred term), time to onset, duration, seriousness 
criteria, relationship to vaccination, outcome, and whether the SAE led to early 
termination from the study, of SAEs throughout the trial. 
•  Occurrence, nature (MedDRA preferred term), time to onset, duration, 
seriousness, relationship to vaccination, and outcome for MAAEs from Visit 2 to 
the 6-month follow-up contact. MAAEs will be collected as unsolicited AEs up to 
Visit 2. 
Planned Sample Size: 
A total of 900 subjects are planned to be enrolled: 
•  Group 1 (MenACYW conjugate vaccine):  
planned = 450; evaluable = 382 
•  Group 2 (Menomune® – A/C/Y/W-135 ):  
planned = 450; evaluable = 382 
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Schedule of Study 
Procedures: 
Vaccination 
All subjects will receive a single dose of either MenACYW conjugate vaccine or 
Menomune® – A/C/Y/W-135 at Visit 1 (D0). 
Blood sampling 
All subjects will provide a pre-vaccination blood sample at Visit 1 and a post-
vaccination sample at Visit 2 (30 to 44 days after the vaccination at Visit 1). 
 
Collection of safety data 
•  All subjects will be observed for 30 minutes after vaccination, and any unsolicited 
systemic AEs occurring during that time will be recorded as immediate unsolicited 
systemic AEs in the CRF. 
•  The subject will record information in a DC about solicited reactions from D0 to 
D07 after vaccination and unsolicited AEs from D0 to Visit 2. SAEs will be 
reported throughout the duration of the trial. 
•  The subject will record information about any possible SAEs and MAAEs in a 
memory aid (MA) from Visit 2 until the 6 month (+14 days) telephone call. 
•  In addition, the subject will be asked to notify the site immediately about any 
potential SAEs at any time during the trial. 
 
•  Staff will contact the subject by telephone on D08 (+2 days) to identify the 
occurrence of any SAE not yet reported and to remind them to complete the DC 
up to Visit 2 and to bring it back to Visit 2. 
•  The completed DC will be reviewed with the subject at Visit 2. 
•  Staff will contact the subject by telephone at 6 months (+14 days) after 
vaccination to review the MA and identify the occurrence of any MAAEs, as well 
as SAEs that have not been reported. 
Duration of 
Participation in the 
Trial: 
The duration of each subject’s participation in the trial will be 180 to 194 days. 
There will be a safety follow-up telephone call 6 months (+14 days) after vaccination. 
Investigational Product: MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, 
and W) Tetanus Toxoid Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, 
USA) 
 Form: 
Liquid Solution 
 Composition: 
Each 0.5 milliliter (mL) dose of MenACYW conjugate vaccine is formulated in 
sodium acetate buffered saline solution to contain the following ingredients: 
Meningococcal capsular polysaccharides: 
 Serogroup A ............................................................................... 
10 micrograms (µg) 
 Serogroup C 
....................................................................................................... 
10 µg 
 Serogroup Y ...................................................................................................... 
10 µg 
 Serogroup W 
...................................................................................................... 
10 µg 
 
Tetanus toxoid protein carrier 
....................................................... approximately 65 µg 
 Route: 
Intramuscular (IM) 
 Batch Number: 
To be determined 
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Control Product: 
Menomune® – A/C/Y/W-135: (Meningococcal Polysaccharide Vaccine, Groups A, C, 
Y, and W-135 Combined) (Sanofi Pasteur, Inc., Swiftwater, PA, USA) 
 Form: 
Lyophilized single-dose vial with 0.6-mL vial of diluent (sterile, pyrogen-free distilled 
water without preservatives) 
 Composition: 
After reconstitution with diluent as indicated in the Prescribing Information, each 
0.5mL dose contains 50 µg of group-specific polysaccharide antigens from each of 
Groups A, C, Y and W-135 in an isotonic sodium chloride solution. 
Each dose of vaccine also contains 2.5 to 5 milligram (mg) of lactose as a stabilizer. 
 Route: 
Subcutaneous 
 Batch Number: 
To be determined (Provided by Sponsor)) 
Inclusion Criteria: 
An individual must fulfill all of the following criteria in order to be eligible for trial 
enrollment: 
1)  Age ≥ 56 years on the day of inclusion 
2)  Informed consent form has been signed and dated 
3)  Able to attend all scheduled visits and to comply with all trial procedures 
Exclusion Criteria: 
An individual fulfilling any of the following criteria is to be excluded from trial 
enrollment: 
1)  Subject is pregnant, or lactating, or of childbearing potential (to be considered of 
non-childbearing potential, a female must be post-menopausal for at least 1 year, 
surgically sterile, or using an effective method of contraception or abstinence 
from at least 4 weeks prior to vaccination until at least 4 weeks after vaccination) 
2)  Participation in the 4 weeks preceding the trial vaccination or planned 
participation during the present trial period in another clinical trial investigating a 
vaccine, drug, medical device, or medical procedure 
 
3)  Receipt of any vaccine in the 4 weeks (28 days) preceding the trial vaccination or 
planned receipt of any vaccine prior to Visit 2 except for influenza vaccination, 
which may be received at least 2 weeks before or after study vaccine. This 
exception includes monovalent pandemic influenza vaccines and multivalent 
influenza vaccines. 
4)  Previous vaccination against meningococcal disease with either the trial vaccine 
or another vaccine (i.e., mono- or polyvalent, polysaccharide, or conjugate 
meningococcal vaccine containing serogroups A, C, Y, or W; or meningococcal 
B vaccine) 
 
5)  Receipt of immune globulins, blood or blood-derived products in the past 
3 months 
 
6)  Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation 
therapy, within the preceding 6 months; or long-term systemic corticosteroid 
therapy (prednisone or equivalent for more than 2 consecutive weeks within the 
past 3 months) 
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7)  History of meningococcal infection, confirmed either clinically, serologically, or 
microbiologically 
8)  At high risk for meningococcal infection during the trial (specifically, but not 
limited to, subjects with persistent complement deficiency, with anatomic or 
functional asplenia, or subjects travelling to countries with high endemic or 
epidemic disease) 
9)  Known systemic hypersensitivity to latex or any of the vaccine components, or 
history of a life-threatening reaction to the vaccine used in the trial or to a vaccine 
containing any of the same substances 
 
10) Personal history of Guillain-Barré syndrome (GBS) 
11) Personal history of an Arthus-like reaction after vaccination with a tetanus 
toxoid-containing vaccine within at least 10 years of the proposed study 
vaccination 
12) Verbal report of thrombocytopenia, contraindicating intramuscular vaccination, in 
the Investigator’s opinion 
13) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding 
inclusion, contraindicating intramuscular vaccination in the Investigator’s opinion 
 
14) Deprived of freedom by an administrative or court order, or in an emergency 
setting, or hospitalized involuntarily 
15) Current alcohol abuse or drug addiction 
16) Chronic illness that, in the opinion of the investigator, is at a stage where it might 
interfere with trial conduct or completion 
 
17) Moderate or severe acute illness/infection (according to investigator judgment) on 
the day of vaccination or febrile illness (temperature ≥ 100.4°F). A prospective 
subject should not be included in the study until the condition has resolved or the 
febrile event has subsided 
 
18) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first 
blood draw 
19) Identified as an Investigator or employee of the Investigator or study center with 
direct involvement in the proposed study, or identified as an immediate family 
member (i.e., parent, spouse, natural or adopted child) of the Investigator or 
employee with direct involvement in the proposed study 
Statistical Methods: 
All immunogenicity analyses will be performed on the Per-Protocol Analysis Set 
(PPAS). Additional immunogenicity analyses will be performed for exploratory 
purposes on the Full Analysis Set (FAS) according to randomization group. All safety 
analyses will be performed on the Safety Analysis Set (SafAS). Subjects will be 
analyzed according to the vaccine they actually received. 
Primary Objective 
Thirty days after the administration of MenACYW conjugate vaccine or Menomune® – 
A/C/Y/W-135 , the percentages of subjects who achieve an hSBA vaccine 
seroresponse* for meningococcal serogroups A, C, Y, and W in Group 1 are non-
inferior to the corresponding percentages in Group 2. 
Null hypothesis (H0): p(
G1) - p(
G2) ≤ -10% 
Alternative hypothesis (H1): p(
G1) - p(
G2) > -10% where p(
G1) and p(
G2) are the 
percentages of subjects who achieve an hSBA vaccine seroresponse in Group 1 and 
Group 2, respectively. Each of the serogroups A, C, Y, and W will be tested separately. 
If the lower limit of the 2-sided 95% confidence interval (CI) of the difference between 
the 2 proportions is > -10%, the inferiority assumption will be rejected. 
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For the 4 non-inferiority hypotheses using the seroresponse rates, the CI of the 
difference in proportions will be computed using the Wilson Score method without 
continuity correction. The overall non-inferiority of this objective will be demonstrated 
if all 4 individual null hypotheses are rejected. 
* hSBA vaccine seroresponse for serogroups A, C, Y, and W is defined as: 
•  For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer must be 
≥ 1:16. 
•  For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer must be 
at least 4-fold greater than the pre-vaccination titer. 
 
Secondary Objectives 
Thirty days after the administration of MenACYW conjugate vaccine or Menomune® 
– A/C/Y/W-135, the hSBA geometric mean titer ratio (GMTR) between Group 1 and 
Group 2 will be calculated and 95% CI will be provided. 
 
Observational Objectives 
Immunogenicity 
Descriptive statistics will be provided for the hSBA and rSBA* antibody titers against 
meningococcal serogroups contained in MenACYW conjugate vaccine and 
Menomune® – A/C/Y/W-135. In general, categorical variables will be summarized and 
presented by frequency counts, percentages, and CIs. The 95% CIs of point estimates 
will be calculated using the normal approximation for quantitative data and the exact 
binomial distribution (Clopper-Pearson method) for percentages. For GMTs, 95% CIs 
of point estimates will be calculated using normal approximation assuming they are 
log-normally distributed. 
* rSBA vaccine seroresponse is defined as a post-vaccination titer ≥ 1:32 for subjects 
with pre-vaccination rSBA titer < 1:8, or a post-vaccination titer ≥ 4 times the pre-
vaccination titer for subjects with pre-vaccination rSBA titer ≥ 1:8. 
 
Reverse cumulative distribution curve (RCDC) figures will be provided for the 
antibody titers against meningococcal serogroups contained in MenACYW conjugate 
vaccine and Menomune® – A/C/Y/W-135 treatment groups. 
 
Safety 
Safety results will be described for subjects in both study groups. The main parameters 
for the safety endpoints will be described by 95% CIs (based on the Clopper-Pearson 
method). 
 
Calculation of Sample Size: 
A total of 900 subjects will be enrolled. 
 
 
 
 
 
 
 
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Table of Study Procedures 
Phase III Trial, 2 Visits, 1 Vaccination, 2 Blood Samples, 2 Telephone Calls,  
180 Days’ Duration per Subject 
Visit/Contact 
Visit 1  Telephone Call 1  Visit 2  Telephone Call 2 
Trial timelines (days) 
D0  
D08  
D30  
D180 
Time windows (days) 
--  
+2 days  
+14 days  
+14 days 
Informed consent form 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Collection of demographic data 
X 
 
 
 
Urine pregnancy test (if applicable) 
X 
 
 
 
Medical history 
X 
 
 
 
Physical examination* 
X 
 
 
 
Review of temporary contraindications for blood 
sampling† 
 
 
X 
 
Randomization/allocation of subject number 
X 
 
 
 
Blood sampling (BL) 10 mL‡ 
BL1 
  
BL2 
 
Vaccination§ 
X 
 
 
 
Immediate surveillance (30 minutes) 
X 
 
 
 
DC provided  
X 
 
 
 
Telephone call 
 
X** 
 
X†† 
Recording of solicited injection site and systemic 
reactions 
D0 to D07   
 
 
 
Recording of unsolicited AEs 
Visit 1 through Visit 2 
 
DC reviewed and collected 
 
 
X 
 
Recording of MAAEs‡‡ 
 
  
After Visit 2 to Telephone Call 2 
Reporting of SAEs 
To be reported throughout the study period 
Collection of reportable concomitant medications   
X 
 
X 
 
MA provided§§ 
 
 
X 
 
Termination of active phase of trial 
 
 
X 
 
Completion of 6-month follow-up 
 
 
 
X 
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* Temperature needs to be measured and recorded in source documents. 
† Should a subject receive oral or injectable antibiotic therapy within 3 days prior to the second blood draw, the Investigator will 
postpone that blood draw until it has been 3 days since the subject last received oral or injectable antibiotic therapy. 
Postponement must still be within the timeframe for blood draw (30 to 44 days after vaccination at Visit 1). If postponement 
would result in the sample collection falling outside of this timeframe, the blood sample should be collected without 
postponement, and it should be documented appropriately that the sample was taken less than 3 days after stopping antibiotic 
treatment. 
‡ A pre-vaccination blood sample will be collected from all subjects at D0. 
§ Subjects will receive 1 dose of MenACYW conjugate vaccine or Menomune® – A/C/Y/W-135. 
** This call is made 8 to10 days after the vaccinations on D0. If D08 (+2 days) falls on a weekend or holiday, the telephone call 
may be made on the following business day. During this telephone call, the staff will find out whether the subject experienced 
any SAE not yet reported, and will remind the subject to continue using the DC up to Visit 2, to bring the DC to the study center 
at Visit 2, and confirm the date and time of Visit 2. 
†† Staff will contact the subject by telephone at 6 months (180 days + 14 days) after D0 vaccination to identify the occurrence of 
any MAAEs or SAEs not yet reported. 
‡‡ MAAEs that occur between the Visit 1 (D0) and Visit 2 will be recorded as unsolicited AEs. 
§§The MA is used for the recording of SAEs and MAAEs. The site staff will make a telephone call to the subject to obtain the 
information 180 days (+ 14 days) after the vaccinations on D0. Since the timeframe between Visit 1 and Visit 2 (inclusive) will 
be captured in the DC, the MA will be used to collect SAE and MAAE data from Visit 2 to Telephone Call 2. 
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List of Abbreviations 
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µg 
microgram 
AE 
adverse event 
AR 
adverse reaction 
BL 
blood sample(ing) 
CDM 
Clinical Data Management 
CFU 
colony-forming unit 
CI 
confidence interval 
C&MQO 
Clinical and Medical Quality Operations 
CRA 
Clinical Research Associate 
CRF 
case report form (electronic) 
CTA 
clinical trial agreement 
CTL  
Clinical Team Leader  
D 
day 
DC 
diary card 
EDC 
electronic data capture 
eSAE 
electronic Serious Adverse Event (Form) 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVFS 
first visit, first subject 
FVLS 
first visit, last subject 
GBS 
Guillain-Barré syndrome  
GCI 
Global Clinical Immunology 
GCP 
Good Clinical Practice 
GMT 
geometric mean titer 
GPV 
Global PharmacoVigilance  
hSBA 
serum bactericidal assay using human complement 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IM 
intramuscular 
IMD 
invasive meningococcal disease 
IND 
investigational new drug (application) 
IOM 
Institute of Medicine 
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IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LCLS 
last contact, last subject 
LLT 
lowest level term 
LLOQ 
lower limit of quantitation 
MA 
memory aid 
MAAE 
medically-attended adverse events 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
NSAID 
non-steroidal anti-inflammatory drug 
PPAS 
Per-Protocol Analysis Set 
PS 
polysaccharides 
PSO 
Product Safety Officer 
R&D 
Research and Development 
RCDC 
reverse cumulative distribution curve 
RMO 
Responsible Medical Officer 
rSBA 
serum bactericidal assay using baby rabbit complement 
SAE 
serious adverse event 
SafAS 
Safety Analysis Set 
SAP 
statistical analysis plan 
SMT 
Safety Management Team 
TMF 
trial master file 
UAR 
unexpected adverse reaction 
ULOQ 
upper limit of quantitation 
UTN 
Universal Trial Number 
WHO 
World Health Organization 
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1  Introduction 
1.1  Background 
This is a trial using MenACYW conjugate vaccine against invasive meningococcal disease. This 
Phase III trial will evaluate the immunogenicity and safety of a single dose of the quadrivalent 
Meningococcal Polysaccharide (Serogroups A, C, Y and W) Tetanus Toxoid Conjugate Vaccine 
(hereafter referred to as MenACYW conjugate vaccine) in adults 56 years of age and older. The 
purpose of MET49 is to demonstrate non-inferiority of immunogenicity and evaluate the safety of 
a single dose of MenACYW conjugate vaccine compared to a single dose of Menomune
®-
A/C/Y/W-135 when given to adults 56 years of age and older. 
Invasive meningococcal disease (IMD) is a serious illness caused by the bacterium Neisseria 
meningitidis (N. meningitidis), a Gram-negative diplococcus found exclusively in humans. 
Symptoms may include intense headache, fever, nausea, vomiting, photophobia, stiff neck, lethargy, 
myalgia, and a characteristic petechial rash (1). At least 12 distinct meningococcal serogroups have 
been classified based on the immunochemistry of the capsular polysaccharides (PS). Some strains 
are more likely than others to cause infection (1) (2) (3). Worldwide, most cases of 
meningococcal disease are caused by serogroups A, B, C, X, Y, and W (2) (3) (4). Serogroup B is 
responsible for endemic disease and some outbreaks, while serogroup C is responsible for large 
outbreaks (5). Serogroup A is the main cause of epidemics in the world, and is especially 
dominant in Africa and Asia. Serogroup W has been seen in Africa, as well as in the United 
Kingdom in residents who participated in the Hajj pilgrimage to the Kingdom of Saudi Arabia 
 (4) (6) (7) and more recently in Chile (8), Turkey (9) (10), China (11) (12), Argentina (13), and 
Brazil (14) (15) and in other parts of the world. Serogroup X causes substantial meningococcal 
disease in parts of Africa but rarely causes disease in other parts of the world (2) (16). Serogroup 
Y has not been associated with outbreaks, but its frequency as a cause of sporadic cases has 
gradually increased in the United States (US) and more recently in Canada and Europe 
 (17) (18) (19). This serogroup is commonly associated with meningococcal pneumonia, 
particularly in older adults > 65 years of age (20). Outbreaks of serogroup B meningococcal 
disease have also been reported on college campuses in the US during the last five-year period; a 
prolonged outbreak of serogroup B on a university campus in Ohio from 2008-2010 and 2 
universities in New Jersey and California in 2013 (21) (22). 
The epidemiology of N. meningitidis can be described as complex, unpredictable, geographically 
variable, and changing over time. Meningococcal disease occurs worldwide in both endemic and 
epidemic forms with seasonal variation. In Europe, the incidence rate of IMD has remained stable 
over the last 5 to 10 years, with the highest peak occurring in the population less than 4 years of 
age and a smaller peak in the 15 to 19 year old group. The highest incidence rate in Europe is 
caused by serogroup B, followed by C (23).
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The highest proportion of meningococcal cases was 
due to serogroup B in the population under 5 years of age. The highest proportion of serogroup C 
cases was observed in the population 25 to 44 years of age while the proportion of serogroup Y 
cases was highest in the population age 65 years and above. 
Surveillance data from England and Wales showed an increase in endemic meningococcal 
serogroup W disease across all age groups, accounting for 15% of all IMD cases in 2013-2014 
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compared with an average of 1% to 2% of all IMD cases in earlier years (24). A gradual increase 
in serogroup Y IMD has also been recently reported in Sweden during 2005-2012 (25) (26). 
Nearly 50% of all IMD was caused by serogroup Y in 2012 (25). Similarly, an increase in the 
proportion of IMD caused by serogroup Y has been observed in other Scandinavian countries, 
accounting for 31% in Norway in 2009-2010 and 38% in Finland in 2010 (27). 
In the US, the incidence rate of IMD was 0.14 per 100,000 in all ages; 0.83 per 100,000 in infants 
less than 1 year; 0.62 per 100,000 in toddlers 1 year of age; 0.27 per 100,000 in children 2 to 
4 years of age; and 0.02 per 100,000 in children 5 to 17 years of age in 2013. The age-specific 
incidence rate per 100,000 was 0.08 in adults 50 to 64 years of age, 0.03 in adults 65 to 74 years 
of age, 0.14 in adults 75 to 84 years of age, and 0.43 in adults 85 years of age and older in 2013  
(28). 
The goal for MenACYW conjugate vaccine is to provide broad protection against IMD caused by 
serogroups A, C, Y, and W in all age groups: children as young as 6 weeks of age, adolescents, 
and adults including those 56 years of age and older. 
1.2  Background of the Investigational Product 
1.2.1  Non-clinical Safety 
 
 
 
 
 
1.2.2  Clinical 
The MenACYW conjugate vaccine formulation was finalized based on data provided by 
2 studies: MET28, a Phase I study in infants, toddlers, and adults 18 to 55 years of age; and 
MET32, a Phase I/II study in toddlers. 
The formulation has been evaluated in over 650 subjects (infants, toddlers, and adults > 55 years 
of age) in MET39 and MET44. Both Phase II studies are discussed below. In addition, the vaccine 
has been evaluated in another Phase II study in 10 to 17 year olds in the US (MET50). The 
MET50 study evaluated the safety and immune response of the MenACYW conjugate vaccine 
when administered alone or along with Tdap and HPV vaccine administered concurrently as 
compared to a licensed vaccine (MENVEO
®
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). A total of 895 subjects received the MenACYW 
conjugate vaccine in this study. The follow up of this study has been completed; however, 
analysis is still ongoing. No safety concerns or signals were identified in this study. 
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The MenACYW conjugate vaccine was found to be well tolerated and no unanticipated or new 
significant safety concerns have been identified in the clinical trials completed to date. 
Study MET39 (Phase II) 
MET39 was a Phase II, randomized, open-label, multi-center study conducted in the US for which 
580 healthy subjects from 2 to 15 months of age were enrolled. This study evaluated the optimal 
vaccination schedule in the infant/toddler population. Subjects in Group 1 through Group 4 
received 1, 2, or 3 primary doses plus an additional dose of the MenACYW conjugate vaccine in 
the second year of life, concomitantly with routine pediatric vaccines at several different 
vaccination schedules. Subjects in Group 5 received 1 dose of the MenACYW conjugate vaccine 
concomitantly with routine pediatric vaccines. The routine pediatric vaccines given concomitantly 
with MenACYW conjugate vaccine at various schedules included Prevnar® or Prevnar 13 
vaccine, Pentacel vaccine, ROTARIX® or RotaTeq vaccine, hepatitis B vaccine, M-M-RII 
vaccine, and VARIVAX vaccine. 
Immunogenicity 
After the primary series consisting of 1, 2, or 3 doses of MenACYW conjugate vaccine, protective 
serum bactericidal assay using human complement (hSBA) threshold titers of ≥ 1:8 were attained 
by > 88% of subjects for serogroup C and by 62% to 74% for serogroup A. For serogroups Y and 
W, ≥ 90% achieved the threshold titer after 3 doses, 75% to 84% after 2 doses, but only 25% after 
a single dose administered at 6 months of age.  
After an additional dose of MenACYW conjugate vaccine in the second year of life (12 or 
15 months), between 91% and 100% of the subjects achieved the protective threshold regardless 
of the number of doses they received in the first year of life. 
Safety 
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MenACYW conjugate vaccine was well tolerated in infants and toddlers regardless of the 
immunization schedule and the number of doses administered. Safety results were comparable to 
those seen in control group subjects regardless of the immunization schedule and the number of 
doses administered. The safety profile of the licensed vaccines given concomitantly with 
MenACYW conjugate vaccine was similar to that of the licensed vaccines given concomitantly 
without MenACYW conjugate vaccine. 
No deaths occurred within 30 days. There were 2 subjects in Group 4 who died during the study, 
one as a result of hypoxic ischemic encephalopathy which started 96 days after the 6-month 
vaccination and one as a result of non-accidental head trauma 36 days after the 12-month 
vaccination. These events were considered by the Investigator as unrelated to study vaccine. 
There were 2 other subjects who discontinued the study due to a serious adverse event (SAE) and 
the receipt of intravenous immunoglobulin treatment: 1 subject in Group 2 with Kawasaki 
disease, 106 days after the 6-month vaccination; and 1 subject in Group 3 with middle lobe 
pneumonia and Kawasaki disease, 50 and 52 days, respectively, after the 4-month vaccinations. 
One other subject in Group 4 was discontinued due to a non-serious adverse event (AE) (viral 
rash 1 day after the 6-month vaccinations). None of these AEs leading to discontinuation were 
considered by the Investigator as related to the vaccine. There were no related SAEs during this 
study. 
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Study MET44 (Phase II) 
MET44 was a Phase II, randomized, open-label (the laboratory technicians were blinded to group 
assignment), multi-center study conducted in the US. This study evaluated the immunogenicity 
and safety profiles of a single dose of MenACYW conjugate vaccine when administered to adults 
56 years of age and older. A total of 301 subjects age 56 years and older on the day of enrollment 
were randomized to receive a single dose of MenACYW conjugate vaccine or Menomune® - 
A/C/Y/W-135; each group was stratified according to age into 2 subsets (subjects 56 to 64 years 
of age and subjects ≥ 65 years of age). The subjects were randomly allocated to Group 1 or 
Group 2 with a 2:1 ratio (201 in Group 1 and 100 in Group 2), and stratified according to age into 
2 subsets (101 in Group 1a, 100 in Group 1b, 50 in Group 2a, and 50 in Group 2b). 
Immunogenicity 
The proportions of subjects with hSBA titers ≥ 1:8 obtained after MenACYW conjugate vaccine 
administration (Group 1) for serogroups A and C were comparable to, or for serogroups Y and W 
higher than, those obtained after Menomune® - A/C/Y/W-135 administration (Group 2): 93.8% in 
Group 1 and 85.1% in Group 2 for serogroup A; 74.9% in Group 1 and 62.8% in Group 2 for 
serogroup C; 80.5% in Group 1 and 59.6% in Group 2 for serogroup Y; 79.5% in Group 1 and 
60.6% in Group 2 for serogroup W. 
Within each group of those who received MenACYW conjugate vaccine or Menomune® - 
A/C/Y/W-135, the proportions of subjects with hSBA titers ≥ 1:8 were comparable between the 
subset of subjects 56 to 64 years of age and the subset ≥ 65 years of age, for all serogroups. 
The hSBA geometric mean titers (GMTs) after MenACYW conjugate vaccine administration for 
serogroups A and W were comparable to, or for serogroups C and Y higher than, those after 
Menomune® - A/C/Y/W-135 administration. Responses with serum bactericidal assay using baby 
rabbit complement (rSBA) in general demonstrated the same trend as with hSBA. 
Safety 
Vaccination with MenACYW conjugate vaccine or Menomune
® - A/C/Y/W-135among adults 
56 years of age and older was found to be well tolerated, with no safety concerns identified. There 
were no immediate unsolicited AEs/reactions reported in either group. There were no deaths, 
SAEs or AEs that led to study discontinuation reported during the study. 
Overall, the safety profile in the subset of subjects 56 to 64 years of age was generally comparable 
to the safety profile in the subset ≥ 65 years of age, with the exception of a small increase in 
injection site reactions found in the subset 56 to 64 years of age in both study groups. 
1.3  Potential Benefits and Risks 
1.3.1  Potential Benefits to Subjects 
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MenACYW conjugate vaccine is an investigational vaccine that is undergoing active clinical 
investigation. There may be no direct benefit from receiving the MenACYW conjugate vaccine. 
However, based on the data generated from previous studies, the immunogenicity profile of the 
MenACYW conjugate vaccine in different age groups shows that the majority of subjects 
developed seroprotective levels of antibodies after vaccination. The safety evaluation indicates 
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that the vaccine is well-tolerated, and no safety issues have been detected to date. In all, the data 
support further evaluation of the MenACYW conjugate vaccine in humans. 
Subjects who receive Menomune® - A/C/Y/W-135 will likely be protected against meningococcal 
disease caused by N. meningitidis serogroups A, C, Y, and W. 
As with any vaccine, MenACYW conjugate vaccine and Menomune® - A/C/Y/W-135 may not 
protect 100% of individuals against the diseases they are designed to prevent. 
1.3.2  Potential Risks to Subjects 
Like other vaccines, MenACYW conjugate vaccine or Menomune® - A/C/Y/W-135 may cause 
injection site reactions such as pain, swelling, and erythema, or certain systemic events such as 
fever, headache, malaise, or myalgia. There may be a rare possibility of an allergic reaction, 
which could be severe. There may be other risks for MenACYW conjugate vaccine that are not 
yet known. 
The following additional adverse events have been reported during post-approval use of 
Menomune® - A/C/Y/W-135: Guillain-Barré syndrome (GBS), vasovagal syncope, dizziness, 
paresthesia, nausea, vomiting, diarrhea, arthralgia, asthenia, chills, fatigue, and hypersensitivity 
reactions such as rash, urticaria, pruritus, dyspnea and angioedema. Because these events were 
reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their 
frequency or to establish a causal relationship to Menomune
® - A/C/Y/W-135 exposure. 
GBS has been reported mostly in persons aged 11 to 19 years who had symptom-onset within 
6 weeks of administration of a US licensed meningococcal conjugate vaccine (29). A 
retrospective cohort study carried out in the US using healthcare claims data found no evidence of 
increased GBS risk associated with the use of that vaccine. This study was able to exclude all but 
relatively small incremental risks (30). 
A review by the Institute of Medicine (IOM) found inadequate evidence to accept or reject a 
causal relationship between tetanus toxoid-containing vaccines and GBS (31). The IOM found 
evidence for a causal relation between tetanus toxoid-containing vaccines and brachial neuritis 
(30). Arthus reactions are rarely reported after vaccination and can occur after tetanus toxoid-
containing vaccines (31).
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No occurrences of GBS, brachial neuritis, or Arthus reaction have been reported with the use of 
MenACYW conjugate vaccine in the completed clinical trials. 
 
 
 
 
 
 Importantly, no similar cases have been reported following the 
administration of MenACYW conjugate vaccine in any other trials. 
The potential risks associated with blood drawing include local pain, bruising and, rarely, fainting. 
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The potential risks listed here are not exhaustive. Refer to the package insert of Menomune® - 
A/C/Y/W-135 (32) and the Investigator’s Brochure of the investigational vaccine for additional 
information regarding the potential risks. 
1.4  Rationale for the Trial 
The MenACYW conjugate vaccine is designed for the immunization of individuals of all ages 
(infants 6 weeks of age and older through and including older adults > 65 years of age) against 
IMD. The purpose of the vaccine is to provide broad coverage against circulating meningococcal 
strains from serogroups A, C, Y, and W. Compared to a previous Sanofi Pasteur meningococcal 
conjugate vaccine, Menactra
®, the MenACYW conjugate vaccine is prepared using tetanus toxoid 
as the carrier protein. Conjugation of polysaccharide antigens to a protein carrier can induce T-
cell-dependent immune responses, which are anticipated to give rise to higher antibody titers, 
longer duration of the immune response, and enhanced immunologic memory that allows for a 
booster response. 
Meningococcal polysaccharide vaccines have two important limitations: a) the antibody response 
is age-dependent, with infants giving the poorest response; and b) polysaccharides alone are T-cell 
independent immunogens, and therefore no anamnestic response is seen. The immunogenicity of 
polysaccharide vaccines in infants and children has been shown to be improved by conjugating the 
polysaccharides to protein carriers. Among the key advantages expected of the tetanus carrier is 
improved immunogenicity in infants and older adults. Pre-clinical studies using a mouse model 
and investigating different carriers, showed significant levels of polysaccharide-specific total 
immunoglobulin G (IgG) and bactericidal responses in response to the formulations with tetanus 
toxoid as a carrier. Early Phase I/II trials including those with the final formulation (MET39 and 
MET44) showed the potential of the candidate vaccine as a very good immunogen in all age 
groups, including young infants and older adults. The MenACYW conjugate vaccine was found to 
be immunogenic and well tolerated; it did not raise any safety concerns in the above trials using 
the final formulation or in the earlier trials. 
The purpose of MET49 is to demonstrate non-inferiority of immunogenicity and evaluate the 
safety of a single dose of MenACYW conjugate vaccine compared to a single dose of 
Menomune® – A/C/Y/W-135 in adults 56 years of age and older in the US. 
2  Trial Objectives 
2.1  Primary Objectives 
To demonstrate the non-inferiority of the vaccine seroresponse to meningococcal serogroups A, 
C, Y, and W following the administration of a single dose of MenACYW conjugate vaccine 
compared to those observed following the administration of a single dose of Menomune
® – 
A/C/Y/W-135. 
The endpoints for the primary objectives are presented in
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2.2  Secondary Objectives 
1) To compare the hSBA antibody GMTs of meningococcal serogroups A, C, Y, and W 
following the administration of MenACYW conjugate vaccine to those observed following the 
administration of Menomune
® – A/C/Y/W-135 
The endpoints for the secondary objectives are presented in Section 9.2.1.1. 
2.3  Observational Objectives 
Immunogenicity 
• To describe antibody titers against meningococcal serogroups A, C, Y, and W measured 
by hSBA at baseline (before vaccination) and 30 days after vaccination with MenACYW 
conjugate vaccine or Menomune
® – A/C/Y/W-135 
• To describe antibody titers against meningococcal serogroups A, C, Y, and W measured 
by rSBA at baseline (before vaccination) and 30 days after vaccination with MenACYW 
conjugate vaccine or Menomune
® – A/C/Y/W-135 in a subset of 100 subjects per 
treatment group 
Safety 
• To describe the safety profile of MenACYW conjugated vaccine compared to that of the 
licensed Menomune® – A/C/Y/W-135 after a single administration. 
The endpoints for the immunogenicity and safety observational objectives are presented in 
Section 9.3.1.1 and Section 9.3.2.2, respectively. 
3  Investigators and Trial Organization 
This trial will be conducted in approximately 35 centers in the US. The Principal Investigators 
and any sub-investigators at the individual sites will be coordinated by one Coordinating 
Investigator. Details of the trial centers, the Investigators at each center, and the Coordinating 
Investigator are provided in the “List of Investigators and Centers Involved in the Trial” 
document. 
An internal safety management team (SMT) will perform a blinded safety analysis on safety data 
after vaccination. 
The Sponsor’s Responsible Medical Officer (RMO) (the person authorized to sign this protocol 
and any amendments on behalf of the Sponsor) is 
 
 
4  Independent Ethics Committee / Institutional Review Board 
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Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent form(s) (ICF), subject 
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recruitment procedures, and any other written information to be provided to subjects must be 
approved by, and / or receive favorable opinion from, the appropriate Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB). 
In accordance with Good Clinical Practice (GCP) and local regulations, each Investigator and / or 
the Sponsor are responsible for obtaining this approval and / or favorable opinion before the start 
of the trial. If the protocol is subsequently amended, approval must be re-obtained for each 
substantial amendment. Copies of these approvals, along with information on the type, version 
number, and date of document, and the date of approval, must be forwarded by the Investigator to 
the Sponsor together with the composition of the IEC / IRB (the names and qualifications of the 
members attending and voting at the meetings). 
The Investigator and Sponsor will submit written summaries of the status of the trial to the IEC / 
IRB annually, or more frequently if requested. All SAEs occurring during the trial that are related 
to vaccination will be reported by the Investigator to the IEC / IRB, according to the IEC / IRB 
policy. 
5  Investigational Plan 
5.1  Description of the Overall Trial Design and Plan 
5.1.1  Trial Design 
This is a Phase III modified double-blind, randomized, parallel-group, active-controlled, multi-
center trial to compare the immunogenicity and safety of MenACYW conjugate vaccine to 
Menomune® - A/C/Y/W-135 in adults ≥ 56 years of age in the US. 
Approximately 900 healthy adults will be randomized in a 1:1 ratio to the following groups: 
• Group 1: MenACYW conjugate vaccine 
• Group 2: Menomune® - A/C/Y/W-135 
Enrollment will be stratified by age (see Table 5.1)
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For subjects 56 to 64 years of age, 200 subjects will be enrolled in both Group 1 and Group 2. 
For subjects 65 years of age and older, 250 subjects will be enrolled in both Group 1 and Group 2. 
These subjects will be further stratified into 2 groups as 65 to 74 years of age and 75 years of age 
and older. At least 25% of the 250 subjects will be enrolled in each of these age groups. 
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Table 5.1: Testing strategy for N. meningitidis serogroups ACYW 
 
ACYW serogroups tested by 
hSBA 
(all subjects) 
ACYW serogroups tested by 
rSBA 
(subset) 
Group 1 
 
 
56-64 years 
200 
50 
≥ 65 years: 
250 
50 
    65-74 years 
70-180 
15-35 
    ≥ 75 years 
70-180 
15-35 
Group 2 
 
 
56-64 years 
200 
50 
≥ 65 years: 
250 
50 
    65-74 years 
70-180 
15-35 
    ≥ 75 years 
70-180 
15-35 
 
All subjects will provide pre-vaccination blood samples for immunogenicity assessment at 
baseline (Visit 1) and at Day (D)30 (+14-day window) post-vaccination (Visit 2). Solicited AE 
information will be collected for 7 days after vaccination, unsolicited AE information will be 
collected from Visit 1 to D30 (Visit 2), and SAE information will be collected from D0 through 
D180 (+14 days) after vaccination. Medically-attended adverse events (MAAEs) will be collected 
from Visit 1 through Visit 2 (as part of the collection of unsolicited AE information) and from 
Visit 2 through D180 (+14 days) (as MAAEs). 
5.1.2  Justification of the Trial Design 
 
 MET49 is a study that will be 
conducted as part of the Phase III of development of the MenACYW conjugate vaccine in which 
the vaccine would be evaluated in the age group 56 years of age and older. 
This study is designed to evaluate immunogenicity responses and safety profiles following the 
administration of a single dose of the MenACYW conjugate vaccine compared to the responses 
observed after a single dose of a licensed quadrivalent meningococcal vaccine (Menomune®
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this population. 
Conjugation of polysaccharide antigens to a protein carrier can induce T-cell-dependent immune 
responses, which give rise to higher antibody titers, longer duration of the immune response, and 
enhanced immunologic memory. Conjugate technology has been successfully applied to Hib, 
pneumococcal, and meningococcal antigens and has demonstrated improvements in cellular 
immune responses, and long-term memory. It is well documented that increasing age is associated 
with a decline in humoral and cell-mediated immunity to both newly-encountered pathogenic 
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organisms and vaccines. As a consequence, adults ≥ 56 years of age are more susceptible to 
infection and less responsive to vaccines. This is felt to be attributable to fewer circulating naïve 
T cells, which also have reduced immune responsiveness relative to T cells in younger 
individuals. 
In addition, there is evidence that T cell immune systems of adults ≥56 years of age are comprised 
primarily of memory T cells, which are more readily activated than naïve T cells. 
It is possible that the ability of MenACYW conjugate vaccine conjugate to confer T cell 
dependent responses will be observed in adults ≥ 56 years of age and could provide an important 
mechanism to compensate for the reduction in naïve T cells while further boosting responses in 
existing memory T cells. Due to more frequent occurrences of chronic illnesses in adults 
≥ 56 years of age, the need for repeat vaccination is not uncommon. Another driver of repeat 
vaccination in this age group is international travel. A conjugate vaccine that could prime, boost, 
prolong the duration of protection, and not induce hyporesponsiveness would be an important 
improvement over existing polysaccharide vaccines. Based on these potential responses to a 
conjugate vaccine in this population, it is expected that MenACYW conjugate vaccine could 
provide an immunogenicity advantage over those seen after the administration of Menomune® - 
A/C/Y/W-135 in the population ≥ 56 years of age. 
The selection of Menomune® – A/C/Y/W-135 as a comparator will contribute towards the total 
database of subjects that is compared to the competitor’s product in the final dossier and will be 
beneficial for the Food and Drug Administration (FDA) review of the file, as Menomune® – 
A/C/Y/W-135 is one of the quadrivalent meningococcal conjugate vaccines licensed in the US. 
5.1.3  Trial Plan 
Vaccination 
All subjects will receive a single dose of either MenACYW conjugate vaccine or Menomune® – 
A/C/Y/W-135 at Visit 1 (D0). 
Blood sampling 
All subjects will provide a pre-vaccination blood sample at Visit 1 and a post-vaccination sample 
at Visit 2 (30 to 44 days after the vaccination at Visit 1). 
Collection of safety data 
• All subjects will be observed for 30 minutes after vaccination, and any unsolicited systemic 
AEs occurring during that time will be recorded as immediate unsolicited systemic AEs in the 
electronic case report form (CRF). 
• The subject will record information in a DC about solicited reactions from D0 to D07 after 
vaccination and unsolicited AEs from D0 to Visit 2. SAEs will be reported throughout the 
duration of the trial. 
• The subject will record information about any possible SAEs and MAAEs in a memory aid 
(MA) from Visit 2 until the 6 month (+14 days) telephone call. 
• 
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In addition, the subject will be asked to notify the site immediately about any potential SAEs 
at any time during the trial. 
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• Staff will contact the subject by telephone on D08 (+2 days) to identify the occurrence of any 
SAE not yet reported and to remind them to complete the DC up to Visit 2 and to bring it back 
to Visit 2. 
• The completed DC will be reviewed with the subject at Visit 2. 
• Staff will contact the subject by telephone at 6 months (+14 days) after vaccination to review 
the MA and identify the occurrence of any MAAEs, as well as SAEs that have not been 
reported. 
5.1.4  Visit Procedures 
Medical procedures (examinations, injections, etc.) must be conducted by appropriately licensed 
or credentialed study site staff working within the scope of their license/credentials. 
Visit 1 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) Give the subject information about the trial, answer any questions, obtain written informed 
consent, and give him / her a signed copy. 
2) Check inclusion and exclusion criteria for eligibility (see Section 5.2.4 and Section 5.2.5, 
respectively). 
3) Collect demographic data. 
4) Urine pregnancy test, if applicable 
5) Obtain verbal medical history about the subject. 
6) Conduct a history-directed physical examination, including temperature (a physical 
examination conducted during the same day as part of routine clinical care may be used for 
this purpose). 
7) Connect to the Interactive Web Response System (IWRS) for randomization, dose number 
assignment, and allocation of subject number (see Section 6.5 for instructions). 
8) Obtain the first blood sample (see Section 7.1 for detailed instructions regarding the handling 
of blood samples). If attempts to obtain the first blood draw are unsuccessful (3 attempts), 
then Visit 1 can be rescheduled to a later date at which point informed consent and 
inclusion/exclusion criteria must be re-validated. If the first blood draw cannot be obtained, 
the subject will be withdrawn from the study without being vaccinated. 
9) Administer the appropriate study vaccine to the subject in the deltoid region. The vaccine 
must be administered on the side opposite to that of the blood sampling according to the study 
group: 
•  Group 1 = MenACYW conjugate vaccine 
•  Group 2 = Menomune® - A/C/Y/W-135 
10) 
Keep the subject under observation for 30 minutes, and record any adverse event (AE) in the 
source document. 
11) 
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12) 
Remind the subject to expect a telephone call 8 days after Visit 1 and to bring back the DC 
when he/she returns for Visit 2 at a specified date and time. 
13) 
Remind the subject to notify the site in case of an SAE. 
14) 
Complete the relevant case report form (CRF) pages for this visit. 
Telephone Call 1 (8 to 10 days after Visit 1) 
Note: If Day 08 falls on a weekend or a holiday, the telephone call may be made on the following 
business day. If the subject is not available, the study staff should document the attempts to make 
contact. 
1) Record relevant information concerning the subject’s health status on the telephone contact 
form. If an SAE occurred, follow the instructions in Section 10 for reporting it. 
2) Remind the subject to do the following: 
• Complete the D0 to D07 pages of the DC 
• Complete the remaining pages of the DC, and bring them to Visit 2. 
• Notify the site in case of an SAE. 
Visit 2 (30 [+14] days after Visit 1): Collection of Safety Information and Blood Sample 
1) Review the pages of the DC with the subject, including any AEs, medications, or therapy that 
occurred since vaccination. 
2) Review the temporary contraindications for blood sampling (see Section 5.2.8). 
3) Obtain the second blood sample (see Section 7.1 for detailed instructions regarding the 
handling of blood samples). 
4) Give the subject an MA. 
5) Complete the termination record of the CRF. 
6) If the subject does not return for Visit 2, and the DC is not received at the site, site personnel 
will contact the subject by telephone. During the telephone call, the subject will be reminded 
to return the DC to the study site. Telephone calls will be documented on the Telephone / 
Interview Record. If the study personnel are unable to contact the subject with 3 attempts, the 
study personnel will follow instructions given in Section 5.2.10. 
Safety Follow-up Telephone Call (180 [+14] days after Visit 1): Collection of SAEs and MAAEs 
Review the MA and ask the subject if he/she has experienced any SAE in the time since 
vaccination that has not been reported to the study personnel and / or MAAE. 
•  If an SAE has occurred, follow the instructions in Section 10 for reporting it. 
• 
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If an MAAE has occurred, follow the instructions in the Operating Guidelines. 
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SAEs and AEs That Are Related to Vaccination or That Led to Discontinuation: 
At any time during the study, a subject who experiences an SAE or an AE must be followed if 
either of the following is true: 
•  The SAE or AE is considered by the Investigator to be related to vaccination, and is not 
resolved by the end of the subject’s participation in the trial 
•  The subject has been discontinued from the trial because of the SAE or AE 
Any such subject must be followed until the condition resolves, becomes stable, or becomes 
chronic. 
5.1.5  Planned Trial Calendar 
The following dates are approximate. The actual dates may differ as, for example, the trial will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned trial period - FVFS to LCLSa: 15 July 2016 - 05 May 2017 
Planned inclusion period - FVFS to FVLS: 15 July 2016 – 04 November 2016 
Planned end of trial: 05 May 2017 
Planned date of final clinical study report: March 2018 
Safety Follow-up Telephone Call (180 [+14] days after Visit 1) of the last subject in either group 
is considered to be the end of the trial. 
5.1.6  Early Safety Data Review 
This trial will not include an early review of safety data (i.e., no early safety review[s] of 
preliminary safety data occurring at pre-determined milestones defined in the protocol with pause 
in enrollment). However, it may be interrupted at any time if new data about the investigational 
product become available, and/or on advice of the Sponsor, the IECs/IRBs, or the governing 
regulatory authorities in the country where the trial is taking place. 
If the trial is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigator’s, the IECs/IRBs, and the regulatory authorities of the reason for the termination or 
suspension. If the trial is prematurely terminated for any reason, the Investigator will promptly 
inform the subjects’ parents / guardian and should assure appropriate therapy and follow-up. 
5.2  Enrollment and Retention of Trial Population 
5.2.1  Recruitment Procedures 
Before the start of the trial, the Investigator and / or study staff may contact subjects of an 
appropriate pool of potential subjects and invite them to participate in the study. The site will 
                                                 
a
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ensure that any advertisements used to recruit subjects (e.g. letters, pamphlets, and posters) are 
submitted to Sanofi Pasteur for review prior to submission to the IEC/ IRB for approval. 
In addition, a subject who visits the trial site for a routine visit may be invited to enroll in the trial, 
if eligible. Subjects may also be recruited from the general population. 
5.2.2  Informed Consent Procedures 
Informed consent is the process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial. Informed consent must be obtained before any study procedures 
are performed. The process is documented by means of a written, signed, and dated ICF. 
In accordance with GCP, prior to signing and dating the consent form, the subject must be informed 
by appropriate study personnel about all aspects of the trial that are relevant to making the 
decision to participate, and must have sufficient time and opportunity to ask any questions. 
A subject who cannot read will not be included in the trial. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial, this will be communicated to him / her in a timely manner. Such 
information will be provided via a revised ICF or an addendum to the original ICF. 
ICFs will be provided in duplicate, or a photocopy of the signed consent will be made. The 
original will be kept by the Investigator, and the copy will be kept by the subject. 
Documentation of the consent process should be recorded in the source documents. 
5.2.3  Screening Criteria 
There are no screening criteria other than the inclusion and exclusion criteria. 
5.2.4  Inclusion Criteria 
An individual must fulfill all of the following criteria in order to be eligible for trial enrollment: 
1) Aged ≥ 56 years on the day of inclusiona 
2) Informed consent form has been signed and dated 
3) Able to attend all scheduled visits and to comply with all trial procedures 
                                                 
a
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5.2.5  Exclusion Criteria 
An individual fulfilling any of the following criteria is to be excluded from trial enrollment: 
1) Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-
childbearing potential, a female must be post-menopausal for at least 1 year, surgically sterile, 
or using an effective method of contraception or abstinence from at least 4 weeks prior to 
vaccination until at least 4 weeks after vaccination) 
2) Participation in the 4 weeks preceding the trial vaccination or planned participation during the 
present trial period in another clinical trial investigating a vaccine, drug, medical device, or 
medical procedure  
3) Receipt of any vaccine in the 4 weeks (28 days) preceding the trial vaccination or planned 
receipt of any vaccine prior to Visit 2 except for influenza vaccination, which may be 
received at least 2 weeks before or after study vaccine. This exception includes monovalent 
pandemic influenza vaccines and multivalent influenza vaccines. 
4) Previous vaccination against meningococcal disease with either the trial vaccine or another 
vaccine (i.e., mono- or polyvalent, polysaccharide, or conjugate meningococcal vaccine 
containing serogroups A, C, Y, or W; or meningococcal B vaccine) 
5) Receipt of immune globulins, blood or blood-derived products in the past 3 months 
6) Known or suspected congenital or acquired immunodeficiency; or receipt of 
immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within 
the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or 
equivalent for more than 2 consecutive weeks within the past 3 months) 
7) History of meningococcal infection, confirmed either clinically, serologically, or 
microbiologically 
8) At high risk for meningococcal infection during the trial (specifically, but not limited to, 
subjects with persistent complement deficiency, with anatomic or functional asplenia, or 
subjects travelling to countries with high endemic or epidemic disease) 
9) Known systemic hypersensitivity to latex or any of the vaccine components, or history of a 
life-threatening reaction to the vaccine used in the trial or to a vaccine containing any of the 
same substances
a 
10) Personal history of Guillain-Barré syndrome (GBS) 
11) Personal history of an Arthus-like reaction after vaccination with a tetanus toxoid-containing 
vaccine within at least 10 years of the proposed study vaccination 
12) Verbal report of thrombocytopenia, contraindicating intramuscular vaccination, in the 
Investigator’s opinion 
                                                 
a The components of MenACYW conjugate vaccine are listed in Section 6.1.1.1 and in the Investigator’s Brochure. 
The components of Menomune® – A/C/Y/W-135 are listed in Section 6.1.2.1 and in the package insert. Menomune
®
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13) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination in the Investigator’s opinion 
14) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
15) Current alcohol abuse or drug addiction 
16) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere 
with trial conduct or completiona 
17) Moderate or severe acute illness/infection (according to investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 100.4°F). A prospective subject should not be 
included in the study until the condition has resolved or the febrile event has subsided 
18) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw 
19) Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (i.e., parent, 
spouse, natural or adopted child) of the Investigator or employee with direct involvement in 
the proposed study 
If the subject has a primary physician who is not the Investigator, the site must contact this 
physician with the subject’s consent to inform him / her of the subject’s participation in the study. 
In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.2.6  Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
medical history (reported as diagnosis) including conditions for which the subject is or has been 
followed by a physician or conditions that could resume during the course of the study or lead to 
an SAE or to a repetitive outpatient care will be collected in the CRF. The significant medical 
history section of the CRF contains a core list of body systems and disorders that could be used to 
prompt comprehensive reporting, as well as space for the reporting of specific conditions and 
illnesses. 
For each condition, the data collected will be limited to: 
•  Diagnosis (this is preferable to reporting signs and symptoms) 
•  Presence or absence of the condition at enrollment 
The reporting of signs and symptoms is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the trial. 
                                                 
a 
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Chronic illness may include, but is not limited to cardiac disorders, renal disorders, auto-immune disorders, 
diabetes, psychomotor diseases, and known congenital or genetic diseases 
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5.2.7  Contraindications for Subsequent Vaccinations 
Not applicable since only one dose of vaccine will be administered in this trial. 
5.2.8  Contraindications for Subsequent Blood Samples 
Should a subject receive oral or injectable antibiotic therapy within 3 days before the second 
blood draw, the Investigator will postpone that blood draw until it has been 3 days since the 
subject last received oral or injectable antibiotic therapy. Postponement must still be within the 
timeframe for blood draw (30 to 44 days after vaccination on D0). If postponement would result 
in the sample collection falling outside of this timeframe, the blood sample should be collected 
without postponement, and it should be documented appropriately that the sample was taken less 
than 3 days after stopping antibiotic treatment. 
5.2.9  Conditions for Withdrawal 
Subjects will be informed that they have the right to withdraw from the trial at any time. A subject 
may be withdrawn from the study: 
• At the discretion of the Investigator or Sponsor due to safety concerns (withdrawal) without 
the subject’s permission 
• At the request of the subject (dropout) 
The following will result in automatic withdrawal or exclusion of a subject from the study: 
• Significant non-compliance with the protocol, based on the Investigator’s judgment 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and on the CRF.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “SAE” or “other AE” as appropriate) 
or for another reason. 
Withdrawn subjects will not be replaced. 
5.2.10 Lost to Follow-up Procedures 
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In the case of subjects who fail to return for a follow-up examination, documented reasonable 
effort (i.e., documented telephone calls and certified mail) should be undertaken to locate or recall 
them, or at least to determine their health status while fully respecting their rights. These efforts 
should be documented in the CRF and in the source documents. 
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5.2.11 Classification of Subjects Who Discontinue the Trial 
For any subject who discontinues the trial prior to completion, the most significant reason for 
early termination will be checked in the CRF. Reasons are listed below from the most significant 
to the least significant (refer to the CRF completion guidelines for additional details and 
examples): 
• Serious adverse event: To be used when a subject drops out of or is withdrawn from the 
study by the Investigator because of the occurrence of an SAE, as defined in Section 9.3.2.1. 
• Other adverse event: To be used when a subject drops out of or is withdrawn from the study 
by the Investigator because of the occurrence of an AE other than an SAE, as defined in 
Section 9.3.2.1. 
• Non-compliance with protocol: To be used when the Investigator withdraws a subject from 
the study because of failure to follow the protocol, including when it is retrospectively 
discovered that a subject did not fulfill the eligibility criteria. The Investigator will provide a 
comment as to the specific cause of non-compliance. 
• Lost to follow-up: To be used when the Investigator withdraws a subject from the study 
because of failure to establish contact, as outlined in Section 5.2.10. The Investigator will 
provide documentation that contact was attempted (i.e., return of unsigned certified letter 
receipt). 
• Voluntary withdrawal not due to an adverse event: To be used when a subject drops out of 
the study for any reason other than those listed above. 
5.2.12 Follow-up of Discontinuations 
The site should complete all scheduled safety follow-ups and contact any subject who has 
prematurely terminated the trial because of an SAE, other type of AE, non-compliance with the 
protocol, or loss of eligibility, including definite contraindications.  
For subjects where the reason for early termination was lost to follow-up or if the subject 
withdrew informed consent and specified that they do not want to be contacted again and it is 
documented in the source document, the site will not attempt to obtain further safety information. 
For subjects where the reason for early termination is voluntary withdrawal, the site will attempt 
to contact them for the 6-month follow-up except if they specified that they do not want to be 
contacted again and it is documented in the source document. 
5.2.13 Follow-up and Reporting of Pregnancies 
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Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy and if the single dose of the study 
vaccine has been administered, the subject will not be discontinued from the trial and will be 
followed for safety assessment (and may be followed for immunogenicity assessment, if 
applicable).  
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All pregnancy cases should be reported if they occurred during the study and during the 6-month 
follow-up period, or if the start date of the pregnancy cannot be determined. To report the 
pregnancy case, the Investigator must fill out a Pregnancy Reporting Form in the electronic data 
capture (EDC) system and send it to the Sponsor within 1 month of identifying a pregnancy case.  
Study staff must then maintain contact with the subject to obtain information about the outcome—
i.e., details about the delivery and the newborn, or about pregnancy termination—and must update 
the electronic Pregnancy Reporting Form. This information should be provided to the Sponsor 
within 1 month of delivery. 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases could be considered SAEs. Spontaneous abortions, fetal 
death, stillbirth, and congenital anomalies reported in the baby are always considered as SAEs, 
and the information should be provided to the Global PharmacoVigilance (GPV) Department 
regardless of when the SAE occurs (e.g., even after the end of the trial). 
5.3  Safety Emergency Call 
If, as per the Investigator’s judgment, a subject experiences a medical emergency, the Investigator 
may contact the Sponsor’s RMO for advice on trial related medical question or problem. If the 
RMO is not available, then the Investigator may contact the Call Center - available 24 hours a 
day, 7 days a week - that will forward all safety emergency calls to the appropriate primary or 
back-up Sanofi Pasteur contact, as needed. The toll-free contact information for the Call Center is 
provided in the Operating Guidelines. 
This process does not replace the need to report an SAE. The investigator is still required to 
follow the protocol defined process for reporting SAEs to GPV (Please refer to Section 10). 
In case of emergency code-breaking, the Investigator is required to follow the code-breaking 
procedures described in Section 6.4. 
5.4  Modification of the Trial and Protocol 
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Any amendments to this trial plan and protocol must be discussed with and approved by the 
Sponsor. If agreement is reached concerning the need for an amendment, it will be produced in 
writing by the Sponsor, and the amended version of the protocol will replace the earlier version. 
All substantial amendments e.g., that affect the conduct of the trial or the safety of subjects, 
require IRB approval and must also be forwarded to regulatory authorities. 
An administrative amendment to a protocol is one that modifies some administrative or logistical 
aspect of the trial but does not affect its design or objectives or have an impact on the subjects’ 
safety. Administrative changes do not require IRB approval; however, the IRB must be notified 
whenever one is made. 
The Investigator is responsible for ensuring that changes to an approved trial, during the period 
for which IRB approval has already been given, are not initiated without IRB review and 
approval, except to eliminate apparent immediate hazards to subjects. 
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5.5  Interruption of the Trial 
The trial may be discontinued if new data about the investigational product resulting from this or 
any other trials become available; or for administrative reasons; or on advice of the Sponsor, the 
Investigators, and / or the IECs / IRBs. If the trial is prematurely terminated or suspended, the 
Sponsor shall promptly inform the Investigators, the regulatory authorities, and the IECs / IRBs of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the trial subjects and assure appropriate therapy and / or 
follow-up for them. 
6  Vaccines Administered 
6.1  Identity of the Investigational Product 
6.1.1  Identity of Trial Product 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) 
Tetanus Toxoid Conjugate vaccine (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Form:    
   
Liquid solution 
Dose:     
   
0.5 milliliter (mL) 
Route:   
  
IM 
Batch number:   To be determined 
6.1.1.1  Composition 
Each 0.5 mL dose of MenACYW conjugate vaccine is formulated in sodium acetate buffered 
saline solution to contain the following ingredients: 
Meningococcal capsular polysaccharides: 
Serogroup A  
.............................................................................................................. 10 µg 
Serogroup C  
.............................................................................................................. 10 µg 
Serogroup Y  
.............................................................................................................. 10 µg 
Serogroup W  
............................................................................................................. 10 µg 
Tetanus toxoid protein carrier  ...................................................................... approximately 65 µg 
6.1.1.2  Preparation and Administration 
MenACYW conjugate vaccine is supplied in single-dose (0.5 mL) vials. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1)
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, and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 
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The rubber stopper should not be removed from any of the vaccine vials. 
One dose (0.5 mL) of MenACYW conjugate vaccine will be administered IM into the deltoid 
muscle of the arm. The site of injection should be prepared with a suitable antiseptic. After 
administration of the vaccine, the used syringe and needle will be disposed of in accordance with 
currently established guidelines. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the CRF. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic or other immediate allergic reaction. 
6.1.1.3  Dose Selection and Timing 
All subjects in Group 1 will receive 1 dose of MenACYW conjugate vaccine on D0. 
6.1.2  Identity of Control Product 
Menomune® - A/C/Y/W-135: Meningococcal Polysaccharide Vaccine, Groups A, C, Y, W-135 
Combined (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Form: 
Lyophilized single-dose vial with 0.6-mL vile of diluent (sterile, pyrogen-
free distilled water without preservatives 
Dose:     
  
0.5 mL 
Route:   
   
Subcutaneous 
Batch number:   To be determined (Provided by Sponsor) 
6.1.2.1  Composition 
After reconstitution with diluent as indicated in the Prescribing Information, each 0.5 mL dose 
contains 50 µg of polysaccharide from each of serogroups A, C, Y, and W-135 (32). 
Each dose of vaccine contains 2.5 milligrams (mg) to 5 mg of lactose added as a stabilizer. 
6.1.2.2  Preparation and Administration 
Refer to Section 6.1.1.2 for general precautions regarding inspection of study products before use. 
Menomune® – A/C/Y/W-135 is supplied as a single-dose vial of lyophilized vaccine, with a 
corresponding single-dose vial of diluent. After reconstitution of the lyophilized vaccine with the 
diluent, each dose consists of a 0.5 mL suspension for injection. 
The vaccine will be reconstituted using only the diluent supplied for this purpose. The supplied 
diluent (0.6 mL) is to be withdrawn using a suitable syringe and injected into the vial containing 
the lyophilized vaccine. The vial is to be swirled until the vaccine is thoroughly dissolved. When 
reconstituted, the vaccine should be a clear, colorless liquid and should be used immediately after 
reconstitution.  
The site of subcutaneous injection should be prepared with a suitable antiseptic prior to 
administration of 1 dose of Menomune
® – A/C/Y/W-135 in the deltoid region of the arm. Using a 
suitable sterile needle and syringe and aseptic technique, a 0.5 mL dose of Menomune
®
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A/C/Y/W-135 should be administered by SC injection. After vaccine administration, the used 
syringe and needle will be disposed of in accordance with currently established guidelines. 
Care will be taken by the Investigator and other trial personnel to ensure the safe and effective use 
of this vaccine. Prior to injection, all known precautions will be taken to prevent adverse 
reactions. This includes a review of the subject’s history with respect to previous immunizations 
and to a possible sensitivity to the vaccine or similar vaccine.  
Vaccinations should not be given to individuals known to be allergic to any vaccine component. 
The stopper of the vial of Menomune® – A/C/Y/W-135 contains dry natural latex rubber, to which 
certain individuals may be allergic. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the source documents and transferred 
to the CRF. Appropriate medical equipment and emergency medications, including epinephrine 
(1:1000), must be available on site in the event of an anaphylactic or other immediate allergic 
reaction. 
6.1.2.3  Dose Selection and Timing 
All subjects in Group 2 will receive one 0.5 mL dose of Menomune
® – A/C/Y/W-135 on D0 
(Visit 1). 
6.2  Identity of Other Products 
Not applicable. 
6.3  Product Logistics 
6.3.1  Labeling and Packaging 
MenACYW conjugate vaccine will be supplied in single-dose vials, labeled and packaged 
according to national regulations. 
Commercial lots of Menomune® – A/C/Y/W-135 (supplied in 2 vials that must be combined prior 
to administration to produce a single dose) will be supplied by the Sponsor. 
6.3.2  Product Shipment, Storage, and Accountability 
6.3.2.1  Product Shipment 
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The Clinical Logistics Coordinator or designee will contact the Investigator or a designee in order 
to determine the dates and times of delivery of products. 
Each vaccine shipment will include a temperature-monitoring device to verify maintenance of the 
cold chain during transit. On delivery of the product to the site, the person in charge of product 
receipt will follow the instructions given in the Operating Guidelines, including checking that the 
cold chain was maintained during shipment (i.e., verification of the temperature recorders). If 
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there is an indication that the cold chain was broken, this person should immediately quarantine 
the product, alert the Sanofi Pasteur representative, and request authorization from Sanofi Pasteur 
to use the product. 
6.3.2.2  Product Storage 
The Investigator will be personally responsible for product management or will designate a 
qualified staff member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the trial site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 
6.3.2.3  Product Accountability 
The person in charge of product management at the site will maintain records of product delivery 
to the trial site, product inventory at the site, the dose(s) given to each subject, and the disposal of 
or return to the Sponsor of unused doses. 
The necessary information on the product labels is to be entered into the source document and the 
CRF. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the trial site’s product accountability records against 
the record of administered doses in the CRFs and the communication from the IWRS (if 
applicable). 
In case of any expected or potential shortage of product during the trial, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.3.3  Replacement Doses 
If a replacement dose is required for MenACYW conjugate vaccine or Menomune
® – A/C/Y/W-
135 (e.g., because the syringe broke or particulate matter was observed in the syringe), the site 
personnel must either connect to the IWRS to receive the new dose allocation, or follow the 
instructions given in the Operating Guidelines. 
6.3.4  Disposal of Unused Products 
Unused or wasted products will be returned to the Sponsor in accordance with the instructions in 
the Operating Guidelines. Product accountability will be verified throughout the trial period. 
6.3.5  Recall of Products 
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If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
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6.4  Blinding and Code-breaking Procedures 
This trial is a modified double-blind, which means that both the subject and the Investigator 
remain unaware of the treatment assignments throughout the trial. An unblinded vaccine 
administrator will administer the appropriate vaccine but will not be involved in safety data 
collection. The Sponsor and laboratory personnel performing the serology testing will also remain 
blinded to treatment assignments throughout the trial until database lock. 
The code may be broken by the Investigator only in the event of an SAE and if identification of 
the vaccine received could influence the treatment of the SAE. Code-breaking should be limited, 
as far as possible, to the subject(s) experiencing the SAE. 
The blind can be broken by the Investigator or a sub-investigator (medical doctor onlya), by 
connecting to the IWRS as explained in the code-breaking procedures described in the Operating 
Guidelines. Once the emergency has been addressed by the site, the Investigator must notify the 
Sanofi Pasteur RMO if a subject’s code was broken. All contact attempts with the Sponsor prior 
to unblinding are to be documented in the source documents. 
A request for the code to be broken may be made: 
• by GPV department for reporting to Health authorities in the case of an SAE as described in 
the International Conference on Harmonisation (ICH) E2A. In this case, the code will be 
broken only for the subject(s) in question. The information resulting from code-breaking (i.e., 
the subject’s vaccine or group assignment) will not be communicated to either the Investigator 
or the immediate team working on the study, except for the GPV representative.  
The IEC / IRB must be notified of the code-breaking. All documentation pertaining to the event 
must be retained in the site’s study records and in the Sanofi Pasteur files. Any intentional or 
unintentional code-breaking must be reported, documented, and explained, and the name of the 
person who requested it must be provided to the Sponsor. 
6.5  Randomization and Allocation Procedures 
Each subject who signs the ICF and who meets the inclusion / exclusion criteria will be randomly 
assigned to 1 of 2 trial groups. Site staff will connect to the IWRS, enter the identification and 
security information, and confirm a minimal amount of data in response to IWRS prompts. The 
IWRS will then provide the product dose number assignment. The full detailed procedures for 
group allocation are described in the Operating Guidelines. If the subject is not eligible to 
participate in the trial, then the information will only be recorded on the subject recruitment log. 
Subject numbers that are assigned by the IWRS will consist of an 8-digit string (a 3-digit trial 
center identifier and a 5-digit subject identifier connected by “-”). For example, 
. 
Subject numbers should not be reassigned for any reason. The Research and Development (R&D) 
Site Quality Operations Department at Sanofi Pasteur will hold the randomization codes in a 
secured location. 
                                                 
a
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6.6  Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified trial personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the trial site, product inventory at the site, dose(s) given to each subject, 
and the disposal of unused or wasted doses 
6.7  Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications including other therapies e.g., blood products, 
should be recorded in the source document as well as new medications prescribed for new 
medical conditions / AEs during trial participation.  
Documentation in the CRF of concomitant medication will be limited to specific categories of 
medication of interest beginning on the day of vaccination. This may include medications of 
interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRF from the day of vaccination to the end of the 
solicited and unsolicited follow-up period (e.g., 30 day safety follow-up) as they may impact the 
response to the vaccination and impact the consistency of the information collected on 
concomitant medications at any vaccination.  
The “reportable” medications are distributed according to two categories. These are: 
• Category 1 antipyretics, analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), 
corticosteroids, and other immune modulators.  
Note: inhaled and topical steroids should not be captured. 
• Category 2: Reportable medications used to define the Per-Protocol Analysis Set (PPAS). For 
example: 
• Influenza and other non-study vaccines: Influenza vaccine in the 2 weeks preceding the 
trial vaccination up to the subject’s termination from the trial and any other vaccines 
(other than the study vaccine) in the 4 weeks preceding the trial vaccination up to the 
subject’s termination from the trial 
• Immune globulins, blood or blood-derived products: used in the 3 months preceding the 
first blood draw and up to the last blood draw 
• Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy: used 
in the 6 months preceding the trial vaccination and the 4 weeks following the trial 
vaccination 
• 
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Category 3: Oral or injectable antibiotics, which may interfere with bioassays used for 
antibody testing when taken before a blood draw. 
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•  The period of collection should be within 3 days before the first blood draw and up to the 
last scheduled blood draw. 
Note: Inhaled and topical antibiotics (drops, creams or ointments) should not be captured. 
The information reported in the CRF for each reported medication will be limited to: 
• Trade name 
• Given as treatment or as prophylaxis 
• Medication category 
• Start and stop dates 
Dosage and administration route will not be recorded. Homeopathic medication will not be 
recorded. Topical treatment will not be recorded. 
The fact that a medication was given in response to an AE will be captured in the “Action Taken” 
column of the AE only. No details will be recorded in the concomitant medication module of the 
CRF unless the medication received belongs to one of the prelisted categories. Medications will 
not be coded. 
7  Management of Samples 
Blood samples for the assessment of antibody responses will be collected at Visit 1 and Visit 2. 
See the Table of Study Procedures and Section 5.1.3 for details of the sampling schedule. 
7.1  Sample Collection 
At Visit 1 and Visit 2, 10 mL of blood will be collected in tubes provided by or recommended by 
the Sponsor. Immediately prior to the blood draw, the staff member performing the procedure will 
verify the subject’s identity; will verify the assigned subject’s number on the pre-printed label that 
contains that subject’s number and the sampling stage; and will attach the label to the tube. Blood 
is to be taken from the limb opposite to the one that will be used for vaccination. 
7.2  Sample Preparation 
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Detailed instructions on how to prepare blood samples for assessment of antibody response are 
contained in the Operating Guidelines provided to the site. An overview of the procedures is 
provided here. 
After the blood draw, the sampling tubes are to be left undisturbed, positioned vertically and not 
shaken, for a minimum of 1 hour and a maximum of 24 hours in order to allow the blood to clot. 
Samples can be stored at room temperature for up to 2 hours; beyond 2 hours, they must be 
refrigerated at a temperature of +2°C to +8°C and must be centrifuged within a maximum of 
24 hours. 
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The samples are then centrifuged, and the separated serum is transferred to the appropriate 
number of aliquoting tubes. These tubes are pre-labeled with adhesive labels that identify the 
study code, the subject’s number, and the sampling stage or visit number. 
The subject’s number and the date of sampling, the number of aliquots obtained, the date and time 
of preparation, and the subject’s consent for future use of his / her samples are to be specified on a 
sample identification list and recorded in the source document. Space is provided on this list for 
comments on the quality of samples. 
7.3  Sample Storage and Shipment 
During storage, serum tubes are to be kept in a freezer whose temperature is set and maintained at 
-20°C or below. The temperature will be monitored and documented on the appropriate form 
during the entire trial. If it rises above -10°C for any period of time, the Clinical Logistics 
Coordinator must be notified. See the Operating Guidelines for further details. 
Shipments to the laboratories will be made only after appropriate monitoring, and following 
notification of the Clinical Logistics Coordinator. Sera will be shipped frozen, using dry ice to 
maintain them in a frozen state, in the packaging container provided by the carrier. Again, 
temperatures will be monitored. Shipments must be compliant with the International Air 
Transport Association (IATA) 602 regulations. 
Samples will be shipped to Global Clinical Immunology (GCI) at Sanofi Pasteur. The address is 
provided in the Operating Guidelines. 
7.4  Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored by Sanofi Pasteur for at least 
5 years after the last license approval in the relevant market areas has been obtained for the 
vaccine being tested. 
The subjects will be asked to indicate in the ICF whether they will permit the future use of any 
unused stored serum samples for other tests. If they refuse permission, the samples will not be 
used for any testing other than that directly related to this study. If they agree to this use, they will 
not be paid for giving permission. (Anonymity of samples will be ensured.) The aim of any 
possible future research is unknown today, and may not be related to this particular study. It may 
be to improve the knowledge of vaccines or infectious diseases, or to improve laboratory 
methods. Genetic tests will never be performed on these samples without individual informed 
consent. 
8  Clinical Supplies 
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Sanofi Pasteur will supply the trial sites with protocols, ICFs, CRFs, SAE reporting forms, 
pregnancy reporting forms, DCs, MAs, and other trial documents, as well as with the following 
trial materials: all study vaccines, blood collection tubes, cryotubes, cryotube storage boxes, 
cryotube labels, temperature recorders, shipping containers, rulers, and digital thermometers. 
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The means for performing EDC will be defined by Sanofi Pasteur. If a computer is provided by 
Sanofi Pasteur, it will be retrieved at the end of the trial. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines. 
They must allow approximately 1 week for an order to be filled and to have the supplies sent to 
their site. 
9  Endpoints and Assessment Methods 
9.1  Primary Endpoints and Assessment Methods 
9.1.1  Immunogenicity 
9.1.1.1  Immunogenicity Endpoints 
The primary endpoints for the evaluation of immunogenicity are: 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by hSBA assessed 
at baseline (D0, before vaccination) and 30 days after vaccination 
9.1.1.2  Immunogenicity Assessment Methods 
 
 
 
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9.1.2  Safety 
There are no primary objectives for safety. 
9.1.3  Efficacy 
No clinical efficacy data will be obtained in the trial. 
9.2  Secondary Endpoints and Assessment Methods 
9.2.1  Immunogenicity 
9.2.1.1  Immunogenicity Endpoints 
The secondary endpoints for immunogenicity are: 
1) GMTs against meningococcal serogroups A, C, Y, and W measured by hSBA assessed at 
30 days (+14 days) after vaccination with MenACYW conjugate vaccine and Menomune® – 
A/C/Y/W-135 
9.2.1.2  Immunogenicity Assessment Methods 
The immunogenicity assessment method for the secondary endpoints for hSBA is the same as that 
presented in Section 9.1.1.2. 
9.2.2  Safety 
There are no secondary objectives for safety. 
9.2.3  Efficacy 
No clinical efficacy data will be obtained in the trial. 
9.3  Observational Endpoints and Assessment Methods 
9.3.1  Immunogenicity 
9.3.1.1  Immunogenicity Endpoints 
Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA and rSBA 
before and 30 days (+14 days) after vaccination with MenACYW conjugate vaccine or 
Menomune®
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9.3.1.2  Immunogenicity Assessment Methods 
 
 
Antibodies to Meningococcal Antigen (rSBA Method) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.2  Safety 
9.3.2.1  Safety Definitions 
The following definitions are taken from the ICH E2A Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting. 
Adverse Event (AE): 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product.  
Therefore an AE may be: 
• A new illness 
• The worsening of a concomitant illness 
                                                 
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• An effect of the vaccination, including the comparator 
• A combination of the above 
All AEs include serious and non-serious AEs. 
Surgical procedures are not AEs; they are the action taken to treat a medical condition. It is the 
condition leading to the action taken that is the AE (if it occurs during the trial period). 
Pre-existing medical conditions are not to be reported as AEs. However, if a pre-existing 
condition worsens in frequency or intensity, or if in the assessment of the treating physician there 
is a change in its clinical significance, this change should be reported as an AE (exacerbation). 
This applies equally to recurring episodes of pre-existing conditions (e.g., asthma) if the 
frequency or intensity increases post-vaccination. 
Serious Adverse Event (SAE): 
Serious and severe are not synonymous. The term severe is often used to describe the intensity of 
a specific event as corresponding to Grade 3. This is not the same as serious which is based on 
patient / event outcome or action criteria usually associated with events that pose a threat to a 
patient’s life or functioning. Seriousness, not severity, serves as a guide for defining regulatory 
reporting obligations. 
An SAE is any untoward medical occurrence that at any dose  
• Results in death 
• Is life-threatening
a 
• Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• Results in persistent or significant disability / incapacityc 
• Is a congenital anomaly / birth defect 
• Is an important medical event
d 
                                                 
a  The term “life-threatening” refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
b  All medical events leading to hospitalizations will be recorded and reported as SAEs, with the exception of: 
hospitalization planned before inclusion into the study or out-patient treatment with no hospitalization.  
c   “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability 
to carry out normal life functions. 
d
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  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 may jeopardize the health of the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above. These should also usually be considered serious. Examples of such 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse, GBS, new onset diabetes, or autoimmune disease. 
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Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
(The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility) 
Unexpected Adverse Reaction (UAR): 
An unexpected adverse reaction is an AR, the nature or severity of which is not consistent with 
the applicable product information (e.g., Investigator’s Brochure for an unapproved 
investigational medicinal product). 
The following additional definitions are used by Sanofi Pasteur: 
Solicited Reaction: 
A solicited reaction is an event that is prelisted in the CRF. The assessment of these AEs post-
vaccination is mandatory. A solicited reaction is defined by a combination of: 
• Symptom and 
• Onset post-vaccination 
e.g., injection site pain between D0 and D07 after vaccination, or headache between D0 and D07 
A solicited reaction is therefore an AR observed and reported under the conditions (symptom and 
onset) prelisted (i.e., solicited) in the CRF and considered as related to vaccination. 
Unsolicited AE / AR: 
An unsolicited AE is an observed AE that does not fulfill the conditions prelisted in the CRF in 
terms of diagnosis and / or onset post-vaccination, i.e., excluding solicited reactions, e.g., if 
headache between D0 and D7 is a solicited reaction (i.e., prelisted in the CRF), then a headache 
starting on D7 is a solicited reaction, whereas headache starting on D8 post-vaccination is an 
unsolicited AE. 
An unsolicited non-serious AE is an unsolicited AE excluding SAEs. 
Injection Site Reaction: 
An injection site reactiona is an AR at and around the injection site. Injection site reactions are 
commonly inflammatory reactions.  
Systemic AE: 
Systemic AEs are all AEs that are not injection site reactions. They therefore include systemic 
manifestations such as headache, fever, as well as localized or topical manifestations that are not 
                                                 
a  All injection site AEs are considered to be related to vaccination and are therefore all injection site reactions
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associated with the vaccination site, e.g., erythema that is localized but that is not at the injection 
site. 
Medically-Attended Adverse Events (MAAEs): 
An MAAE is defined, for the purpose of this study, as a new onset of a condition that prompts the 
subject to seek unplanned medical advice at a physician’s office or Emergency Department.  
This definition excludes pre-planned medical office visits for routine check-ups or follow-up 
visits of chronic conditions with an onset prior to entry in the study. Physician contact made over 
the phone or by email will be considered a physician office visit for the purpose of MAAE 
collection. 
The outcome of the physician contact (whether it results in a prescription or not) will not be 
considered as a basis for reporting the event as an MAAE and all contacts should be reported. 
Sufficient data should be collected for the event to allow an assessment of the causality and 
diagnosis, if possible. 
9.3.2.2  Safety Endpoints 
The observational endpoints for the evaluation of safety are: 
• Occurrence, nature (Medical Dictionary for Regulatory Activities [MedDRA] preferred 
term), duration, intensity, and relationship to vaccination of any unsolicited systemic AEs 
reported in the 30 minutes after vaccination. 
• Occurrence, time to onset, number of days of occurrence, intensity, action taken, and 
whether the reaction led to early termination from the study, of solicited (prelisted in the 
subject’s DC and electronic case report form [CRF]) injection site reactions occurring up 
to 7 days after vaccination. 
• Occurrence, time to onset, number of days of occurrence, intensity, action taken, and 
whether the reaction led to early termination from the study, of solicited (prelisted in the 
subject’s DC and CRF) systemic reactions occurring up to 7 days after vaccination. 
• Occurrence, nature (MedDRA preferred term), time to onset, duration, intensity, action 
taken, relationship to vaccination (for systemic AEs only), and whether the event led to 
early termination from the study, of unsolicited AEs occurring up to Visit 2. 
• Occurrence, nature (MedDRA preferred term), time to onset, duration, seriousness criteria, 
relationship to vaccination, outcome, and whether the SAE led to early termination from 
the study, of SAEs throughout the trial. 
• Occurrence, nature (MedDRA preferred term), time to onset, duration, seriousness, 
relationship to vaccination, and outcome for MAAEs from Visit 2 to the 6-month follow-
up contact. MAAEs will be collected as unsolicited AEs up to Visit 2. 
9.3.2.3  Safety Assessment Methods 
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At Visit 2, the Investigator or a delegate will ask the subject about any solicited reactions and 
unsolicited AEs recorded in the DC, as well as about any other AEs that may have occurred since 
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the previous visit. All relevant data will be transcribed into the CRF according to the instructions 
provided by the Sponsor. 
9.3.2.3.1  Immediate Post-vaccination Surveillance Period 
Subjects will be kept under observation for 30 minutes after vaccination to ensure their safety. 
The post-vaccination surveillance should be documented in the source document. Any AE that 
occurs during this period will be noted on the source document and recorded in the CRF, as 
follows: 
•  Any unsolicited systemic AE occurring during the first 30 minutes post-vaccination will 
be recorded on the CRF as immediate unsolicited systemic AE.  
•  Solicited and unsolicited injection site reactions and solicited systemic reactions will be 
recorded and analyzed as starting on the day of vaccination.  
•  Any SAE occurred during the first 30 minutes post-vaccination will be reported in the 
same way as any other SAE and to the Sponsor, according to the procedures described in 
Section 10. 
9.3.2.3.2  Reactogenicity (Solicited Reactions from Day 0 to Day 7 after Vaccination) 
After vaccination, subjects will be provided with a safety DC, a digital thermometer, and a 
flexible ruler, and will be instructed how to use them. The following items will be recorded by the 
subjects in the DC on the day of vaccination and for the next 7 days (i.e., D0 to D07) until 
resolution: 
•  Daily temperature, with the route by which it was taken 
•  Daily measurement or intensity grade of all other solicited injection site and systemic 
reactions 
•  Action taken for each event, if any (e.g., medication) 
The action taken by the subject to treat any solicited reactions
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 will be classified in the CRF using 
the following scale: 
0:  None 
1: Medication (self-medication with an existing prescription or over-the-counter medication) 
2: Health care provider contact (no new medication prescribed) 
3:   Health care provider contact and prescription of a new medication (health care provider 
instructed subject to take a new medication, either an over-the-counter medication or one 
requiring a written prescription) 
4: Hospitalization (inpatient) 
Subjects will be contacted by telephone 8 days after vaccination to remind them to record all 
safety information in the DC. 
If the timing of the telephone call should fall on a weekend or a holiday, the call should be made 
on the next business day. If contact is not made on the designated day, study staff will continue 
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calling until contact is made. Every telephone attempt and its outcome will be documented in the 
source document. 
Table 9.1 and Table 9.2 
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present, respectively, the injection site reactions and systemic reactions 
that are prelisted in the DCs and CRF, together with the intensity scales. 
 
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Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA lowest 
level term [LLT]) 
Injection site pain 
Injection site erythema 
Injection site swelling  
DC term 
Pain 
Redness 
Swelling 
Definition 
 
Presence of a redness including the 
approximate point of needle entry 
Swelling at or near the injection site 
Swelling or edema is caused by a fluid 
infiltration in tissue or cavity and, depending 
on the space available for the fluid to 
disperse, swelling may be either soft 
(typically) or firm (less typical) to touch and 
thus can be best described by looking at the 
size of the swelling 
Intensity scale* 
 
Grade 1: No interference with activity 
Grade 2: Some interference with activity 
Grade 3: Significant; prevents daily activity 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
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* For the subjective reaction of pain, subjects will record the intensity level (Grade 1, 2, or 3) in the diary card. For the measurable reactions of redness and swelling, they will record 
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Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA LLT) 
Fever 
Headache 
Malaise 
Myalgia 
DC term 
Temperature 
Headache 
Feeling unwell 
Muscle aches and pains 
Definition 
Elevation of temperature to ≥ 100.4°F 
(≥ 38.0°C) 
Pain or discomfort in the head or 
scalp. Does not include migraine. 
General ill feeling. 
Malaise is a generalized feeling of 
discomfort, illness, or lack of well-
being that can be associated with a 
disease state. It can be accompanied 
by a sensation of exhaustion or 
inadequate energy to accomplish 
usual activities. 
Muscle aches and pains are common 
and can involve more than one 
muscle at the same time. Muscle pain 
can also involve the soft tissues that 
surround muscles. These structures, 
which are often referred to as 
connective tissues, include ligaments, 
tendons, and fascia (thick bands of 
tendons). 
Does not apply to muscle pain at the 
injection site which should be 
reported as injection site pain. 
Intensity scale* 
Grade 1: ≥ 100.4°F to ≤ 101.1°F, 
or≥ 38.0°C to ≤ 38.4°C  
Grade 1: No interference with activity Grade 1: No interference with activity Grade 1: No interference with activity 
 
Grade 2: ≥ 101.2°F to ≤ 102.0°F 
or ≥ 38.5°C to ≤ 38.9°C  
Grade 2: Some interference with 
activity 
Grade 2: Some interference with 
activity 
Grade 2: Some interference with 
activity 
 
Grade 3: ≥ 102.1°F 
or ≥ 39.0°C 
Grade 3: Significant; prevents daily 
activity 
Grade 3: Significant; prevents daily 
activity 
Grade 3: Significant; prevents daily 
activity 
*  For all reactions but fever, subjects or parents / legally acceptable representatives will record the intensity level (Grade 1, 2, or 3) in the diary card. For fever, they will record the 
body temperature, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Important notes for the accurate assessment of temperature: 
Subjects are to measure body temperature once per day, preferably always at the same time. The 
optimal time for measurement is the evening, when body temperature is the highest. Temperature 
is also to be measured at the time of any apparent fever. The observed daily temperature and the 
route of measurement are to be recorded in the DC, and the highest temperature will be recorded 
by the site in the CRF. The preferred route for this trial is oral. Pre-vaccination temperature is also 
systematically collected by the Investigator in the source document. Tympanic thermometers must 
not be used. 
9.3.2.3.3  Unsolicited Non-serious Adverse Events from Day 0 to Day 30 after Vaccination 
In addition to recording solicited reactions, subjects will be instructed to record any other medical 
events that may occur during the 30-day period after vaccination. Space will be provided in the 
DC for this purpose.  
For each unsolicited non-serious AE, the following information is to be recorded: 
• Start and stop datesa  
• Intensity of the event: 
•  For measurable unsolicited non-serious AEs that are part of the list of solicited reactions, 
the size of the AE as well as the temperature for fever will be collected and analyzed 
based on the corresponding scale used for solicited reactions (see Table 9.1 and 
Table 9.2) 
•  Other unsolicited non-serious AEs will be classified according to the following intensity 
scale: 
•  Grade 1: No interference with activity 
•  Grade 2: Some interference with activity 
•  Grade 3: Significant; prevents daily activity 
• Action taken for each AE, if any (e.g., medication) 
The action taken by the subject to treat any unsolicited AEs will be classified in the CRF using 
the following scale: 
0:  None 
1: Medication (self-medication with an existing prescription or over-the-counter medication) 
2: Health care provider contact (no new medication prescribed) 
3:   Health care provider contact and prescription of a new medication (health care provider 
instructed subject to take a new medication, either an over-the-counter medication or one 
requiring a written prescription) 
                                                 
a
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 The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the trial will be 
considered as ongoing at the end of the trial. 
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• Whether the AE led to discontinuation 
• Whether the AE was related to vaccination (for unsolicited systemic AEs) 
9.3.2.3.4  Serious Adverse Events 
Information on SAEs will be collected and assessed throughout the trial, from Visit 1 until 
180 days after vaccination. 
Any SAE occurring at any time during the trial will be reported by the Investigator through the 
EDC system and according to the completion guidelines provided by the Sponsor. All information 
concerning the SAE is to be reported, either as part of the initial reporting or during follow-up 
reporting if relevant information became available later (e.g., outcome, medical history, results of 
investigations, copy of hospitalization reports). The Investigator will assess the causal relationship 
between the SAE and the investigational product as either “Not related” or “Related”, as 
described in Section 10.4. 
See Section 10 for further details on SAE reporting. 
9.3.2.3.5  Adverse Events of Special Interest 
Not applicable. 
9.3.2.3.6  Medically-Attended Adverse Events 
MAAE information will be collected throughout the study. MAAEs that occur from Visit 1 (D0) 
to Visit 2 (D30[+14days]) will be recorded as unsolicited AEs on the diary card as part of all 
unsolicited AEs collected for this post-vaccination period. MAAEs that occur from Visit 2 (D30 
[+14 days]) to D180 (+14 days) will be recorded as such in the MA. An MAAE that occurs within 
the study period but meets the definition of an SAE should be reported only on the SAE Reporting 
Form, but not on the MAAE page of the CRF. The Investigator will assess the causal relationship 
between the MAAE and the investigational or study product as either “not related” or “Related,” 
as described in Section 9.3.2.3.7. 
9.3.2.3.7  Assessment of Causality 
The Investigator will assess the causal relationship between each unsolicited systemic AE and 
vaccination as either not related or related, based on the following definitionsa: 
0: Not related – The AE is clearly / most probably caused by other etiologies such as 
subject’s underlying condition, therapeutic intervention, or concomitant therapy; or the 
delay between vaccination and the onset of the AE is incompatible with a causal 
relationship; or the AE started before the vaccination (screening phase, if applicable) 
1:  Related – There is a “reasonable possibility” that the AE was caused by the vaccination, 
meaning that there is evidence or arguments to suggest a causal relationship 
                                                 
a
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Note: By convention, all injection site AEs (solicited and unsolicited) and all solicited systemic 
reactions are considered to be related to vaccination and referred to as reactions, and therefore do 
not require the Investigator’s opinion on relatedness. 
AEs likely to be related to the product, whether serious or not, that persist at the end of the trial 
will be followed up by the Investigator until their complete disappearance or the stabilization of 
the subject’s condition. The Investigator will inform the Sponsor of the date of final 
disappearance of the event. 
9.3.3  Efficacy 
No clinical efficacy data will be obtained in the trial. 
10 Reporting of Serious Adverse Events 
In order to comply with current regulations on SAE reporting to health authorities, the 
Investigator must document all SAEs regardless of causal relationship, and notify the Sponsor and 
the Clinical Research Associate (CRA) within the notification timelines stated in the following 
sections. The Investigator will give access and provide the Sponsor and the CRA with all 
necessary information to allow the Sponsor to conduct a detailed analysis of the safety of the 
investigational product. It is the responsibility of the Investigator to request all necessary 
documentation (e.g., medical records, discharge summary, autopsy) in order to provide 
comprehensive safety information. All relevant information must then be transcribed into the 
electronic Serious Adverse Events (eSAE) Form. 
10.1 Initial Reporting by the Investigator 
SAEs occurring during a subject’s participation in the trial or experiment must be reported within 
24 hours to the Sponsor’s GPV Department and to the CRA. Every SAE must be reported, even if 
the Investigator considers that it is not related to the vaccine. The SAE form must be signed by a 
licensed physician (M.D. or D.O.) for whom the task is listed on the Study Task Delegation and 
Signature List after each update to the Form. 
The Investigator must complete the “eSAE Form” in the EDC application. After validation, an e-
mail alert will automatically be sent to the GPV mailbox, the CRA and the Clinical Team Leader 
(CTL). This message will include the country, the study code, the subject number, whether the 
report is initial or a follow-up, the diagnosis and / or symptoms, the seriousness criteria, the 
relationship, if related and the outcome, if fatal. 
If the EDC system is unavailable, the site must notify the Sponsor using the paper version of the 
SAE Reporting Form, as follows: 
The Investigator must complete the SAE Reporting Form, check off the “Initial Reporting Form” 
box, and send it to the Sponsor by one of the following means (preferably by fax or email): 
• 
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By fax, to the following number: 
 
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• In PDF format to the following e-mail address, using a method of transmission that 
includes password protection: 
(see the Operating 
Guidelines for directions on how to send a password protected email). 
• By express mail, to the following address:  
Sanofi Pasteur Inc. 
Reception and Triage – Case Management 
Global PharmacoVigilance 
Mail Drop: 45D38 
Discovery Drive 
Swiftwater, PA 18370 
When the system becomes available, the Investigator must transcribe the information from the 
paper version of the eSAE Form into the EDC system. 
If there is need for urgent consultation, the Investigator is to contact the RMO. If the RMO cannot 
be reached, the Investigator may contact the Call Center as described in Section 5.3.  
10.2 Follow-up Reporting by the Investigator 
The eSAE Form completed initially must be updated within 24 hours after the Investigator has 
become aware of any new relevant information concerning the SAE (e.g., outcome, precise 
description of medical history, results of the investigation). After validation, an e-mail alert will 
be sent automatically to the GPV Department and to the CRA. All relevant information must be 
included directly in the eSAE Form. Copies of documents (e.g., medical records, discharge 
summary, autopsy) may be requested by the GPV Department.  
The anonymity of the subject must always be respected when forwarding this information. 
10.3 Reporting of SAEs Occurring After a Subject Has Completed the Study 
Any SAE that occurs after a subject has completed the study but that is likely to be related to the 
product or to the experiment must also be reported as soon as possible. In such a case, the 
reporting procedure to be followed is identical to that described in Section 10.1. 
10.4 Assessment of Causality 
The causal relationship between the SAE and the product will first be evaluated by the 
Investigator, using the following definitions: 
0 - Not related: The AE is clearly / most probably caused by other etiologies such as an 
underlying condition, therapeutic intervention, or concomitant therapy; or the delay between 
vaccination and the onset of the SAE is incompatible with a causal relationship; or the SAE 
started before the vaccination (screening phase, if applicable). 
1 - Related: There is a “reasonable possibility” that the SAE was caused by the vaccination, 
meaning that there is evidence or arguments to suggest a causal relationship. 
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Following this, the Sponsor’s Product Safety Officer (PSO) will also assess the causal relationship 
to the product, based on the available information and current medical knowledge. 
The decision to modify or discontinue the trial may be made after mutual agreement between the 
Sponsor and the Investigator(s). 
10.5 Reporting SAEs to Health Authorities and IECs / IRBs 
The Sponsor will inform the relevant health authorities of any reportable SAEs according to the 
local regulatory requirements. Reporting to the health authorities will be according to the 
Sponsor’s standard operating procedures. 
The Sponsor’s RMO, 
,   ,  
 will notify the Investigators 
in writing of the occurrence of any reportable SAEs. The Investigators / Sponsor will be 
responsible for informing the IECs or IRBs that reviewed the trial protocol. 
11 Data Collection and Management 
11.1 Data Collection and CRF Completion 
Individual safety DCs, specifically designed for this trial by the Sponsor and provided to the study 
sites, will be given to study participants for the recording of daily safety information as described 
in Section 9.3.2.3. The DCs will include prelisted terms and intensity scales (see Table 9.1 and 
Table 9.2)
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 as well as areas for free text to capture additional safety information or other relevant 
details. Subjects will also be provided with rulers for measuring the size of injection site reactions, 
and with standard digital thermometers for measuring daily temperatures. To ensure consistency 
of reporting, the study sites will instruct subjects on how to correctly use these tools. 
The 6-month follow-up will be done by interviewing subjects either during a visit or over the 
telephone using a questionnaire to capture SAEs and AEs of particular interest, if applicable. An 
MA will be provided to the subjects at the preceding trial visit to help them record information on 
events occurring between this visit and the 6-month follow-up. 
Relevant information will be transcribed into the CRF. Any SAEs captured during this 6-month 
follow-up period will be reported and followed-up as per the normal process for reporting SAEs. 
The clinical team may decide to replace the MA by a diary card if a follow-up visit is planned for 
the subjects. 
At specified intervals, the Investigator or an authorized designee will interview the subjects to 
collect the information recorded in the diary card, and will attempt to clarify anything that is 
incomplete or unclear. All clinical trial information gathered by the study site will be reported 
electronically by the Investigator or authorized designee using a web-based CRF. (Any 
information that was not documented in the diary card will first be captured in the source 
document and then reported electronically.) The CRF has been designed specifically for this trial 
under the responsibility of the Sponsor, using a validated Electronic Records / Electronic 
Signature-compliant platform (21 CFR Part 11). 
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To ensure the correct and consistent completion of the CRFs, the Sponsor or authorized 
representative will provide all necessary tools, instructions, and training to all site staff involved 
in data entry prior to study start. Additional instructional documents such as training manuals and 
completion guidelines will be provided to assist with data entry during the course of the trial. 
Upon completion of training, each user requiring access to the EDC system will be issued a 
unique username and password. In the event of a change in trial personnel, each newly assigned 
individual will receive a unique username and password; the username and password of a 
previous user may not be reissued. If any trial personnel leave the study, the Investigator is 
responsible for informing the Sponsor immediately so that their access is deactivated. An audit 
trail will be initiated in the EDC system at the time of the first data entry in order to track all 
modifications and to ensure database integrity. 
The Investigator is responsible for the timeliness, completeness, and accuracy of the information 
in the CRFs; must provide explanations for all missing information; and must sign the CRF using 
an e-signature. 
11.2 Data Management 
Management of Clinical Data 
Data generated during the trial will be managed following two different processes: 
• Clinical data, defined as all data reported in the CRF, and laboratory data will be handled 
by the Sponsor’s Clinical Data Management (CDM) platform or authorized representative. 
• 
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Data pertaining to SAEs, which are reported by the Investigator on the eSAE Forms or 
SAE Reporting Forms, will be handled by the Sponsor’s GPV Department. 
During the trial, clinical data reported in the CRFs will be integrated into the clinical database 
under the responsibility of the Sanofi Pasteur CDM platform. Data monitoring at the sites and 
quality control in the form of computerized logic and / or consistency checks will be 
systematically applied in order to detect errors or omissions. In addition, data reviews may be 
performed several times by the Sponsor’s staff in the course of the trial. Any questions pertaining 
to the reported clinical data will be submitted to the investigator for resolution using the EDC 
system. Each step of this process will be monitored through the implementation of individual 
passwords to maintain appropriate database access and to ensure database integrity. 
The validation of the immunogenicity data will be performed at the laboratory level following the 
laboratory’s procedures. Information from the laboratory will be checked for consistency before 
integration into the clinical database. 
After integration of all corrections in the complete set of data, and after the SAE information 
available from CDM and the GPV Department has been reconciled, the database will be released for 
statistical analysis. 
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SAE Data Management 
During the trial, data pertaining to SAEs reported on eSAE Forms will be integrated into the 
Sponsor’s centralized GPV database. 
Upon receipt of an eSAE Form, the data will be entered into the GPV database after a duplicate 
check. Each SAE case will be assigned a case identification number. Each case will be entered in 
the GPV database and assessed by the case management platform or its delegate before being 
reported to the relevant authorities as necessary. Assessment of related cases will be done in 
collaboration with the PSO and the RMO. Follow-up information concerning a completed case 
will be entered into the GPV database, and a new version of the case will be created. 
The information pertaining to SAEs in the GPV database will be reconciled with that in the 
clinical database. 
11.3 Data Review 
A review of the data is anticipated through the data review process led by Data Management 
before database lock. 
The safety of the investigational product will be continuously monitored by the Sponsor. Periodic 
safety data review will be performed by the Sponsor’s Safety Management Team (SMT). For all 
periodic safety reviews, blinded safety data will be provided to the Sponsor’s SMT.  
12 Statistical Methods and Determination of Sample Size 
12.1 Statistical Methods 
Clinical data will be analyzed under the responsibility of the Biostatistics Platform of the Sponsor. 
A statistical analysis plan (SAP) will be written and peer reviewed before any analyses. In 
accordance with the protocol, the SAP will describe all analyses to be performed under the 
responsibility of the Sponsor and all the conventions to be taken. 
12.1.1 Hypotheses and Statistical Methods for Primary Objective 
Thirty days after the administration of MenACYW conjugate vaccine or Menomune
® – 
A/C/Y/W-135, the percentages of subjects who achieve an hSBA vaccine seroresponse
a for 
meningococcal serogroups A, C, Y, and W in Group 1 are non-inferior to the corresponding 
percentages in Group 2. 
Null hypothesis (H0): p(
G1) - p(
G2) ≤ -10% 
                                                 
a 
hSBA vaccine seroresponse for serogroups A, C, Y, and W is defined as: 
•  For a subject with a pre-vaccination titer < 1:8, the post-vaccination titer must be ≥ 1:16. 
• 
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For a subject with a pre-vaccination titer ≥ 1:8, the post-vaccination titer must be at least 4-fold greater than the 
pre-vaccination titer. 
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Alternative hypothesis (H1): p(
G1) - p(
G2) > -10% 
where p(
G1) and p(
G2) are the percentages of subjects who achieve an hSBA seroresponse in 
Group 1 and Group 2, respectively. Each of the serogroups A, C, Y, and W will be tested 
separately. If the lower limit of the 2-sided 95% confidence interval (CI) of the difference 
between the 2 proportions is > -10%, the inferiority assumption will be rejected. 
For the 4 non-inferiority hypotheses using the seroresponse rates, the CI of the difference in 
proportions will be computed using the Wilson Score method without continuity correction (33). 
The overall non-inferiority of this objective will be demonstrated if all 4 individual null 
hypotheses are rejected. 
12.1.2 Hypotheses and Statistical Methods for Secondary Objectives 
Descriptive statistics will be presented. 
Thirty days after the administration of MenACYW conjugate vaccine or Menomune® – 
A/C/Y/W-135, the hSBA geometric mean titer ratio (GMTR) between Group 1 and Group 2 will 
be calculated and 95% CI will be provided. 
12.1.3 Statistical Methods for Observational Objectives 
No hypotheses will be tested. Descriptive statistics will be presented. 
Immunogenicity 
Descriptive statistics will be provided for the hSBA and rSBAa antibody titers against 
meningococcal serogroups contained in MenACYW conjugate vaccine and Menomune® – 
A/C/Y/W-135. In general, categorical variables will be summarized and presented by frequency 
counts, percentages, and CIs. The 95% CIs of point estimates will be calculated using the normal 
approximation for quantitative data and the exact binomial distribution (Clopper-Pearson method) 
for percentages (34). For GMTs, 95% CIs of point estimates will be calculated using normal 
approximation assuming they are log-normally distributed. 
Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA before and 
30 days after vaccination with MenACYW conjugate vaccine will be described by: 
•  GMT and 95% CI 
•  Titer distribution and reverse cumulative distribution curves (RCDCs) 
•  Percentage of subjects with titer ≥ 1:4 and ≥ 1:8 and 95% CI 
•  Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to post-vaccination, 
and 95% CI 
                                                 
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  rSBA vaccine seroresponse is defined as a post-vaccination titer ≥ 1:32 for subjects with pre-vaccination rSBA 
titer < 1:8, or a post-vaccination titer ≥ 4 times the pre-vaccination titer for subjects with pre-vaccination rSBA 
titer ≥ 1:8. 
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Antibody titers against meningococcal serogroups A, C, Y, and W measured by rSBA before and 
30 days after vaccination with MenACYW conjugate vaccine will be tested and described in a 
subset of 100 subjects per treatment group by: 
•  GMT and 95% CI 
•  Titer distribution and RCDCs 
•  Percentage of subjects with titer ≥ 1:8 and ≥ 1:128 and 95% CI 
•  Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to post-vaccination, 
and 95% CI 
•  Percentage of subjects with rSBA vaccine seroresponsea 
Safety 
For this trial, the safety data will be assessed by applying descriptive statistical methods, 
supplemented by the calculation of CIs to aid interpretation. The exact binomial distribution 
(Clopper-Pearson method) for proportions will be used in the calculation of the 95% CIs of 
events. 
The frequency and percentage of subjects who had solicited injection site and systemic reactions 
and their 95% CIs will be provided. These events will be tabulated by type of reactions and 
intensity for each study group. These events will also be summarized by other categories specified 
in the endpoints (e.g., time of onset, number of days of occurrence, action taken). 
Unsolicited AEs will be collected, coded, and summarized by MedDRA system organ class and 
preferred term. For each unsolicited AE, the number of subjects with at least one instance of that 
event will be reported. Unsolicited AEs will also be tabulated by intensity and relatedness of 
study vaccine and by other categories specified in the endpoints. 
Immediate reactions, SAEs, and any event that leads to subject withdrawal from the study will be 
tabulated separately. 
12.2 Analysis Sets 
Three analysis sets will be used: the Full Analysis Set (FAS), the PPAS, and the Safety Analysis 
Set (SafAS). 
12.2.1 Full Analysis Set 
The FAS is defined as the subset of subjects who received at least 1 dose of the study vaccine and 
had a valid post-vaccination serology result. All subjects will be analyzed according to the 
treatment group to which they were randomized. 
                                                 
a
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  rSBA vaccine seroresponse is defined as a post-vaccination titer ≥ 1:32 for subjects with pre-vaccination rSBA 
titer < 1:8, or a post-vaccination titer ≥ 4 times the pre-vaccination titer for subjects with pre-vaccination rSBA 
titer ≥ 1:8. 
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12.2.2 Safety Analysis Set 
The SafAS is defined as those subjects who have received at least 1 dose of the study vaccine and 
have any safety data available. All subjects will have their safety analyzed according to the 
vaccine they actually received. 
If the vaccine received by a subject does not correspond to any study group, the subject will be 
excluded from the SafAS. The corresponding safety data will be presented in separate listings. 
12.2.3 Per-Protocol Analysis Set 
The PPAS is a subset of the FAS. The subjects presenting with at least one of the following 
relevant protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not receive vaccine 
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• Subject did not provide the post-dose serology sample in the proper time window or a post-
dose serology sample was not drawn. Time window will be defined as D30 to D44 post-
vaccination. 
• Subject received a protocol-prohibited Category 2 or Category 3 therapy / medication / 
vaccine 
• Subject’s serology sample did not produce a valid test result 
• Subject had other protocol violations that affected the subject’s immune response, as 
determined by the clinical team before locking the database 
12.2.4 Populations Used in Analyses 
All immunogenicity analyses will be performed on the PPAS. Additional immunogenicity 
analyses will be performed for exploratory purposes on the FAS according to randomization 
group. All safety analyses will be performed on the SafAS. Subjects will be analyzed according to 
the vaccine they actually received. 
12.3 Handling of Missing Data and Outliers 
12.3.1 Safety 
No replacement will be done. 
12.3.2 Immunogenicity 
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Missing data will not be imputed. No test or search for outliers will be performed. 
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In order to appropriately manage extreme values (undetectable responses < LLOQ and ≥ upper 
limit of quantitation [ULOQ]), the following computational rule is applied to the values provided 
in the clinical database for each blood sample drawn for analysis purposes: 
• If a value is < LLOQ, then use the computed value LLOQ/2 
• If a value is between ≥ LLOQ and < ULOQ, then use the value 
• If a value is ≥ ULOQ, then use the computed value ULOQ 
The derived endpoint of fold-rise is computed as follows for extreme values, to minimize the 
numerator and maximizes the denominator: 
• If the baseline computed value is < LLOQ and the post-baseline computed value is < LLOQ 
then the fold-rise is 1 
• If the baseline computed value is ≥ LLOQ and the post-baseline computed value is ≥ LLOQ 
then the fold-rise is post-baseline computed value / baseline computed value 
• If the baseline computed value is ≥ LLOQ and the post-baseline computed value is < LLOQ 
then the fold-rise is (LLOQ/2) / baseline computed value 
• If the baseline computed value is < LLOQ and the post-baseline computed value is ≥ LLOQ 
then the fold-rise is post-baseline computed value /LLOQ 
12.3.3 Efficacy 
Not applicable. 
12.4 Interim / Preliminary Analysis 
No interim / preliminary analyses are planned.  
12.5 Determination of Sample Size and Power Calculation 
A total of 900 subjects will be enrolled. 
 
 
 
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13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Trial / Good Clinical Practice 
The conduct of this trial will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
13.2 Source Data and Source Documents 
“Source data” are the data contained in source documents. Source documents are original 
documents or certified copies, and include, but are not limited to, diary cards, medical and 
hospital records, screening logs, informed consent / assent forms, telephone contact logs, and 
worksheets. The purpose of trial source documents is to document the existence of subjects and to 
substantiate the integrity of the trial data collected. Investigators must maintain source documents 
so that they are accurate, complete, legible, and up to date. 
For missing or discrepant data on a DC, the study coordinator will obtain verbal clarification from 
the subject, enter the response into the “Investigator’s comment” page of the DC, and transfer the 
information to the CRF. 
The subject pre-screening log should list all individuals contacted by the Investigators to 
participate in the trial, regardless of the outcome. 
The Investigator must printa any electronic records on an ongoing basis, sign and date them 
immediately after creation, and keep the printouts on file as source documents that can be verified 
                                                 
a
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  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
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by the Sponsor or an inspector against the electronic records. Any later changes of an electronic 
record require the record to be re-printed, dated (with an indication of the date of change), and 
signed. Such records must also be kept together with the original printed copy. 
13.3 Confidentiality of Data and Access to Subject Records 
Prior to initiation of the trial, the Investigator will sign a fully executed confidentiality agreement 
with Sanofi Pasteur. 
Sanofi Pasteur personnel (or designates), the IECs / IRBs, and regulatory agencies, including the 
Food and Drug Administration (FDA), require direct access to all study records, and will treat 
these documents in a confidential manner. 
In the event a subject’s medical records are not at the investigational site, it is the responsibility of 
the investigator to obtain those records if needed. 
13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring 
Before the start of the trial (i.e., before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the trial protocol and the detailed trial procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRF completion, and the handling of samples and products. The Sponsor’s 
staff or a representative will ensure and document that all material to be used during the trial has 
been received at the site; and that the study investigator team and local Sponsor/delegate staff 
have been properly informed about the trial, GCP and regulatory requirements, and the Sponsor’s 
procedures. Specific training sessions for the study investigator team and the CRAs on these 
topics may be performed as necessary, and should be documented. 
The following instruction manuals will be provided: the CRF Completion Guidelines for entering 
data into the CRF, and the Operating Guidelines for detailed trial procedures such as the product 
management and sample-handling procedures. 
After the start of the trial, the Sponsor’s staff or a representative will be in regular contact with the 
investigational team through telephone calls and regular follow-up visits. The Investigator or 
delegate must be available for these visits, and must allow the Sponsor/delegate staff direct access 
to subject medical files and CRFs. During these visits, the Sponsor/delegate staff will: 
• Evaluate the quality of the trial progress (adherence to protocol and any study-specific 
guidelines, quality of data collection and document completion, signature of consent forms, 
occurrence of SAEs, sample and product management, cold-chain monitoring, archiving) 
• Source-verify completed CRFs and any corresponding answered 
• 
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Determine the number of complete or ongoing issues identified at monitoring visits (e.g., 
protocol deviations, SAEs). Any identified problems will be discussed with the Investigator, 
and corrective or preventive actions will be determined, as appropriate. 
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• After all protocol procedures have been completed and the data have been entered into the 
CRF, the Investigator must still be available to answer any queries forwarded by the Sponsor. 
All data-related queries must be completed prior to database lock. 
At the end of the trial, a close-out visit will be performed to ensure that: 
• The center has all the documents necessary for archiving 
• All samples have been shipped to the appropriate laboratories 
• All unused materials and products have been either destroyed or returned to the Sponsor 
13.4.2 Audits and Inspections 
A quality assurance audit may be performed at any time by the Sponsor’s Clinical and Medical 
Quality Operations department (C&MQO) or by independent auditors to verify that the trial has 
been conducted according to the protocol, GCP and ICH requirements, and other applicable 
regulations. An inspection may be conducted by regulatory authorities. The Investigator must 
allow direct access to trial documents during these inspections and audits. 
13.4.3 Archiving 
The Investigator must keep all trial documents after the completion or discontinuation of the trial, 
whatever the nature of the investigational center (private practice, hospital, or institution), for as 
long as required by applicable laws and regulations. In the absence of any applicable laws or 
regulations, trial documents will be kept at a minimum for the duration indicated on the Clinical 
Trial Agreement (CTA). In no event, should study personnel destroy or permit the destruction of 
any trial documents upon less than 90 days advance written notification to the Sponsor. In 
addition, trial documents should continue to be stored, at Sponsor’s sole expense, in the event that 
the Sponsor requests in writing that such storage continues for a period of time that exceeds that 
required by any applicable law or regulation or the CTA. The Investigator will inform Sanofi 
Pasteur of any address change or if they will no longer be able to house the trial documents. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the trial, including certificates attesting that satisfactory audit and inspection 
procedures have been carried out, will be kept by the Sponsor in the Trial Master File (TMF). 
Data on AEs are included in the TMF. All data and documents will be made available if requested 
by relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
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A CTA will be signed by all the parties involved in the trial’s performance, if relevant. The 
Sponsor has an insurance policy to cover any liabilities that may arise from use of the product and 
/ or the study protocol. 
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13.6 Stipends for Participation 
Additionally, address any incentives the subject may receive, other than stipends given to cover 
their expenses for participating in the study (usually incentives are given for phase I). 
13.7 Publication Policy 
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Data derived from this trial are the exclusive property of Sanofi Pasteur. Any publication or 
presentation related to the trial must be submitted to Sanofi Pasteur for review before submission 
of the manuscript. After publication of the results of the trial, any participating center may publish 
or otherwise use its own data provided that any publication of data from the trial gives recognition 
to the trial group. In addition, Sanofi Pasteur shall be offered an association with all such 
publications, it being understood that Sanofi Pasteur is entitled to refuse the association. 
Sanofi Pasteur must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this trial at least 90 days prior to submission for publication / presentation. 
Any information identified by Sanofi Pasteur as confidential must be deleted prior to submission, 
it being understood that the results of this trial are not to be considered confidential. 
Sanofi Pasteur’s review can be expedited to meet publication guidelines. 
 
 
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14 References List 
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1   Granoff DM, Harrison LH, Pelton S. Meningococcal vaccines. In: Plotkin SA, Orenstein 
WA, Offit PA, editors. Vaccines. 6th ed. Philadelphia (PA): Saunders (Elsevier); 2013:388-
418. 
2  Harrison LH, Trotter CL, Ramsay ME. Global epidemiology of meningococcal disease. 
Vaccine. 2009;27(Suppl 2):B51-63. 
3  Harrison OB, Claus H, Jiang Y, et al. Description and nomenclature of Neisseria 
meningitidis capsule locus. Emerg Infect Dis. 2013;19(4):566-73. 
4   Pollard AJ. Global epidemiology of meningococcal disease and vaccine efficacy. Pediatr 
Infect Dis J. 2004;23(12 Supp):S274-9. 
5   Kvalsvig AJ, Unsworth DJ. The immunopathogenesis of meningococcal disease. J Clin 
Pathol. 2003;56(6):417-22. 
6   Sidikou F, Djibo S, Taha MK, et al. Polymerase chain reaction assay and bacterial 
meningitis surveillance in remote areas, Niger. Emerg Infect Dis. 2003;9(11):1486-8. 
7   World Health Organization. Meningococcal disease, serogroup W135 (update). WER. 
2001;76(28):213-4. 
8  Ibarz-Pavon AB, Gabastou J-M. Improving surveillance and characterization of 
meningococcal disease in Latin America and the Caribbean region: a collaborative research 
program for strengthening regional surveillance network based on laboratory evidence of N. 
meningitidis. Final Report 2010-2013. Available at URL: 
https://partners.sanofi.com/global/menactra/Documents/PAHO%20SIREVA%202%20Meni
ngococcal%20Surveillance%20Final%20Report.pdf. Accessed 25 August 2015. 
9   Ceyhan M, Yildirim I, Balmer P, et al. A prospective study of etiology of childhood acute 
bacterial meningitis, Turkey. Emerg Infect Dis. 2008;14(7):1089-96. 
10   Kilic A, Urwin R, Li H, Saracli MA, Stratton CW, Tang YW. Clonal spread of serogroup 
W135 meningococcal disease in Turkey. J Clin Microbiol. 2006;44(1):222-4. 
11   Shao Z, Zhou H, Gao Y, et al. Neisseria meningitidis serogroup W135, China. Emerg Infect 
Dis. 2010;16(2):348-9. 
12   Zhou H, Liu W, Xu L, et al. Spread of Neisseria meningitidis serogroup W clone, China. 
Emerg Infect Dis. 2013;19(9):1496-9. 
13   Efron AM, Sorhouet C, Salcedo C, Abad R, Regueira M, Vazquez JA. W135 invasive 
meningococcal strains spreading in South America: significant increase in Argentina. J Clin 
Microbiol. 2009;47(6):1979-80. 
14  Weidlich L, Baethgen LF, Mayer LW, et al. High prevalence of Neisseria meningitidis 
hypervirulent lineages and emergence of W135:P1.5,2:ST-11 clone in southern Brazil. J 
Infect. 2008;57(4):324-31. 
15  Barroso DE, Rebelo MC. Recognition of the epidemiological significance of Neisseria 
meningitidis capsular serogroup W135 in the Rio de Janeiro region, Brazil. Mem Inst 
Oswaldo Cruz. 2007;102(6):773-5. 
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16   Boisier P, Nicolas P, Djibo S, et al. Meningococcal meningitis: unprecedented incidence of 
serogroup X-related cases in Niger. Clin Infect Dis. 2007;44(5):657-63. 
17   Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiology of 
meningococcal disease in the United States, 1992-1996. J Infect Dis. 1999;180(6):1894-901. 
18   Canadian Immunization Committee and Public Health Agency of Canada. Advice for 
consideration of quadrivalent (A, C, Y, W135) meningococcal conjugate vaccine, for use by 
provinces and territories. CCDR. 2010;36(S2):1-35. 
19   Broker M, Jacobsson S, Kuusi M, et al. Meningococcal serogroup Y emergence in Europe: 
update 2011. Hum Vaccin Immunother. 2012;8(12):1907-11. 
20  Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease 
epidemiology in the United States, 1998-2007: implications for prevention of 
meningococcal disease. Clin Infect Dis. 2010;50(2):184-91. 
21   National Foundation for Infectious Diseases. Addressing the challenges of Serogroup B 
meningococcal disease outbreaks on campuses: A report by the National Foundation for 
Infectious Diseases. May 2014. Available online: http://www.nfid.org/meningococcal-b. 
Accessed 25 August 2015. 
22   Centers for Disease Control and Prevention. Interim guidance for control of serogroup B 
meningococcal disease outbreaks in organizational settings. Available online: 
http://www.cdc.gov/meningococcal/downloads/interim-guidance.pdf. Accessed 25 August 
2015. 
23   European Centre for Disease Prevention and Control. Annual epidemiological report 2014 -
Vaccine-preventable diseases - invasive bacterial diseases. Stockholm: ECDC; 2015. 
Available online: http://ecdc.europa.eu/en/publications/Publications/AER-VPD-IBD-
2014.pdf. Accessed 11 June 2015. 
24   Public Health England. Increase in endemic Meningococcal group W (MenW) ST-11 
complex associated with severe invasive disease in England and Wales. Health Protection 
Weekly Report. Vol 8 No 41 Published on: 24 October 2014. Available online: 
https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/367588/hpr4
114.pdf). Accessed 25 August 2015. 
25   Törös B, Thulin Hedberg S, Jacobsson S, Fredlund H, Olcén P, Mölling P. Surveillance of 
invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012. Euro 
Surveill. 2014;19(42):pii=20940. Available online: 
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20940. Accessed 25 August 
2015. 
26   Thulin Hedberg S, Törös B, Fredlund H, Olcén P, Mölling P. Genetic characterisation of the 
emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010. Euro 
Surveill. 2011;16(23):pii=19885. Available online: 
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19885. Accessed 25 August 
2015. 
27  The European Meningococcal Disease Society (EMGM). 11th EMGM Meeting, 18-20 May 
2011. Ljubljana Slovenia. Poster abstracts P035, 037-040. Available online: 
http://emgm.eu/meetings/emgm2011/abstracts.pdf. Accessed 25 August 2015. 
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28  Centers for Disease Control and Prevention. Active Bacterial Core surveillance (ABCs) 
Report: Neisseria meningitidis, 2013. Available online: http://www.cdc.gov/abcs/reports-
findings/survreports/mening13.html. Accessed 22 September 2015. 
29  Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among 
recipients of Menactra meningococcal conjugate vaccine--United States, June 2005-
September 2006. MMWR Morb Mortal Wkly Rep. 2006; 55(41):1120-4. 
30   Velentgas P, Amato AA, Bohn RL, et al. Risk of Guillain-Barre syndrome after 
meningococcal conjugate vaccination. Pharmacoepidemiol Drug Saf. 2012;21(12):1350-8. 
31   National Research Council. Diphtheria toxoid, tetanus toxoid, and acellular pertussis-
containing vaccines. In: Stratton K, Ford A, Rusch E, Clayton EW, editors. Adverse effects 
of vaccines: evidence and causality. Washington (DC): The National Academies Press; 
2012:557-8. 
32   Menomune® - A/C/Y/W-135 [package insert]. Swiftwater, PA: Sanofi Pasteur Inc. 
33  Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med. 1998;17:873-90. 
34  Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of 
seven methods. Stat Med. 1998;17:857-72. 
 
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15 Signature Pages 
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Document Number
CLI_1496076
Version Number
3.0
Project Code
MENINGE ACWY INFANT
Document Name
Protocol body
-
-
-
Approver Name
Date
(Universal Time)
Reason for Signature
Approval
 (sanofi pasteur)
23 May 2016
16:16:12
I am approving this document
 
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