Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine Administered in Healthy Children 2 to 9 Years of Age
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 Administered in Healthy Children 2 to 9 Years of Age 
Phase III, modified double-blind, randomized, parallel-group, active-controlled, multi-center trial to evaluate the 
immunogenicity and describe the safety of MenACYW conjugate vaccine compared to a licensed quadrivalent 
meningococcal conjugate vaccine in healthy children 2 to 9 years of age in the United States and Puerto Rico 
Clinical Trial Protocol, Amendment 2 
Health Authority File Number(s): 
BB-IND #: 
14171 
WHO Universal Trial Number 
(UTN): 
U1111-1161-2625 
Trial Code: 
MET35 
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 children 2 to 9 years 
Manufacturer: 
Same as Sponsor 
Coordinating Investigator 
, 
 
 
Sponsor’s Responsible Medical 
Officer: 
 
 Sanofi Pasteur Inc. 
  
 
 
Product Safety Officer: 
 
 Sanofi Pasteur Inc. 
  
 
 
Clinical Trial Manager: 
 
 Sanofi Pasteur Inc. 
  
 
Version and Date of the Protocol: 
Version 3.0 dated 23 February 2018 
This protocol version 3.0 is the second amendment to the initial trial protocol version 1.0, dated 11 July 2016. 
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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History of Protocol Versions 
Table 1: Previous versions of the protocol 
Version* 
Date 
Comments 
1.0 
11 July 2016 
Original protocol; first version used in the study 
2.0 
23 August 2017 
Amendment 1 
*Versions in bold font have been approved by the Independent Ethics Committees (IECs)/ Institutional 
Review Boards (IRBs) and used in the study. 
 
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Table of Contents 
History of Protocol Versions........................................................................................................... 2 
List of Tables .................................................................................................................................... 8 
Synopsis ............................................................................................................................................ 9 
Table of Study Procedures ............................................................................................................ 18 
List of Abbreviations ..................................................................................................................... 20 
1 
Introduction ..................................................................................................................... 22 
1.1 
Background ..................................................................................................................... 22 
1.2 
Background of the Investigational Product ..................................................................... 23 
1.2.1 
Non-clinical Safety ....................................................................................................... 23 
1.2.2 
Clinical ......................................................................................................................... 23 
1.2.2.1 
Study MET39 (Phase II) ............................................................................................ 24 
1.2.2.2 
Study MET44 (Phase II) ............................................................................................ 25 
1.2.2.3 
Study MET50 (Phase II) ............................................................................................ 25 
1.2.2.4 
Study MET54 (Phase II) ............................................................................................ 26 
1.3 
Potential Benefits and Risks ........................................................................................... 27 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 27 
1.3.2 
Potential Risks to Subjects ........................................................................................... 28 
1.4 
Rationale for the Trial ..................................................................................................... 29 
2 
Trial Objectives ............................................................................................................... 29 
2.1 
Primary Objective ........................................................................................................... 29 
2.2 
Secondary Objectives ...................................................................................................... 30 
2.3 
Observational Objectives ................................................................................................ 30 
3 
Investigators and Trial Organization ............................................................................ 30 
4 
Independent Ethics Committee / Institutional Review Board .................................... 31 
5 
Investigational Plan ......................................................................................................... 31 
5.1 
Description of the Overall Trial Design and Plan ........................................................... 31 
5.1.1 
Trial Design .................................................................................................................. 31 
5.1.2 
Justification of the Trial Design ................................................................................... 32 
5.1.3 
Trial Plan ...................................................................................................................... 32 
5.1.4 
Visit Procedures ............................................................................................................ 34 
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5.1.5 
Planned Trial Calendar ................................................................................................. 36 
5.1.6 
Early Safety Data Review............................................................................................. 36 
5.2 
Enrollment and Retention of Trial Population ................................................................ 37 
5.2.1 
Recruitment Procedures ................................................................................................ 37 
5.2.2 
Informed Consent Procedures ...................................................................................... 37 
5.2.3 
Screening Criteria ......................................................................................................... 38 
5.2.4 
Inclusion Criteria .......................................................................................................... 38 
5.2.5 
Exclusion Criteria ......................................................................................................... 38 
5.2.6 
Medical History ............................................................................................................ 40 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 40 
5.2.8 
Contraindications for Subsequent Blood Samples ....................................................... 40 
5.2.9 
Conditions for Withdrawal ........................................................................................... 40 
5.2.10 
Lost to Follow-up Procedures....................................................................................... 41 
5.2.11 
Classification of Subjects Who Discontinue the Trial.................................................. 41 
5.2.12 
Follow-up of Discontinuations ..................................................................................... 42 
5.2.13 
Follow-up and Reporting of Pregnancies ..................................................................... 42 
5.3 
Safety Emergency Call ................................................................................................... 42 
5.4 
Modification of the Trial and Protocol ........................................................................... 43 
5.5 
Interruption of the Trial .................................................................................................. 43 
6 
Vaccines Administered ................................................................................................... 43 
6.1 
Identity of the Investigational Product ............................................................................ 43 
6.1.1 
Identity of Trial Product ............................................................................................... 43 
6.1.1.1 
Composition ............................................................................................................... 44 
6.1.1.2 
Preparation and Administration ................................................................................. 44 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 44 
6.1.2 
Identity of Control Product ........................................................................................... 44 
6.1.2.1 
Composition ............................................................................................................... 45 
6.1.2.2 
Preparation and Administration ................................................................................. 45 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 45 
6.2 
Identity of Other Products ............................................................................................... 45 
6.3 
Product Logistics ............................................................................................................ 45 
6.3.1 
Labeling and Packaging ............................................................................................... 45 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 46 
6.3.2.1 
Product Shipment ....................................................................................................... 46 
6.3.2.2 
Product Storage .......................................................................................................... 46 
6.3.2.3 
Product Accountability ............................................................................................... 46 
6.3.3 
Replacement Doses....................................................................................................... 47 
6.3.4 
Disposal of Unused Products ........................................................................................ 47 
6.3.5 
Recall of Products ......................................................................................................... 47 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 47 
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6.5 
Randomization and Allocation Procedures ..................................................................... 48 
6.6 
Treatment Compliance .................................................................................................... 48 
6.7 
Concomitant Medications and Other Therapies ............................................................. 48 
7 
Management of Samples ................................................................................................. 49 
7.1 
Sample Collection ........................................................................................................... 50 
7.2 
Sample Preparation ......................................................................................................... 50 
7.3 
Sample Storage and Shipment ........................................................................................ 50 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 51 
8 
Clinical Supplies .............................................................................................................. 51 
9 
Endpoints and Assessment Methods ............................................................................. 52 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 52 
9.1.1 
Immunogenicity ............................................................................................................ 52 
9.1.1.1 
Immunogenicity Endpoint .......................................................................................... 52 
9.1.1.2 
Immunogenicity Assessment Method ........................................................................ 52 
9.1.2 
Safety ............................................................................................................................ 52 
9.1.3 
Efficacy ......................................................................................................................... 52 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 53 
9.2.1 
Immunogenicity ............................................................................................................ 53 
9.2.1.1 
Immunogenicity Endpoints ........................................................................................ 53 
9.2.1.2 
Immunogenicity Assessment Method ........................................................................ 53 
9.2.2 
Safety ............................................................................................................................ 53 
9.2.3 
Efficacy ......................................................................................................................... 53 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 53 
9.3.1 
Immunogenicity ............................................................................................................ 53 
9.3.1.1 
Immunogenicity Endpoints ........................................................................................ 53 
9.3.1.2 
Immunogenicity Assessment Methods ...................................................................... 54 
9.3.2 
Safety ............................................................................................................................ 54 
9.3.2.1 
Safety Definitions ....................................................................................................... 54 
9.3.2.2 
Safety Endpoints ........................................................................................................ 57 
9.3.2.3 
Safety Assessment Methods ....................................................................................... 57 
9.3.2.3.1 
Immediate Post-vaccination Surveillance Period .................................................... 58 
9.3.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 07 After 
Vaccination) ............................................................................................................. 58 
9.3.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 30 After 
Vaccination .............................................................................................................. 62 
9.3.2.3.4 
Serious Adverse Events ........................................................................................... 63 
 
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9.3.2.3.6 
Medically-Attended Adverse Events ....................................................................... 64 
9.3.2.3.7 
Assessment of Causality .......................................................................................... 64 
9.3.3 
Efficacy ......................................................................................................................... 64 
10 
Reporting of Serious Adverse Events ............................................................................ 64 
10.1 
Initial Reporting by the Investigator ............................................................................... 65 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 65 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 66 
10.4 
Assessment of Causality ................................................................................................. 66 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 66 
11 
Data Collection and Management ................................................................................. 67 
11.1 
Data Collection and CRF Completion ............................................................................ 67 
11.2 
Data Management ........................................................................................................... 68 
11.3 
Data Review .................................................................................................................... 68 
12 
Statistical Methods and Determination of Sample Size ............................................... 69 
12.1 
Statistical Methods .......................................................................................................... 69 
12.1.1 
Hypotheses and Statistical Methods for Primary Objective ......................................... 69 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 69 
12.1.2.1 
Secondary Objective 1 ............................................................................................... 69 
12.1.2.2 
Secondary Objective 2 ............................................................................................... 70 
12.1.2.3 
Secondary Objective 3 ............................................................................................... 70 
12.1.3 
Statistical Methods for Observational Objectives ........................................................ 70 
12.1.3.1 
Immunogenicity ......................................................................................................... 70 
12.1.3.2 
Safety .......................................................................................................................... 71 
12.2 
Analysis Sets ................................................................................................................... 72 
12.2.1 
Full Analysis Set ........................................................................................................... 72 
12.2.2 
Safety Analysis Set ....................................................................................................... 72 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 72 
12.2.4 
Populations Used in Analyses ...................................................................................... 73 
12.3 
Handling of Missing Data and Outliers .......................................................................... 73 
12.3.1 
Safety ............................................................................................................................ 73 
12.3.2 
Immunogenicity ............................................................................................................ 73 
12.3.3 
Efficacy ......................................................................................................................... 73 
12.4 
Interim / Preliminary Analysis ........................................................................................ 74 
12.5 
Determination of Sample Size and Power Calculation ................................................... 74 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 74 
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13.1 
Ethical Conduct of the Trial / Good Clinical Practice .................................................... 74 
13.2 
Source Data and Source Documents ............................................................................... 75 
13.3 
Confidentiality of Data and Access to Subject Records ................................................. 75 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 75 
13.4.1 
Monitoring .................................................................................................................... 75 
13.4.2 
Audits and Inspections ................................................................................................. 76 
13.4.3 
Archiving ...................................................................................................................... 76 
13.5 
Financial Contract and Insurance Coverage ................................................................... 77 
13.6 
Stipends for Participation ................................................................................................ 77 
13.7 
Publication Policy ........................................................................................................... 77 
14 
References List ................................................................................................................. 78 
15 
Signature Pages ............................................................................................................... 82 
 
 
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List of Tables 
Table 1: Previous versions of the protocol ........................................................................................2 
Table 5.1: Testing strategy for N meningitidis serogroups A, C, Y, and W ....................................33 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales ...........60 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales .................61 
Table 12.1: Power of the study based on the primary objective .....................................................74 
 
 
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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 Administered in Healthy Children 2 to 
9 Years of Age 
Development Phase: 
Phase III 
Coordinating Investigator: 
 
 
Trial Centers: 
This will be a multi-center trial with approximately 40 sites in the United 
States and Puerto Rico. 
Investigators and sites will be listed in the “List of Investigators and Centers 
Involved in the Trial” document. 
Planned Trial Period: 
1Q 2017 to 4Q 2017 
Trial Design and Methodology: 
This will be a Phase III, modified double-blind, randomized, parallel-group, 
active-controlled, multi-center trial to evaluate the immunogenicity and 
describe the safety of MenACYW conjugate vaccine compared to 
MENVEO® in healthy children 2 to 9 years of age in the United States and 
Puerto Rico. 
Approximately 1000 healthy, meningococcal-vaccine naïve children aged 2 
to 9 years will be randomized in a 1:1 ratio to the following 2 groups: 
Group 1: MenACYW conjugate vaccine 
Group 2: MENVEO® 
Enrollment will be stratified by age: 250 children 2 to 5 years old and 
250 children 6 to 9 years old, respectively, will be enrolled in each group. 
All subjects will provide blood samples for immunogenicity assessment at 
baseline (pre-vaccination) and at 30 to 44 days after vaccination. Solicited 
adverse event (AE) information will be collected for 7 days after vaccination; 
unsolicited AE information will be collected from Visit 1 (Day [D] 0) to 
Visit 2 (D30 [+14 days]), and serious adverse event (SAE) information 
 will be collected 
throughout the study period 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).  
A preliminary analysis of safety and immunogenicity, without 
immunogenicity data generated using rSBA, is planned for all subjects 
enrolled in the study.  
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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 subjects’ parent(s) / 
guardian and should assure appropriate therapy and follow-up. 
Primary Objective: 
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 that observed 
following the administration of a single dose of MENVEO® in children aged 
2 to 9 years. 
Primary Endpoint: 
Vaccine seroresponse against meningococcal serogroups A, C, Y, and W 
measured by serum bactericidal assays using human complement (hSBA) 
assessed at baseline (D0, before vaccination) and 30 days (+14 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 MENVEO® in children 2 to 9 years of 
age 
2) 
To evaluate the hSBA antibody GMTs of meningococcal serogroups 
A, C, Y, and W following the administration of MenACYW conjugate 
vaccine and those observed following the administration of 
MENVEO® in children 2 to 5 years of age, and in children 6 to 9 years 
of age, respectively 
3) 
To evaluate the hSBA vaccine seroresponse to meningococcal 
serogroups A, C, Y, and W before and 30 days (+14 days) post-
vaccination in children 2 to 5 years of age, and in children 6 to 9 years 
of age, respectively 
Secondary Endpoints: 
• 
GMTs against meningococcal serogroups A, C, Y, and W measured by 
hSBA before and 30 days (+14 days) after vaccination with 
MenACYW conjugate vaccine or MENVEO® 
• 
Vaccine seroresponse against meningococcal serogroups A, C, Y, and 
W measured by hSBA before and 30 days (+14 days) after vaccination 
with MenACYW conjugate vaccine or MENVEO® 
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Observational Objectives: 
Immunogenicity 
1) 
To describe the antibody titers against meningococcal serogroups A, C, 
Y, and W measured by hSBA before and 30 days (+14 days) after 
vaccination with MenACYW conjugate vaccine or MENVEO® 
2) 
To describe the antibody titers against meningococcal serogroups A, C, 
Y, and W measured by rSBA before and 30 days (+14 days) after 
vaccination with MenACYW conjugate vaccine or MENVEO® in a 
subset of subjects 
Safety 
To describe the safety profile of MenACYW conjugate vaccine and that of 
the licensed MENVEO®  
Observational Endpoints: 
Immunogenicity 
1) 
Antibody titers against meningococcal serogroups A, C, Y, and W 
measured by hSBA before and 30 days after vaccination with 
MenACYW conjugate vaccine or MENVEO® 
2) 
Antibody titers against meningococcal serogroups A, C, Y, and W 
measured by rSBA before and 30 days after vaccination with 
MenACYW conjugate vaccine or MENVEO® in a subset of subjects 
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 of 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 and electronic 
case report form [CRF]) injection site reactions occurring up to 7 days 
after vaccination. 
• 
Occurrence, time of 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 and CRF) 
systemic reactions occurring up to 7 days after vaccination. 
• 
Occurrence, nature (MedDRA preferred term), time of 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 up to Visit 2 after vaccination. 
• 
Occurrence, nature (MedDRA preferred term), time of 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 of 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. 
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Planned Sample Size: 
A total of 1000 children 2 to 9 years old are planned to be enrolled: 
• 
Group 1 (MenACYW conjugate vaccine): planned=500 
(evaluable=400) 
Group 1a: 250 children 2 to 5 years of age (from the day of the 2nd 
birthday to the day before the 6th birthday) 
Group 1b: 250 children 6 to 9 years of age (from the day of the 6th 
birthday to the day before the 10th birthday) 
• 
Group 2 (MENVEO®): planned=500 (evaluable=400) 
Group 2a: 250 children 2 to 5 years of age (from the day of the 2nd 
birthday to the day before the 6th birthday) 
Group 2b: 250 children 6 to 9 years of age (from the day of the 6th 
birthday to the day before the 10th birthday) 
The planned number of subjects is based on a 20% dropout rate 
(400 evaluable subjects in each group) allowing 90% power to reject the 
primary hypotheses simultaneously assuming the independence between 
each of the endpoints. 
Schedule of Study Procedures: 
Vaccination 
All subjects will receive a single dose of either MenACYW conjugate 
vaccine or MENVEO® at Visit 1 (D0). 
Blood sampling 
All subjects will provide a pre-vaccination blood sample at D0 and a post-
vaccination sample at Visit 2 (30 to 44 days after the vaccination at Visit 1). 
Antibodies to meningococcal serogroups A, C, Y, and W antigens will be 
measured by hSBA for all subjects, and by rSBA for a subset of subjects. 
Table S1: Testing strategy for N meningitidis serogroups A, C, Y, and 
W 
 
ACYW serogroups 
tested by hSBA* 
(all subjects) 
ACYW 
serogroups tested 
by rSBA† 
(subset) 
Group 1 
 
 
Group 1a (2 to 5 years old) 
250 
100 
Group 1b (6 to 9 years old) 
250 
100 
Group 2 
 
 
Group 2a (2 to 5 years old) 
250 
100 
Group 2b (6 to 9 years old) 
250 
100 
* hSBA: serum bactericidal assay using human complement 
† rSBA: serum bactericidal assay using baby rabbit complement 
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.  
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• 
The subject’s parent / guardian will record information in a diary card 
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’s parent / guardian will record information only about 
possible SAEs and MAAEs in a memory aid (MA) from Visit 2 until 
the 6-month (+14 days) telephone call. 
• 
In addition, the subject’s parent / guardian will be asked to notify the 
site immediately about potential SAEs at any time during the trial. 
• 
Staff will contact subject’s parent / guardian by telephone on D08 
(+2 days) to identify the occurrence of any SAE not yet reported, and 
to remind them to complete the diary card up to Visit 2 and to bring it 
back at Visit 2. 
• 
The completed diary card will be reviewed with the subject’s parent / 
guardian at Visit 2. 
 
• 
Staff will contact subject’s parent / guardian by telephone at 6 months 
(+14 days) post-vaccination to review the MA and identify the 
occurrence of any MAAEs as well as SAEs that may not have been 
reported. 
Duration of Participation in the 
Trial: 
The duration of each subject’s participation in the trial will be approximately 
180 to 194 days. 
There will be a safety follow-up telephone call at 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 milliliters (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: 
MENVEO®: Meningococcal (Groups A, C, Y and W-135) Oligosaccharide 
Diphtheria CRM197 Conjugate Vaccine (Novartis Vaccines and Diagnostics 
S.r.l., Sovicille, Italy) 
 Form: 
Lyophilized powder and liquid components are combined to produce a 
solution for intramuscular injection  
 Composition: 
Each 0.5 mL dose of vaccine contain the following active ingredients: 
MenA oligosaccharide ...................................................................... 10 µg 
MenC oligosaccharide ........................................................................ 5 µg 
MenY oligosaccharide ........................................................................ 5 µg 
MenW-135 oligosaccharide ................................................................ 5 µg 
CRM197 protein .................................................................. 32.7 to 64.1 µg 
Other ingredients per 0.5 mL dose: residual formaldehyde ≤ 0.30 µg 
 Route: 
IM 
 Batch Number: 
To be determined (control product will be supplied by the Sponsor) 
Inclusion Criteria 
An individual must fulfill all of the following criteria in order to be eligible 
for trial enrollment: 
1) Aged 2 to 9 years on the day of inclusion 
2) Assent form has been signed and dated by the subject (as required by 
local regulations) and informed consent form (ICF) has been signed and 
dated by the parent(s) or guardian 
3) Subject and parent / guardian are 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 and not 
using an effective method of contraception or abstinence from at least 
4 weeks prior to vaccination until at least 4 weeks after vaccination. To 
be considered of non-childbearing potential, a female must be pre-
menarche. 
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 the study investigational vaccines. This exception includes 
monovalent, multivalent, live, and attenuated 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 serogroup containing 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 traveling to countries with 
high endemic or epidemic disease) 
9) Known systemic hypersensitivity to any of the vaccine components, or 
history of a life-threatening reaction to the vaccines used in the trial or 
to a vaccine containing any of the same substances 
10) Verbal report of thrombocytopenia, contraindicating intramuscular 
vaccination in the Investigator’s opinion 
 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding 
inclusion, contraindicating intramuscular vaccination in the 
Investigator’s opinion 
12) Personal history of Guillain-Barre syndrome (GBS) 
13) Personal history of an Arthus-like reaction after vaccination with a 
tetanus toxoid-containing vaccine  
14) Chronic illness that, in the opinion of the Investigator, is at a stage 
where it might interfere with trial conduct or completion 
 
15) Moderate or severe acute illness/infection (according to Investigator’s 
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 
16) Receipt of oral or injectable antibiotic therapy within 72 hours prior to 
the first blood draw 
17) Identified as a 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). All 
safety analyses will be performed on the Safety Analysis Set (SafAS). 
Primary Objective 
Thirty days (D30 [+14 days]) after the administration of MenACYW 
conjugate vaccine or MENVEO®, 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. 
 
Secondary Objectives 
1) 
Thirty days (D30 [+14 days]) after the administration of MenACYW 
conjugate vaccine or MENVEO®, the hSBA geometric mean titer ratio 
(GMTR) between Group 1 and Group 2 will be calculated and 95% CI 
will be provided. 
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2) 
Thirty days (D30 [+14 days]) after the administration of MenACYW 
conjugate vaccine or MENVEO®, the hSBA GMTR between Group 1a 
and Group 2a, and between Group 1b and Group 2b will be calculated 
and 95% CI will be provided, respectively. 
3) 
Thirty days (D30 [+14 days]) after the administration of MenACYW 
conjugate vaccine or MENVEO®, the difference of hSBA vaccine 
seroresponse* rates between Group 1a and Group 2a, and between 
Group 1b, and Group 2b will be calculated and 95% CI will be 
provided, respectively. 
 
*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  
 
Observational Objectives 
Immunogenicity 
Descriptive statistics will be provided for the antibody titers against 
meningococcal serogroups contained in MenACYW conjugate vaccine and 
MENVEO®. 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.  
Reverse cumulative distribution curve (RCDC) figures will be provided for 
the antibody titers against meningococcal serogroups contained in 
MenACYW conjugate vaccine and MENVEO® treatment groups. 
Descriptive analyses on A, C, Y, and W serogroups on D0 and D30 
(+14 days) using hSBA will include but not be limited to: 
• 
GMT and 95% CI in Group 1, Group 2, Group 1a, Group 1b, Group 
2a, and Group 2b 
• 
Titer distribution and RCDC 
• 
Percentage of subjects with titer ≥ 1:4 and ≥ 1:8 and 95% CI in 
Group 1, Group 2, Group 1a, Group 1b, Group 2a, and Group 2b 
• 
Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to 
post-vaccination, and 95% CI in Group 1, Group 2, Group 1a, 
Group 1b, Group 2a, and Group 2b 
• 
Percentage of subjects with hSBA vaccine seroresponse* and 95% CI 
in Group 1, Group 2, Group 1a, Group 1b, Group 2a, and Group 2b 
* 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. 
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Descriptive analyses on A, C, Y, and W serogroups on D0 and D30 
(+14 days) using rSBA will include but not be limited to: 
• 
GMT and 95% CI in a subset of 200 subjects in Group 1 and Group 2, 
and in a subset of 100 subjects in Group 1a, Group 1b, Group 2a, and 
Group 2b 
• 
Titer distribution and RCDCs 
• 
Percentage of subjects with titer ≥ 1:8 and ≥ 1:128 and 95% CI in a 
subset of 200 subjects in Group 1 and Group 2, and in a subset of 
100 subjects in Group 1a, Group 1b, Group 2a, and Group 2b 
Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to post-
vaccination, and 95% CI in a subset of 200 subjects in Group 1 and Group 2, 
and in a subset of 100 subjects in Group 1a, Group 1b, Group 2a, and Group 
2b 
 
• 
Percentage of subjects with rSBA vaccine seroresponse* and 95% CI in 
a subset of 200 subjects in Group 1 and Group 2, and in a subset of 
100 subjects in Group 1a, Group 1b, Group 2a, and Group 2b 
* 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. 
Safety 
Safety results will be described for subjects in Group 1 and Group 2. The 
main parameters for the safety endpoints will be described by 95% CIs 
(based on the Clopper-Pearson method). 
 
Calculation of Sample Size: 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table of Study Procedures 
Phase III Trial, 2 Visits, 1 Vaccination, 2 Telephone Calls, 2 Blood Samples, 180 Days Duration per Subject 
Visit/Contact 
Visit 1 
Telephone 
Call (TC) 1 
Visit 2 
TC2 
Trial timelines (days) 
D0 
D08 
D30 
D180 
Time windows (days) 
-- 
+2 days  
+14 days 
+14 days 
Informed consent form/assent form (if applicable) 
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), 5 mL‡ 
BL1 
 
BL2 
 
Vaccination§ 
X 
 
 
 
Immediate surveillance (30 minutes) 
X 
 
 
 
Diary card provided 
X 
 
 
 
Telephone call 
 
X** 
 
X†† 
Recording of solicited injection site & systemic 
reactions 
D0 to D07 
 
 
 
Recording of unsolicited AEs 
D0 to Visit 2 
 
Recording of MAAEs‡‡ 
 
 
 
After Visit 2 to TC2 
Reporting of SAEs 
 
To be reported throughout the study period 
Diary card reviewed and collected 
 
 
X 
 
Collection of reportable concomitant medications 
X 
 
X 
 
Memory aid (MA) provided*** 
 
 
X 
 
Termination of active phase of trial 
 
 
X 
 
Completion of 6-month follow-up 
 
 
 
X 
*Temperature needs to be measured by axillary, oral, or rectal route (axillary is the preferred route) 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 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. 
‡Blood sample at Visit 1 will be drawn before administration of vaccine 
§Subjects will receive a single dose of MenACYW conjugate vaccine or a single dose of MENVEO®. 
**This call is made 8 to 10 days after the vaccination at Visit 1. 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’s parent/guardian to continue using the diary card up to Visit 2, to bring the 
diary card to the study center at Visit 2, and confirm the date and time of Visit 2. 
††Staff will contact the subject’s parent/guardian by telephone at 6 months (180 days +14 days) after vaccination at Visit 1 to 
identify the occurrence of any MAAEs as well as SAEs not yet reported. 
‡‡MAAEs that occur between Visit 1 and Visit 2 will be recorded as unsolicited AEs. 
§§
 
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***The MA is used for the recording of SAEs and MAAEs. The site staff will make a telephone call to the parent/guardian to 
obtain the information 180 days (+14 days) after the vaccination at Visit 1. Since the timeframe between Visit 1 and Visit 2 
(inclusive) will be captured in the diary card, the MA will be used to collect SAE and MAAE data from Visit 2 to TC2. 
 
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List of Abbreviations 
µg 
microgram(s) 
Ab 
antibody 
ACIP 
Advisory Committee on Immunization Practices 
AE 
adverse event 
 
 
AR 
adverse reaction 
CBER 
Center for Biologics Evaluation and Research 
CDM 
Clinical Data Management 
CFU 
colony - forming unit 
CI 
confidence interval 
C&MQO 
Clinical and Medical Quality Operations 
CRA 
Clinical Research Associate 
CRF 
electronic case report form 
CTA 
clinical trial agreement 
CTL  
Clinical Team Leader  
D 
day 
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 
GMTR 
geometric mean titer ratio 
GPV 
Global PharmacoVigilance  
HCP 
health care provider 
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 
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IM 
intramuscular(ly) 
IMD 
invasive meningococcal disease 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
ITP 
idiopathic thrombocytopenic purpura 
IWRS 
interactive web response system 
LCLS 
last contact, last subject 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
MA 
memory aid 
MAAE 
medically-attended adverse event 
MCV 
meningococcal conjugate vaccine 
MCV4 
quadrivalent meningococcal conjugate vaccine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter(s) 
N. 
Neisseria 
NSAID 
non-steroidal anti-inflammatory drug 
PPAS 
Per-Protocol Analysis Set 
PS 
polysaccharide 
PSO 
Product Safety Officer 
R&D 
Research and Development 
RCDC 
reverse cumulative distribution curve 
RMO 
Responsible Medical Officer 
rSBA 
serum bactericidal assay using 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 trial (MET35) 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 children 2 to 
9 years of age. The purpose of the MET35 trial is to demonstrate that the immunogenicity and 
safety profiles of the MenACYW conjugate vaccine are comparable with those of the MENVEO® 
in this age group. 
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 different 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 remains the main cause of epidemics in the 
world and is especially dominant in Africa and Asia. Serogroup W has been observed in Africa, 
as well as 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), Brazil (14) (15), and 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 the frequency with which 
it causes sporadic cases has gradually increased in the US and more recently in Canada and 
Europe (17) (18) (19). The Y 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). 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 aged 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 compared with an average of 1% to 2% of all 
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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 including children as young as 6 weeks of age, 
adolescents, and adults 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 1639 subjects (infants, toddlers, adolescents, and 
adults > 55 years of age) in completed studies MET39, MET44, MET50, and MET54. 
MenACYW conjugate vaccine is also being evaluated in an ongoing Phase III study (MET56 in 
adolescents and adults). The relevant Phase II studies are discussed below.  
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 or in the 
ongoing MET56 study. 
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1.2.2.1 
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 
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, 
1 as a result of hypoxic ischemic encephalopathy which started 96 days after the 6-month 
vaccination and 1 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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1.2.2.2 
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 aged 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). 
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 SBA 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-135 among 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. 
The safety profile of the vaccines when compared by subject age was generally comparable 
between both age groups, with no clinical impact in the differences observed. In general, no 
increase in reactogenicity was observed in the older vaccine recipients as compared to the 
younger cohort in this study. 
1.2.2.3 
Study MET50 (Phase II) 
MET50 was a Phase II, randomized, open-label, parallel-group, controlled, multi-center trial 
conducted in the US. This trial evaluated the immunogenicity and safety profile of a single dose 
of MenACYW conjugate vaccine when given alone compared to that of the licensed vaccine 
MENVO® and when given concomitantly with Adacel® (Tetanus, diphtheria, acellular pertussis 
[Tdap] vaccine) and GARDASIL® (human papilloma virus [HPV] vaccine) in healthy, 
meningococcal vaccine-naïve adolescents 10 to 17 years of age. Subjects in Group 1 received a 
single dose of MenACYW conjugate vaccine, subjects in Group 2 received a single dose of 
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MENVEO®, subjects in Group 3 received a single dose each of MenACYW conjugate vaccine 
and Tdap vaccine and a total of 3 doses of HPV vaccine (Dose 1 on D0, Dose 2 and Dose 3 were 
given 2 and 6 months, respectively, after Dose 1), subject in Group 4 received a single dose of 
Tdap vaccine and 3 doses of HPV vaccine on the same schedule as Group 3.  
Safety 
Vaccination with MenACYW conjugate vaccine among adolescents was found to be safe with no 
safety concerns identified when given alone or concomitantly with Tdap and HPV vaccines. The 
MenACYW conjugate vaccine was well tolerated with no immediate hypersensitivity reactions 
and no related SAEs. 
The safety profile of MenACYW conjugate vaccine was comparable to that of the licensed 
vaccine MENVEO® when given alone, while the systemic reactogenicity was found to be higher 
when MenACYW conjugate vaccine was given with Tdap and HPV vaccines. However, 
reactogenicity remained comparable to that observed with the control Group 4, when the licensed 
concomitant vaccines were given without MenACYW conjugate vaccine. 
The safety profiles of the concomitant licensed vaccines were comparable when administered 
with or without MenACYW conjugate vaccine.  
No new clinically important findings were identified with administration of the MenACYW 
conjugate vaccine. 
1.2.2.4 
Study MET54 (Phase II) 
MET54 was a Phase II, randomized, open-label, active-controlled, multi-center study conducted 
in Europe (Finland). This study evaluated the immunogenicity and safety profile of a single dose 
of MenACYW conjugate vaccine when given alone in healthy, meningococcal-vaccine naïve 
toddlers compared to that of the licensed vaccine Nimenrix®. A total of 200 meningococcal 
vaccine naïve subjects aged 12 to 23 months on the day of enrollment were randomized to 1 of 
2 groups. Group 1 received a single dose of MenACYW conjugate vaccine and Group 2 received 
a single dose of Nimenrix®. 
Immunogenicity 
Antibody responses to the antigens (serogroups A, C, Y, and W) were evaluated by serum 
bactericidal assay using rSBA and hSBA. MenACYW conjugate vaccine immune responses 
evaluated by rSBA and hSBA were generally comparable to Nimenrix® immune responses with 
some variation by serogroup: 
rSBA 
Most subjects had rSBA titers ≥ 1:128 at D30. The percentages after MenACYW conjugate 
vaccine were similar (100.0% [91/91] for serogroups A, Y, and W) or numerically higher 
(100.0% [91/91] for serogroup C) compared to Nimenrix® (100.0% [86/86] for serogroups A, Y, 
and W and 94.2% [81/86] for serogroup C). At D30, most subjects in both groups demonstrated 
an rSBA vaccine seroresponse as defined in the SAP and as defined in the protocol. The 
percentage of subjects with any rSBA vaccine seroresponse by either definition for serogroup A 
was numerically lower after MenACYW conjugate vaccine (91.2% [83/91]) than Nimenrix® 
(98.8% [85/86]) and the percentages of subjects with any rSBA vaccine seroresponse by either 
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definition were similar or comparable between the 2 groups for serogroups C, Y, and W (all 
> 96%). 
hSBA 
Most subjects in both groups had hSBA titers ≥ 1:8 at D30: the percentages after MenACYW 
conjugate vaccine for serogroups A, Y, and W (ranging from 97.8% [89/91] to 98.9% [90/91]) 
were comparable to those after Nimenrix® (ranging from 91.9% [79/86] to 100.0% [86/86]). The 
percentage of subjects with hSBA titers ≥ 1:8 for serogroup C was higher after MenACYW 
conjugate vaccine (100.0% [91/91]) than after Nimenrix® (89.5% [77/86]). At D30, most subjects 
in both groups demonstrated an hSBA vaccine seroresponse. The percentage of subjects with an 
hSBA vaccine seroresponse for serogroups A, Y, and W was comparable in both groups (ranging 
from 96.7% [87/90] to 98.9% [90/91] after MenACYW conjugate vaccine and from 91.9% 
[79/86] to 98.8% [85/86] after Nimenrix®). The percentage of subjects with an hSBA vaccine 
seroresponse for serogroup C was higher after MenACYW conjugate vaccine (100.0% [91/91]) 
than after Nimenrix® (86.0% [74/86]). 
Safety 
Overall, vaccination with MenACYW conjugate vaccine among toddlers aged 12 to 23 months 
was found to be safe with no safety concerns identified. The MenACYW conjugate vaccine was 
well tolerated with no immediate AEs or ARs, no discontinuations due to an SAE or other AE, 
and no related SAEs. 
The safety profile of MenACYW conjugate vaccine was comparable to that of the licensed 
vaccine, Nimenrix®. 
No new clinically important findings were identified with administration of the MenACYW 
conjugate vaccine. 
1.3 
Potential Benefits and Risks 
1.3.1 
Potential Benefits to Subjects 
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 
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 MENVEO® 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 MENVEO® may not protect 100% of 
individuals against the diseases they are designed to prevent. 
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1.3.2 
Potential Risks to Subjects 
Like other vaccines, MenACYW conjugate vaccine or MENVEO® may cause injection site 
reactions such as pain, swelling, and erythema, or certain systemic events such as fever, headache, 
malaise, and myalgia. Common reactions following administration of MENVEO® in children 2 
through 10 years of age also include induration at the injection site, irritability, and sleepiness. 
There may be a rare possibility of an allergic reaction, which could be severe. There may also be a 
risk of febrile convulsion in some children who experience high fever. There may be other risks 
for MenACYW conjugate vaccine that are not yet known. 
 
 
 
 
Importantly, no similar cases have 
been reported following the administration of MenACYW conjugate vaccine in any other trials. 
Guillain-Barré syndrome (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. The 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 
(32). Arthus reactions are rarely reported after vaccination and can occur after tetanus toxoid-
containing vaccines (33). 
No occurrences of GBS, brachial neuritis, or Arthus reaction have been reported with the use of 
MenACYW conjugate vaccine in the completed clinical trials. 
The risk of vasovagal syncope exists after any vaccination in the adolescent age group, although it 
has not been specifically reported in the age group under study as part of this protocol (34). 
Syncope, sometimes resulting in falling injury associated with seizure-like movements, has been 
reported following vaccination with the MENVEO®. A few cases of immediate vasovagal-like 
response or syncope have been observed in adolescent subjects who had received MenACYW 
conjugate vaccine. 
The potential risks associated with blood drawing include local pain, bruising, and, rarely, 
fainting. 
The potential risk listed here are not exhaustive. Refer to the MENVEO® package insert (35) and 
the Investigator’s Brochure of the investigational vaccine for additional information regarding the 
potential risks. 
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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 MET35 is to demonstrate that the immunogenicity profile of a single dose of the 
MenACYW conjugate vaccine in children 2 to 9 years of age is comparable with MENVEO®, a 
US licensed quadrivalent diphtheria CRM197 protein conjugate meningococcal vaccine, and 
describe the safety profiles of both vaccines. 
2 
Trial Objectives 
2.1 
Primary Objective 
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 that observed following the administration of a single dose of MENVEO® in children 
aged 2 to 9 years 
The endpoints for the primary objective are presented in Section 9.1. 
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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 MENVEO® in children aged 2 to 9 years of age 
2) 
To evaluate the hSBA antibody GMTs of meningococcal serogroups A, C, Y, and W 
following the administration of MenACYW conjugate vaccine and those observed following 
the administration of MENVEO® in children 2 to 5 years of age, and in children 6 to 9 years 
of age, respectively  
3) 
To evaluate the hSBA vaccine seroresponse to meningococcal serogroups A, C, Y, and W 
before and 30 days (+14 days) post-vaccination in children 2 to 5 years of age, and in 
children 6 to 9 years of age, respectively 
The endpoints for the secondary objectives are presented in Section 9.2. 
2.3 
Observational Objectives 
Immunogenicity 
1) 
To describe the antibody titers against meningococcal serogroups A, C, Y, and W measured 
by hSBA before and 30 days (+14 days) after vaccination with MenACYW conjugate vaccine 
or MENVEO® 
2) 
To describe the antibody titers against meningococcal serogroups A, C, Y, and W measured 
by rSBA before and 30 days (+14 days) after vaccination with MenACYW conjugate vaccine 
or MENVEO® in a subset of subjects 
Safety 
To describe the safety profile of MenACYW conjugate vaccine and that of the licensed 
MENVEO® 
The endpoints for the observational objectives are presented in Section 9.3.1.1 and  
Section 9.3.2.2, for immunogenicity and safety, respectively. 
3 
Investigators and Trial Organization 
This trial will be conducted in approximately 40 centers in the USA and Puerto Rico. 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 
, 
, Clinical Team Leader. 
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4 
Independent Ethics Committee / Institutional Review Board 
Before the investigational product can be shipped to the investigational site and before the 
inclusion of the first subject, this protocol, the informed consent form(s) (ICFs), assent form(s), 
subject recruitment procedures, and any other written information to be provided to subjects must 
be approved by, and / or receive favorable opinion from, the appropriate Independent Ethics 
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 evaluate the immunogenicity and describe the safety of MenACYW conjugate 
vaccine compared to the MENVEO® in healthy children 2 to 9 years of age in the United States 
and Puerto Rico. 
Healthy, meningococcal-vaccine naïve children aged 2 to 9 years will be randomized in a 1:1 ratio 
as follows: 
• 
Group 1: MenACYW conjugate vaccine: 
N = 500 
Group 1a:   
 
 
 
250 children 2 to 5 years of agea 
Group 1b:   
 
 
 
250 children 6 to 9 years of ageb 
• 
Group 2: MENVEO®:   
 
 
N = 500 
Group 2a:   
 
 
 
250 children 2 to 5 years of agea 
Group 2b:   
 
 
 
250 children 6 to 9 years of ageb 
                                                 
a  “2 to 5 years of age” means from the day of the 2nd birthday to the day before the 6th birthday 
b  “6 to 9 years of age” means from the day of the 6th birthday to the day before the 10th birthday 
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All subjects will provide blood samples for immunogenicity assessment at baseline (pre-
vaccination) and at 30 to 44 days after vaccination. 
Solicited AE information will be collected for 7 days after vaccination; unsolicited AE 
information will be collected from Visit 1 (Day [D] 0) to Visit 2 (D30 [+14 days]) and SAE 
information 
 will be collected throughout the 
study period from D0 through D180 (+14 days) after vaccination. 
Medically-attended adverse events (MAAEs) will be collected throughout the study 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 
 
MET35 is a study that will be conducted as part of 
the Phase III development of the MenACYW conjugate vaccine in which the vaccine candidate 
will be evaluated in the age group of 2 to 9 year old children. 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 (MENVEO®) in this population. Enrollment in the 
study will be stratified in 2 age groups, 2 to 5 years of age and 6 to 9 years of age. Age stratified 
data will be presented in a descriptive fashion. Data in the 2 to 9 year age range are needed as part 
of the overall data for key age groups typically required by the Center for Biologics Evaluation 
and Research (CBER) in the context of achieving licensure with a broad age indication.  
In the US, meningococcal vaccination is not routinely recommended for children ≤ 10 years of 
age, however the vaccination is recommended for individuals at risk of disease. ACIP 
recommends routine administration of a quadrivalent meningococcal conjugate vaccine (MCV4) 
for all persons aged 11 through 18 years. A single dose of vaccine should be administered at age 
11 or 12 years, and a booster dose should be administered at age 16 years. The minimum interval 
between doses of MCV4 is 8 weeks. Children who receive meningococcal conjugate containing 
vaccines before age 10 years should receive the routinely recommended dose at age 11 or 
12 years and a booster dose at age 16 years (36). 
The selection of MENVEO® 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 MENVEO® is one of the quadrivalent 
meningococcal conjugate vaccines licensed in the US. 
5.1.3 
Trial Plan 
A schedule of assessments and study vaccinations is provided in the Table of Study Procedures. 
Vaccination 
All subjects will receive a single dose of either MenACYW conjugate vaccine or MENVEO® at 
Visit 1 (D0). 
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Blood Sampling 
All subjects will provide a pre-vaccination blood sample at D0 and a post-vaccination sample at 
Visit 2 (30 to 44 days after the vaccination at Visit 1). 
Antibodies to meningococcal serogroups A, C, Y, and W antigens will be measured by hSBA for 
all subjects, and by rSBA for a subset of subjects. 
Table 5.1: Testing strategy for N meningitidis serogroups A, C, Y, and W 
 
ACYW serogroups tested by 
hSBA* 
(all subjects) 
ACYW serogroups tested by 
rSBA† 
(subset) 
Group 1 
 
 
 
Group 1a (2 to 5 years old) 
250 
100 
 
Group 1b (6 to 9 years old) 
250 
100 
Group 2 
 
 
 
Group 2a (2 to 5 years old) 
250 
100 
 
Group 2b (6 to 9 years old) 
250 
100 
* hSBA: serum bactericidal assay using human complement 
† rSBA: serum bactericidal assay using baby rabbit complement 
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) (see Section 9.3.2.3.1). 
• The subject’s parent / guardian will record information in a diary card 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’s parent / guardian will record information only about possible SAEs and MAAEs 
in a memory aid (MA) from Visit 2 until the 6-month (+14 days) telephone call. 
• In addition, the subject’s parent / guardian will be asked to notify the site immediately about 
potential SAEs at any time during the trial. 
• Staff will contact the subject’s parent / guardian by telephone on D08 (+2 days) to identify the 
occurrence of any SAE not yet reported and to remind them to complete the diary card up to 
Visit 2 and to bring it back at Visit 2. 
• The completed diary card will be reviewed with the subject’s parent / guardian at Visit 2. 
• Staff will contact the subject’s parent / guardian by telephone at 6 months (+14 days) post-
vaccination to review the MA and identify the occurrence of any MAAEs as well as SAEs that 
may not have been reported. 
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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 and / or the subject’s parent / guardian information about the trial, answer any 
questions, obtain written informed consent and assent (as applicable) and give the subject’s 
parent / guardian a signed copy of the ICF and a signed copy of the assent form (as 
applicable). 
2) Check inclusion and exclusion criteria for eligibility (see Section 5.2.4 and Section 5.2.5, 
respectively). 
3) 
Collect relevant demographic information. 
4) 
Perform 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 subject identification number 
and randomization (see Section 6.5 for instructions). 
8) 
Obtain the first blood sample (5 milliliter [mL]) (see Section 7 for detailed instructions 
regarding the handling of blood samples). If attempts to obtain the first blood draw are 
unsuccessful (no more than 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 muscle. 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 = MENVEO®  
10) Observe the subject for 30 minutes, and record any AE in the source document. 
11) Give the subject’s parent / guardian a diary card, a thermometer, and a ruler, and go over the 
instructions for their use. 
12) Remind the subject’s parent / guardian to expect a telephone call 8 days after Visit 1 and to 
bring back the diary card when they return for Visit 2 at a specified date and time. 
13) Remind the subject’s parent / guardian to notify the site in case of an SAE. 
14) Complete the relevant CRF pages for this visit. 
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Telephone Call 1 (D08 [+2 days] after Visit 1) 
Note: If D08 falls on a weekend or a holiday, the telephone call may be made on the following 
business day. If the subject’s parent / guardian 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’s parent / guardian to do the following: 
• 
Complete the D0 to D07 pages of the diary card.  
• 
Complete the remaining pages of the diary card, and bring them to Visit 2. 
• 
Notify the site in case of an SAE. 
Visit 2 (D30 [+14 days] after Visit 1): Collection of Safety Information and Blood Sample 
1) 
Review the pages of the diary card with the subject’s parent / guardian, 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 for detailed instructions regarding the 
handling of blood samples). 
4) 
Give the subject’s parent / guardian an MA. 
5) 
Complete the termination record of the CRF. 
6) 
If the subject’s parent / guardian does not return for Visit 2, and the diary card is not received 
at the site, site personnel will contact the subject’s parent / guardian by telephone. During the 
telephone call, the subject’s parent / guardian will be reminded to return the diary card to the 
study site. Telephone calls will be documented on the Telephone / Interview Record. If the 
study personnel are unable to contact the subject’s parent / guardian with 3 attempts, the 
study personnel will follow instructions given in Section 5.2.10. 
Safety Follow-up Telephone Call 2 (D180 [+14 days] after Visit 1): Collection of SAEs and 
MAAEs 
Review the MA and ask the subject’s parent / guardian if the subject 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. 
• 
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 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 (first visit, first subject) to LCLS (last contact, last subject): 
17 February 2017 to 10 October 2017. 
Planned inclusion period - FVFS to FVLS (first visit, last subject): 17 February 2017 to 
30 March 2017 
Planned primary vaccination period: 17 February 2017 – 30 March 2017 
Planned end of trial (LCLS): 10 October 2017 
Planned date of preliminary clinical study report: July 2018 
Planned date of final clinical study report: September 2018 
The safety follow-up Telephone Call 2 (6 months [+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. 
 
 
 
 
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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 the parents / 
guardians of an appropriate pool of potential subjects and invite them to participate in the study. 
The site will ensure that any advertisements used to recruit subjects (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 parent who brings a child to the trial site for a routine visit may be invited to enroll 
the subject 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 or a subject’s parent or guardian voluntarily 
confirms his or her willingness to participate / allow his or her child 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 this study, each subject as required by local regulations will sign a separate assent form. This 
form is to be used in addition to, not in place of, the ICF that is signed by the subject’s parent / 
guardian. 
In accordance with GCP, prior to signing and dating the consent form, the subject or parent / 
guardian 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. Prior to signing the assent form, children as required by local regulations must 
also be informed by appropriate study personnel regarding aspects of the trial that are relevant to 
making the decision to participate and have sufficient time and opportunity to ask any questions. 
A subject whose parent / guardian cannot read or write will not be included in the trial. A subject 
who is required to sign an assent form and cannot read or write 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 or subject’s parent’s / 
guardian’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. 
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Informed consent forms will be provided in duplicate, or a photocopy of the signed consent will 
be made. The original will be kept by the Investigator, and the copy will be kept by the subject’s 
parent / guardian. The assent forms will also be provided in duplicate, or a photocopy of the 
signed assent form will be made. The original will be kept by the Investigator, and the copy will 
be kept by the subject or subject’s parent / guardian. 
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 2 to 9 years on the day of inclusiona 
2) 
Assent form has been signed and dated by the subject (as required by local regulations) and 
informed consent form (ICF) has been signed and dated by the parent(s) or guardian 
3) 
Subject and parent / guardian are able to attend all scheduled visits and to comply with all 
trial procedures. 
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 and not using an effective 
method of contraception or abstinence from at least 4 weeks prior to vaccination until at least 
4 weeks after vaccination. To be considered of non-childbearing potential, a female must be 
pre-menarche.b 
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 the study investigational vaccines. This exception 
includes monovalent, multivalent, live, and attenuated influenza vaccines 
                                                 
a  “2 to 9 years” means from the day of the 2nd birthday to the day before the 10th birthday 
b  Pre-menarche females will declare by themselves that they have not yet started menstruation. If a young female 
subject reaches menarche during the study, then she is to be considered as a woman of childbearing potential from 
that time forward 
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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 serogroup containing 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 traveling to countries with high endemic or epidemic disease) 
9) 
Known systemic hypersensitivity to any of the vaccine components, or history of a life-
threatening reaction to the vaccines used in the trial or to a vaccine containing any of the 
same substancesa 
10) Verbal report of thrombocytopenia, contraindicating intramuscular vaccination by the 
Investigator’s judgment 
11) Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, 
contraindicating intramuscular vaccination in the Investigator’s opinion 
12) Personal history of Guillain-Barré syndrome (GBS) 
13) Personal history of an Arthus-like reaction after vaccination with a tetanus toxoid-containing 
vaccine  
14) Chronic illness that, in the opinion of the Investigator, is at a stage where it might interfere 
with trial conduct or completionb 
15) Moderate or severe acute illness/infection (according to Investigator’s 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 
16) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw 
17) Identified as a 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 parent’s / guardian’s consent to inform him / her of the subject’s participation 
                                                 
a  The components of the MenACYW conjugate vaccine are listed in Section 6.1.1 and in the Investigator’s 
Brochure. The components of the MENVEO® vaccine are listed in Section 6.1.2.1 
b  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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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. 
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 prior to the second 
blood draw, the Investigator will postpone that blood draw until it has been 3 days (72hrs) 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 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 
Parents / guardians will be informed that they have the right to withdraw their child 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 permission of the subject’s parent / guardian  
• 
At the request of the subject or subject’s parent / guardian (dropout) 
 
 
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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 
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. 
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. 
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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 
Pregnancy is an exclusion criterion for enrollment in this study, but a subject could potentially 
become pregnant during her participation. In case of pregnancy and if at least one 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). 
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). 
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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 
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 IEC / 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 IEC / IRB approval; however, the IEC / 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 IEC / IRB approval has already been given, are not initiated without IEC / IRB review 
and approval, except to eliminate apparent immediate hazards to subjects. 
5.5 
Interruption of the 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 mL 
Route: 
 
IM 
Batch number: 
To be determined 
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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 micrograms (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 vials (0.5 mL). 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), and extraneous particulate matter and / or discoloration, 
whenever solution and container permit. If any of these conditions exists, the vaccine must not be 
administered. A replacement dose is to be used, and the event is to be reported to the Sponsor. 
The rubber stopper should not be removed from any of the vaccine vials. 
The site of IM injection should be prepared with a suitable antiseptic prior to administration of 
one dose (0.5 mL) of MenACYW conjugate vaccine in the deltoid muscle of the arm. After 
vaccine administration, 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 
MENVEO®: Meningococcal (Groups A, C, Y, and W-135) Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine (Novartis Vaccines and Diagnostics S.r.1., Sovicille, Italy) 
Form: 
Lyophilized powder and liquid components are combined to produce a 
 
solution for intramuscular injection 
Dose: 
0.5 mL 
Route: 
IM 
Batch number: 
To be determined (control product will be supplied by the Sponsor) 
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6.1.2.1 
Composition 
Each 0.5 mL dose of vaccine contains the following active ingredients: 
MenA oligosaccharide ............................................................................................... 10 µg 
MenC oligosaccharide ................................................................................................. 5 µg 
MenY oligosaccharide ................................................................................................. 5 µg 
MenW-135 oligosaccharide ......................................................................................... 5 µg 
CRM197 protein carrier ........................................................................................... 32.7 to 64.1 µg 
Other ingredients per 0.5 mL dose: residual formaldehyde ≤ 0.30 µg 
6.1.2.2 
Preparation and Administration 
The MENVEO® is supplied in 2 vials, a lyophilized MenA conjugate vaccine component to be 
reconstituted with the accompanying MenCYW-135 liquid conjugate component. A single dose 
after reconstitution is 0.5 mL. 
See the MENVEO® package insert (35).The procedures for administering the control product are 
the same as those described for the trial product in Section 6.1.1.2. 
6.1.2.3 
Dose Selection and Timing 
All subjects in Group 2 will receive 1 dose of MENVEO® on D0. 
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. The information on the label and packaging will include: 
• Study code 
• Product name 
• Pharmaceutical form 
• Dosage 
• Storage conditions 
• Name of manufacturer 
• The statement: “Caution: New Drug – Limited by Federal Law to Investigational 
Use” 
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Commercial lots of MENVEO® (supplied in 2 vials that must be combined prior to administration 
to produce a single dose) will be supplied by the Sponsor, with the manufacturer’s labeling and 
packaging. 
6.3.2 
Product Shipment, Storage, and Accountability 
6.3.2.1 
Product Shipment 
The Clinical Logistics Coordinator or designee will contact the Investigator or a designee 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 
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 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 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. 
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6.3.3 
Replacement Doses 
If a replacement dose is required (e.g., because the vial broke or particulate matter was observed in 
the vial), 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 either disposed of or 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 
If the Sponsor makes a decision to launch a retrieval procedure, the Investigator(s) will be 
informed of what needs to be done. 
6.4 
Blinding and Code-breaking Procedures 
This trial is a modified double-blind trial, which means that the subject, the subject’s parent / 
guardian, the Investigator, and other study personnel 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 system 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 
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. 
                                                 
a  according to local regulations 
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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 2- to 9-year-old subject (who signs an assent form, if ≥ 7 years old), whose parent / guardian 
signs the ICF, and who meets the inclusion / exclusion criteria will be randomly assigned to 1 of 
2 trial treatment groups (Group 1 and Group 2) in a 1:1 ratio, stratified according to age such that 
each group will have approximately 500 children: 250 children 2 to 5 years old and 250 children 6 
to 9 years old. 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 group assignment and have the site staff confirm it. The full detailed procedures 
for group allocation are described in the Operating Guidelines. If the subject is not eligible to 
participate in the 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 a “-”). For example, Subject 001-
00001 is the first subject enrolled in center number 1. 
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. 
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 (see list under Categories 1, 2, and 3 below) will be collected in the CRF 
from the day of vaccination to the end of the solicited and unsolicited follow-up period (e.g., 
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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 3 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 
• 
Category 3: Oral or injectable antibiotics, which may interfere with bioassays used for 
antibody testing when taken before a blood draw. 
• 
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 Visits 1 and 2. See 
the Table of Study Procedures and Section 5.1.3 for details of the sampling schedule. 
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7.1 
Sample Collection 
At Visits 1 and 2, 5 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 
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. 
Following the blood draw, the sample 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. 
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. 
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7.4 
Future Use of Stored Serum Samples for Research 
Any unused part of the serum samples will be securely stored at the Sanofi Pasteur serology 
laboratory (GCI) for at least 5 years after the last license approval in the relevant market areas has 
been obtained for the vaccine being tested. 
The subjects’ parents / guardians 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 
Sanofi Pasteur will supply the trial sites with protocols, ICFs, CRFs, SAE reporting forms, 
pregnancy reporting forms, diary cards, memory aids, 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, digital 
thermometers, and pregnancy testing supplies.  
The means for performing Electronic Data Capture (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. 
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9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Immunogenicity 
9.1.1.1 
Immunogenicity Endpoint 
The primary endpoint for the evaluation of immunogenicity is: 
• 
Vaccine seroresponse against meningococcal serogroups A, C, Y, and W measured by serum 
bactericidal assays using human complement (hSBA) assessed at baseline (D0, before 
vaccination) and 30 days (+14 days) after vaccination. 
9.1.1.2 
Immunogenicity Assessment Method 
 
 
 
 
 
 
 
 
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. 
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9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Immunogenicity 
9.2.1.1 
Immunogenicity Endpoints 
The secondary endpoints for immunogenicity are: 
• 
GMTs against meningococcal serogroups A, C, Y, and W measured by hSBA before and 
30 days (+14 days) after vaccination with MenACYW conjugate vaccine or MENVEO® 
• 
Vaccine seroresponse against meningococcal serogroups A, C, Y, and W measured by hSBA 
before and 30 days (+14 days) after vaccination with MenACYW conjugate vaccine or 
MENVEO® 
9.2.1.2 
Immunogenicity Assessment Method 
The immunogenicity hSBA assessment method for the secondary endpoints 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 
The observational endpoints for immunogenicity are: 
1) Antibody titers against meningococcal serogroups A, C,Y, and W measured by hSBA before 
and 30 days after vaccination with MenACYW conjugate vaccine or MENVEO® 
2) Antibody titers against meningococcal serogroups A, C, Y, and W measured by rSBA before 
and 30 days after vaccination with MenACYW conjugate vaccine or MENVEO® in a subset 
of subjects 
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9.3.1.2 
Immunogenicity Assessment Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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-threateninga 
• 
Requires inpatient hospitalization or prolongation of existing hospitalizationb 
• 
Results in persistent or significant disability / incapacityc 
• 
Is a congenital anomaly / birth defect 
• 
Is an important medical eventd 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse reactions (AR). 
                                                 
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  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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(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 
Examples of solicited reactions include injection site pain between D0 and D07 post-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 D07 is a solicited reaction (i.e., prelisted in the CRF), then a headache 
starting on D07 is a solicited reaction, whereas headache starting on D08 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 
associated with the vaccination site, e.g., erythema that is localized but that is not at the injection 
site. 
                                                 
a  All injection site AEs are considered to be related to vaccination and are therefore all injection site reactions. 
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Medically-Attended Adverse Event (MAAE) 
An MAAE is defined, for the purpose of this study, as a new onset of a condition that prompts the 
subject or subject’s parent/guardian to seek unplanned medical advice at a physician’s office or 
Emergency Department. This definition excludes pre-planned medical office visits for routine 
pediatric 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 of 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 and electronic case report form [CRF]) injection site reactions occurring up to 
7 days after vaccination. 
• 
Occurrence, time of 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 and CRF) systemic reactions occurring up to 7 days after vaccination. 
• 
Occurrence, nature (MedDRA preferred term), time of 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 up to Visit 2 after vaccination. 
• 
Occurrence, nature (MedDRA preferred term), time of 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 of 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 
At Visit 2, the Investigator or a delegate will ask the subject’s parent / guardian about any 
solicited reactions and unsolicited AEs recorded in the diary card, as well as about any other AEs 
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that may have occurred since 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 07 After Vaccination) 
After vaccination, subjects’ parents / guardians will be provided with a safety diary card, 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 diary card 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 parent or guardian to treat any solicited reactions 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’ parents / guardians will be contacted by telephone 8 days after vaccination to remind 
them to record all safety information in the diary card. 
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 present, respectively, the injection site reactions and systemic reactions 
that are prelisted in the diary cards 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  
Diary card 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: Easily tolerated 
Grade 2: Sufficiently discomforting to 
interfere with normal behavior or activities 
Grade 3: Incapacitating, unable to perform 
usual activities 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
Grade 1: > 0 to < 25 mm 
Grade 2: ≥ 25 to < 50 mm 
Grade 3: ≥ 50 mm 
*For the subjective reaction of pain, subjects or parents / guardians 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 just the size of the reaction, and the classification as Grade 1, 2, or 3 will be assigned at the time of the statistical analysis. 
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Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales 
CRF term 
(MedDRA LLT) 
Fever 
Headache 
Malaise 
Myalgia 
Diary card 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 / guardians 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: 
Parents / guardians 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 diary card, and the highest 
temperature will be recorded by the site in the CRF. The preferred route for this trial is axillary. 
Pre-vaccination temperature is also systematically collected by the investigator on 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, parents / guardians 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 diary card 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 parent or guardian 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) 
                                                 
a The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the trial will be 
considered as ongoing at the end of the trial. 
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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) 
• 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 inclusion until 
180 days after the last vaccination. The collection of SAEs begins at the time of first dose and 
ends 180 days (+14 days) post last dose. 
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. 
In case a subject experiences convulsion / seizure episode associated or not with fever, the 
assessment will be performed according to the “Guideline for definition and collection of cases of 
febrile convulsion” (37) and this event will be considered an SAE. 
See Section 10 for further details on SAE reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 memory aid. 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 
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 
                                                 
a  ICH Guidelines, Clinical Safety Data Management E2A 
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necessary information to allow the Sponsor to conduct a detailed analysis of the safety of the 
investigational product(s). It is the responsibility of the Investigator to request all necessary 
documentation (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 Event (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 e-mail): 
• 
By fax, to the following number:
 
• 
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 
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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. 
(ICH Guidelines, Clinical Safety Data Management E2A) 
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 Investigators. 
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 
, 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. 
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11 Data Collection and Management 
11.1 Data Collection and CRF Completion 
Individual safety diary cards, 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. These diary cards will include prelisted terms and intensity scales 
(see Table 9.1 and Table 9.2) as well as areas for free text to capture additional safety information 
or other relevant details. Parents or guardians 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 parents / guardians 
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 (or the subject’s parent / guardian) 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 memory aid 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 parents / 
guardians 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). 
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. 
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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. 
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. 
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 blind 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 SMT. For all 
periodic safety reviews, blinded safety data will be provided to the Sponsor’s SMT. 
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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 daysa after the administration of MenACYW conjugate vaccine or MENVEO®, the 
percentages of subjects who achieve an hSBA vaccine seroresponseb 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. 
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  
(44). 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 
No hypotheses will be tested. Descriptive statistics will be presented. 
12.1.2.1 Secondary Objective 1 
Thirty daysa after the administration of MenACYW conjugate vaccine or MENVEO®, the hSBA 
geometric mean titer ratio (GMTR) between Group 1 and Group 2 will be calculated and 95% CI 
will be provided. 
                                                 
a  D30 (+14 days) 
b  The 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. 
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12.1.2.2 Secondary Objective 2 
Thirty daysa after the administration of MenACYW conjugate vaccine or MENVEO®, the hSBA 
GMTR between Group 1a and Group 2a, and between Group 1b and Group 2b will be calculated 
and 95% CI will be provided, respectively. 
12.1.2.3 Secondary Objective 3 
Thirty daysa after the administration of MenACYW conjugate vaccine or MENVEO®, the 
difference of hSBA vaccine seroresponseb rates between Group 1a and Group 2a, and between 
Group 1b and Group 2b will be calculated and 95% CI will be provided, respectively. 
12.1.3 Statistical Methods for Observational Objectives 
No hypotheses will be tested. Descriptive statistics will be presented. 
12.1.3.1 Immunogenicity 
Descriptive statistics will be provided for the antibody titers against meningococcal serogroups 
contained in MenACYW conjugate vaccine and MENVEO®. 
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. 
Reverse cumulative distribution curve (RCDC) figures will be provided for the antibody titers 
against meningococcal serogroups contained in MenACYW conjugate vaccine and MENVEO® 
treatment groups. 
Descriptive analyses on A, C, Y, and W serogroups on D0 and D30 (+14 days) using hSBA will 
include but not be limited to: 
• 
GMT and 95% CI in Group 1, Group 2, Group 1a, Group 1b, Group 2a, and Group 2b 
• 
Titer distribution and RCDC 
• 
Percentage of subjects with titer ≥ 1:4 and ≥ 1:8 and 95% CI in Group 1, Group 2, 
Group 1a, Group 1b, Group 2a, and Group 2b 
• 
Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to post-vaccination, 
and 95% CI in Group 1, Group 2, Group 1a, Group 1b, Group 2a, and Group 2b 
                                                 
a  D30 (+14 days) 
b  The 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. 
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• 
Percentage of subjects with hSBA vaccine seroresponsea and 95% CI in Group 1, Group 2, 
Group 1a, Group 1b, Group 2a, and Group 2b 
Descriptive analyses on A, C, Y, and W serogroups on D0 and D30 (+14 days) using rSBA will 
include but not be limited to: 
• 
GMT and 95% CI in a subset of 200 subjects in Group 1 and Group 2, and in a subset of 
100 subjects in Group 1a, Group 1b, Group 2a, and Group 2b 
• 
Titer distribution and RCDCs 
• 
Percentage of subjects with titer ≥ 1:8 and ≥ 1:128 and 95% CI in a subset of 200 subjects 
in Group 1 and Group 2, and in a subset of 100 subjects in Group 1a, Group 1b, Group 2a, 
and Group 2b 
• 
Percentage of subjects with titer ≥ 4-fold rise from pre-vaccination to post-vaccination and 
95% CI in a subset of 200 subjects in Group 1 and Group 2, and in a subset of 100 subjects 
in Group 1a, Group 1b, Group 2a, and Group 2b 
• 
Percentage of subjects with rSBA vaccine seroresponseb and 95% CI in a subset of 
200 subjects in Group 1 and Group 2, and in a subset of 100 subjects in Group 1a, 
Group 1b, Group 2a, and Group 2b 
12.1.3.2 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 Group 1 and Group 2. 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. 
                                                 
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. 
• 
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. 
b  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 Analysis Sets 
Three analysis sets will be used: the Full Analysis Set (FAS), the Per-Protocol Analysis Set 
(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 one 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. 
12.2.2 Safety Analysis Set 
The Safety Analysis Set (SafAS) is defined as those subjects who have received study vaccinea 
and have any safety data available. All subjects will have their safety analyzed according to the 
vaccine they actually received. 
Safety data recorded for a vaccine received out of the protocol design will be excluded from the 
analysis (and listed separately). 
12.2.3 Per-Protocol Analysis Set 
The Per-Protocol Analysis Set (PPAS) is a subset of the FAS. The subjects presenting with at 
least one of the following relevant protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not receive vaccine  
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• Subject did not receive vaccine in the proper time window 
• Subject did not provide the post-dose serology sample in the proper time window or a post-
dose serology sample was not drawn. The time window will be defined as D30 to D44 
(D30 +14 days) 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. 
                                                 
a  For which safety data are scheduled to be collected 
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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. In the FAS, subjects will be 
analyzed by the vaccine group to which they were randomized. 
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 
Missing data will not be imputed. No test or search for outliers will be performed. 
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. 
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12.4 Interim / Preliminary Analysis 
Due to the possibility of delayed availability of the immunogenicity data generated using rSBA in 
a subset of subjects, and in order to not delay the analysis of safety data and available hSBA 
immunogenicity data, the analysis on rSBA immunogenicity data will be done separately when all 
rSBA testing has been completed. No statistical adjustment will be applied as there will be no 
repeat analysis of the same parameter and because the rSBA immunogenicity analysis is 
descriptive in nature. 
12.5 Determination of Sample Size and Power Calculation 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 good clinical practice (GCP) as well as with 
all local and / or national regulations and directives. 
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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 diary card, the study coordinator will obtain verbal clarification 
from the subject, enter the response into the “investigator’s comment” page of the diary card, 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 
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 
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 
                                                 
a  Unless the electronic medical records are managed by validated computerized systems that are compliant with US 
21 CFR Part 11, in which case they are acceptable on their own. 
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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 queries 
• 
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. 
• 
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 
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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 
A Clinical Trial Agreement 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. 
13.6 Stipends for Participation 
The subject’s parent / guardian may be provided with a stipend according to local practice to 
compensate for the time and travel required for study visits and procedures. 
13.7 Publication Policy 
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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