Immune Lot Consistency, Immunogenicity, and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine in Adolescents and Adults Aged 10 to 55 Years
Phase: PHASE3
Conditions: Meningitis, Meningococcal Meningitis, Meningococcal Infections
Sponsor: Sanofi Pasteur, a Sanofi Company

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Sanofi Pasteur 
MET43 
395 – MenACYW Conjugate Vaccine 
Confidential/Proprietary Information 
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Table of Contents 
List of Tables .................................................................................................................................... 7 
Synopsis ............................................................................................................................................ 8 
Table of Study Procedures ............................................................................................................ 19 
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 
1.3 
Potential Benefits and Risks ........................................................................................... 25 
1.3.1 
Potential Benefits to Subjects ....................................................................................... 25 
1.3.2 
Potential Risks to Subjects ........................................................................................... 26 
1.4 
Rationale for the Trial ..................................................................................................... 27 
2 
Trial Objectives ............................................................................................................... 28 
2.1 
Primary Objectives .......................................................................................................... 28 
2.2 
Secondary Objectives ...................................................................................................... 28 
2.3 
Observational Objectives ................................................................................................ 28 
3 
Investigators and Trial Organization ............................................................................ 29 
4 
Independent Ethics Committee / Institutional Review Board .................................... 29 
5 
Investigational Plan ......................................................................................................... 30 
5.1 
Description of the Overall Trial Design and Plan ........................................................... 30 
5.1.1 
Trial Design .................................................................................................................. 30 
5.1.2 
Justification of the Trial Design ................................................................................... 30 
5.1.3 
Trial Plan ...................................................................................................................... 31 
5.1.4 
Visit Procedures ............................................................................................................ 32 
5.1.5 
Planned Trial Calendar ................................................................................................. 34 
5.1.6 
Early Safety Data Review............................................................................................. 34 
5.2 
Enrollment and Retention of Trial Population ................................................................ 35 
5.2.1 
Recruitment Procedures ................................................................................................ 35 
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5.2.2 
Informed Consent Procedures ...................................................................................... 35 
5.2.3 
Screening Criteria ......................................................................................................... 36 
5.2.4 
Inclusion Criteria .......................................................................................................... 36 
5.2.5 
Exclusion Criteria ......................................................................................................... 36 
5.2.6 
Medical History ............................................................................................................ 38 
5.2.7 
Contraindications for Subsequent Vaccinations ........................................................... 38 
5.2.8 
Contraindications for Visit 2 Blood Samples ............................................................... 38 
5.2.9 
Conditions for Withdrawal ........................................................................................... 38 
5.2.10 
Lost to Follow-up Procedures....................................................................................... 39 
5.2.11 
Classification of Subjects Who Discontinue the Trial.................................................. 39 
5.2.12 
Follow-up of Discontinuations ..................................................................................... 40 
5.2.13 
Follow-up and Reporting of Pregnancies ..................................................................... 40 
5.3 
Safety Emergency Call ................................................................................................... 40 
5.4 
Modification of the Trial and Protocol ........................................................................... 41 
5.5 
Interruption of the Trial .................................................................................................. 41 
6 
Vaccines Administered ................................................................................................... 41 
6.1 
Identity of the Investigational Products .......................................................................... 41 
6.1.1 
Identity of Trial Product ............................................................................................... 41 
6.1.1.1 
Composition ............................................................................................................... 42 
6.1.1.2 
Preparation and Administration ................................................................................. 42 
6.1.1.3 
Dose Selection and Timing ........................................................................................ 42 
6.1.2 
Identity of Control Product ........................................................................................... 42 
6.1.2.1 
Composition ............................................................................................................... 43 
6.1.2.2 
Preparation and Administration ................................................................................. 43 
6.1.2.3 
Dose Selection and Timing ........................................................................................ 43 
6.2 
Identity of Other Products ............................................................................................... 43 
6.3 
Product Logistics ............................................................................................................ 43 
6.3.1 
Labeling and Packaging ............................................................................................... 43 
6.3.2 
Product Shipment, Storage, and Accountability ........................................................... 44 
6.3.2.1 
Product Shipment ....................................................................................................... 44 
6.3.2.2 
Product Storage .......................................................................................................... 44 
6.3.2.3 
Product Accountability ............................................................................................... 44 
6.3.3 
Replacement Doses....................................................................................................... 44 
6.3.4 
Disposal of Unused Products ........................................................................................ 45 
6.3.5 
Recall of Products ......................................................................................................... 45 
6.4 
Blinding and Code-breaking Procedures ........................................................................ 45 
6.5 
Randomization and Allocation Procedures ..................................................................... 45 
6.6 
Treatment Compliance .................................................................................................... 46 
6.7 
Concomitant Medications and Other Therapies ............................................................. 46 
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7 
Management of Samples ................................................................................................. 47 
7.1 
Sample Collection ........................................................................................................... 47 
7.2 
Sample Preparation ......................................................................................................... 48 
7.3 
Sample Storage and Shipment ........................................................................................ 48 
7.4 
Future Use of Stored Serum Samples for Research ........................................................ 48 
8 
Clinical Supplies .............................................................................................................. 49 
9 
Endpoints and Assessment Methods ............................................................................. 49 
9.1 
Primary Endpoints and Assessment Methods ................................................................. 49 
9.1.1 
Immunogenicity ............................................................................................................ 49 
9.1.1.1 
Immunogenicity Endpoints ........................................................................................ 49 
9.1.1.2 
Immunogenicity Assessment Method ........................................................................ 50 
9.1.2 
Safety ............................................................................................................................ 50 
9.1.3 
Efficacy ......................................................................................................................... 50 
9.2 
Secondary Endpoints and Assessment Methods ............................................................. 50 
9.2.1 
Immunogenicity ............................................................................................................ 50 
9.2.1.1 
Immunogenicity Endpoints ........................................................................................ 50 
9.2.1.2 
Immunogenicity Assessment Methods ...................................................................... 51 
9.2.2 
Safety ............................................................................................................................ 51 
9.2.3 
Efficacy ......................................................................................................................... 51 
9.3 
Observational Endpoints and Assessment Methods ....................................................... 51 
9.3.1 
Immunogenicity ............................................................................................................ 51 
9.3.1.1 
Immunogenicity Endpoints ........................................................................................ 51 
9.3.1.2 
Immunogenicity Assessment Method ........................................................................ 51 
9.3.2 
Safety ............................................................................................................................ 52 
9.3.2.1 
Safety Definitions ....................................................................................................... 52 
9.3.2.2 
Safety Endpoints ........................................................................................................ 55 
9.3.2.3 
Safety Assessment Methods ....................................................................................... 55 
9.3.2.3.1 
Immediate Post-vaccination Surveillance Period .................................................... 55 
9.3.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 07 After 
Vaccination) ............................................................................................................. 56 
9.3.2.3.3 
Unsolicited Non-serious Adverse Events From Day 0 to Day 30 After 
Vaccination .............................................................................................................. 59 
9.3.2.3.4 
Serious Adverse Events ........................................................................................... 60 
 
 
9.3.2.3.6 
Medically-Attended Adverse Events ....................................................................... 60 
9.3.2.3.7 
Assessment of Causality .......................................................................................... 60 
9.3.3 
Efficacy ......................................................................................................................... 61 
10 
Reporting of Serious Adverse Events ............................................................................ 61 
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10.1 
Initial Reporting by the Investigator ............................................................................... 61 
10.2 
Follow-up Reporting by the Investigator ........................................................................ 62 
10.3 
Reporting of SAEs Occurring After a Subject Has Completed the Study ...................... 62 
10.4 
Assessment of Causality ................................................................................................. 62 
10.5 
Reporting SAEs to Health Authorities and IECs / IRBs................................................. 63 
11 
Data Collection and Management ................................................................................. 63 
11.1 
Data Collection and CRF Completion ............................................................................ 63 
11.2 
Data Management ........................................................................................................... 64 
11.3 
Data Review .................................................................................................................... 65 
12 
Statistical Methods and Determination of Sample Size ............................................... 65 
12.1 
Statistical Methods .......................................................................................................... 65 
12.1.1 
Hypotheses and Statistical Methods for Primary Objectives ....................................... 65 
12.1.1.1 
Primary Objective 1 ................................................................................................... 65 
12.1.1.2 
Primary Objective 2 ................................................................................................... 66 
12.1.2 
Hypotheses and Statistical Methods for Secondary Objectives ................................... 67 
12.1.2.1 
Secondary Objective 1 ............................................................................................... 67 
12.1.2.2 
Secondary Objective 2 ............................................................................................... 67 
12.1.2.3 
Secondary Objective 3 ............................................................................................... 68 
12.1.2.4 
Secondary Objective 4 ............................................................................................... 68 
12.1.3 
Statistical Methods for Observational Objectives ........................................................ 68 
12.1.3.1 
Immunogenicity ......................................................................................................... 68 
12.1.3.2 
Safety .......................................................................................................................... 69 
12.2 
Analysis Sets ................................................................................................................... 69 
12.2.1 
Full Analysis Set ........................................................................................................... 70 
12.2.2 
Safety Analysis Set ....................................................................................................... 70 
12.2.3 
Per-Protocol Analysis Set ............................................................................................. 70 
12.2.4 
Populations Used in Analyses ...................................................................................... 70 
12.3 
Handling of Missing Data and Outliers .......................................................................... 71 
12.3.1 
Safety ............................................................................................................................ 71 
12.3.2 
Immunogenicity ............................................................................................................ 71 
12.3.3 
Efficacy ......................................................................................................................... 71 
12.4 
Interim / Preliminary Analysis ........................................................................................ 71 
12.5 
Determination of Sample Size and Power Calculation ................................................... 71 
13 
Ethical and Legal Issues and Investigator / Sponsor Responsibilities........................ 72 
13.1 
Ethical Conduct of the Trial / Good Clinical Practice .................................................... 72 
13.2 
Source Data and Source Documents ............................................................................... 73 
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13.3 
Confidentiality of Data and Access to Subject Records ................................................. 73 
13.4 
Monitoring, Auditing, and Archiving ............................................................................. 73 
13.4.1 
Monitoring .................................................................................................................... 73 
13.4.2 
Audits and Inspections ................................................................................................. 74 
13.4.3 
Archiving ...................................................................................................................... 74 
13.5 
Financial Contract and Insurance Coverage ................................................................... 75 
13.6 
Stipends for Participation ................................................................................................ 75 
13.7 
Publication Policy ........................................................................................................... 75 
14 
References List ................................................................................................................. 76 
15 
Signature Pages ............................................................................................................... 79 
 
 
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List of Tables 
Table 9.1: Solicited injection site reactions: terminology, definitions, and intensity scales ...........57 
Table 9.2: Solicited systemic reactions: terminology, definitions, and intensity scales .................58 
Table 12.1: Power of the study based on Primary Objective 1 of equivalence ...............................72 
Table 12.2: Power of the study based on Primary Objective 2 of non-inferiority ..........................72 
 
 
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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 trial subjects or the 
subjects’ parents / guardian and should assure appropriate therapy and 
follow-up. 
Primary Objectives: 
1) 
To demonstrate the immune lot consistency of the antibody responses 
to meningococcal serogroups A, C, Y, and W following the 
administration of a single dose of MenACYW conjugate vaccine with 
respect to serum bactericidal assay using human complement (hSBA) 
geometric mean titers (GMTs) 
2) 
To demonstrate the non-inferiority of the antibody responses to 
meningococcal serogroups A, C, Y, and W following the 
administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the 
administration of a single dose of Menactra® 
Primary Endpoints: 
1) 
Geometric mean titer ratios (GMTRs) of antibodies against 
meningococcal serogroups A, C, Y, and W measured by hSBA 30 days 
(+14 days) after vaccination between lots for immune lot consistency 
2) 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W 
measured by hSBA assessed at baseline (D0, before vaccination) and 
30 days (+14 days) after vaccination for immune non-inferiority 
between MenACYW conjugate vaccine and Menactra® (Groups 1 - 3 
pooled versus Group 4) 
Secondary Objectives: 
1) 
To demonstrate the non-inferiority of the antibody responses to 
meningococcal serogroups A, C, Y, and W following the 
administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the 
administration of a single dose of Menactra® in the adult population 
(18 to 55 years old) 
2) 
To demonstrate the non-inferiority of the antibody responses to 
meningococcal serogroups A, C, Y, and W following the 
administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the 
administration of a single dose of Menactra® in the adolescent 
population (10 to 17 years old) 
3) 
To compare the hSBA vaccine seroresponses of meningococcal 
serogroups A, C, Y, and W for each of 3 lots of MenACYW conjugate 
vaccine 30 days (+14 days) after vaccination 
 
4) 
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 Menactra® 
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Secondary Endpoints: 
1) 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W 
measured by hSBA assessed at baseline (D0, before vaccination) and 
30 days (+14 days) after vaccination for immune non-inferiority 
between MenACYW conjugate vaccine and Menactra® adult study 
participants (Groups 1b, 2b, and 3b pooled versus Group 4b) 
2) 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W 
measured by hSBA assessed at baseline (D0, before vaccination) and 
30 days (+14 days) after vaccination for immune non-inferiority 
between MenACYW conjugate vaccine and Menactra® adolescent 
study participants (Groups 1a, 2a, and 3a pooled versus Group 4a) 
3) 
Vaccine seroresponse of meningococcal serogroups A, C, Y, and W 
measured by hSBA 30 days (+14 days) following the administration of 
MenACYW conjugate vaccine (Groups 1, 2, and 3) 
 
4) 
GMTRs of antibodies against meningococcal serogroups A, C, Y, and 
W measured by hSBA for the groups that received MenACYW 
conjugate vaccine (Groups 1 - 3 pooled) and Menactra® (Group 4) 
Observational Objectives: 
Immunogenicity 
To describe the antibody responses to the meningococcal serogroups A, C, 
Y, and W before and 30 days (+14 days) after vaccination with MenACYW 
conjugate vaccine or Menactra® 
Safety 
To describe the safety profile of MenACYW conjugate vaccine and that of 
the licensed Menactra® 
Observational Endpoints: 
Immunogenicity  
Antibody titers against meningococcal serogroups A, C, Y, and W measured 
by hSBA and serum bactericidal assay using baby rabbit complement 
(rSBA) assessed at baseline (D0, before vaccination) and 30 days (+14 days) 
after vaccination in a subset of subjects for all groups 
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. 
 
 
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• 
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.  
Planned Sample Size: 
A total of 3300 subjects are planned to be enrolled: 
• 
Group 1: MenACYW conjugate vaccine (Lot 1): 
planned = 900 (evaluable = 810) 
• 
Group 1a: 400 subjects 10 to 17 years of age 
• 
Group 1b: 500 subjects 18 to 55 years of age 
• 
Group 2: MenACYW conjugate vaccine (Lot 2): 
planned = 900 (evaluable = 810) 
• 
Group 2a: 400 subjects 10 to 17 years of age 
• 
Group 2b: 500 subjects 18 to 55 years of age 
• 
Group 3: MenACYW conjugate vaccine (Lot 3): 
planned = 900 (evaluable = 810) 
• 
Group 3a: 400 subjects 10 to 17 years of age 
• 
Group 3b: 500 subjects 18 to 55 years of age 
• 
Group 4: Menactra®: 
planned = 600 (evaluable = 540) 
• 
Group 4a: 300 subjects 10 to 17 years of age 
• 
Group 4b: 300 subjects 18 to 55 years of age 
The planned number of subjects is based on a 10% dropout rate allowing 
around 88% 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 MenACYW conjugate vaccine 
from 1 of the 3 lots (Lot 1, Lot 2, or Lot 3) or Menactra® on 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). 
A, C, Y, and W antigens of MenACYW conjugate vaccine (Groups 1, 2, and 
3) and Menactra® (Group 4) will be measured by hSBA for all subjects, and 
by rSBA for a subset of 100 subjects per treatment group. 
 
Collection of safety data 
• 
All subjects will be observed for 30 minutes after vaccination, and any 
unsolicited systemic AEs occurring during that time will be recorded as 
immediate unsolicited systemic AEs in the CRF. 
• 
The subject or 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 or the subject’s parent / guardian will record information 
about any possible SAEs and MAAEs in a memory aid (MA) from 
Visit 2 until the 6-month (+14 days) telephone call. 
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• 
In addition, the subject or subject’s parent / guardian will be asked to 
notify the site immediately about any potential SAEs at any time during 
the trial. 
 
• 
Staff will contact the subject or 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 and/or the 
subject’s parent / guardian at Visit 2. 
 
• 
Staff will contact the subject or the subject’s parent / guardian by 
telephone at 6 months (+14 days) after vaccination to review the MA 
and identify the occurrence of any MAAEs, as well as SAEs that may 
have not 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 for subjects in all groups. 
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: 
3 Lots (UD18368, UD18364, UD18365) 
Control Product: 
Menactra®: Meningococcal (Groups A, C, Y and W-135) Polysaccharide 
Diphtheria Toxoid Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, 
USA) 
 Form: 
Solution for injection 
 Composition: 
Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered 
isotonic sodium chloride solution to contain the following ingredients: 
Serogroup A ............................................................................................ 4 µg 
Serogroup C............................................................................................. 4 µg 
Serogroup Y ............................................................................................ 4 µg 
Serogroup W-135 .................................................................................... 4 µg 
Diphtheria toxoid protein carrier ................................... approximately 48 µg 
 Route: 
IM 
 Batch Number: 
U5462AB (provided by the Sponsor) 
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Inclusion Criteria: 
An individual must fulfill all of the following criteria in order to be eligible 
for trial enrollment: 
1) 
Aged 10 to 55 years on the day of inclusion 
2) 
Informed consent form has been signed and dated by the subject (aged 
18 to 55 years) or assent form has been signed and dated by the subject 
and informed consent form has been signed and dated by the parent(s) 
or guardian (for subjects aged 10 to < 18 years) 
3) 
Subject (≥ 18 years) or subject (10 to < 18 years) 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 (to be 
considered of non-childbearing potential, a female must be pre-
menarche or post-menopausal for at least 1 year, surgically sterile, or 
using an effective method of contraception or abstinence from at least 
4 weeks prior to vaccination until at least 4 weeks after vaccination) 
2) Participation in the 4 weeks preceding the trial vaccination or planned 
participation during the present trial period in another clinical trial 
investigating a vaccine, drug, medical device, or medical procedure  
3) Receipt of any vaccine in the 4 weeks (28 days) preceding the trial 
vaccination or planned receipt of any vaccine prior to Visit 2 except for 
influenza vaccination, which may be received at least 2 weeks before or 
after the study investigational vaccines. This exception includes 
monovalent pandemic influenza vaccines and multivalent influenza 
vaccines 
4) Previous vaccination against meningococcal disease with either the trial 
vaccine or another vaccine (i.e., mono- or polyvalent, polysaccharide, or 
conjugate meningococcal vaccine containing serogroups A, C, Y, or W; 
or meningococcal B vaccine) 
5) Receipt of immune globulins, blood or blood-derived products in the 
past 3 months 
6) Known or suspected congenital or acquired immunodeficiency; or 
receipt of immunosuppressive therapy, such as anti-cancer 
chemotherapy or radiation therapy, within the preceding 6 months; or 
long-term systemic corticosteroid therapy (prednisone or equivalent for 
more than 2 consecutive weeks within the past 3 months) 
7) History of meningococcal infection, confirmed either clinically, 
serologically, or microbiologically 
8) At high risk for meningococcal infection during the trial (specifically, 
but not limited to, subjects with persistent complement deficiency, with 
anatomic or functional asplenia, or subjects 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, as reported by the subject or the 
subject’s parent / guardian, contraindicating intramuscular vaccination 
in the Investigator’s opinion 
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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 within 10 years of the proposed study 
vaccination 
14) Deprived of freedom by an administrative or court order, or in an 
emergency setting, or hospitalized involuntarily 
15) Current alcohol abuse or drug addiction  
16) Chronic illness that, in the opinion of the investigator, is at a stage 
where it might interfere with trial conduct or completion 
17) Moderate or severe acute illness/infection (according to investigator 
judgment) on the day of vaccination or febrile illness (temperature 
≥ 100.4°F). A prospective subject should not be included in the study 
until the condition has resolved or the febrile event has subsided 
18) Receipt of oral or injectable antibiotic therapy within 72 hours prior to 
the first blood draw 
19) Identified as an Investigator or employee of the Investigator or study 
center with direct involvement in the proposed study, or identified as an 
immediate family member (i.e., parent, spouse, natural or adopted child) 
of the Investigator or employee with direct involvement in the proposed 
study 
Statistical Methods: 
All immunogenicity analyses will be performed on the Per-Protocol 
Analysis Set (PPAS). Additional immunogenicity analyses will be 
performed for exploratory purposes on the Full Analysis Set (FAS) 
according to randomization group. All safety analyses will be performed on 
the Safety Analysis Set (SafAS). 
 
Primary Objective 1 
Equivalence of 3 MenACYW conjugate vaccine lots in terms of GMTs 
Thirty days after the administration of the MenACYW conjugate vaccine, 
GMTs of antibodies against meningococcal serogroups A, C, Y, and W in 
Groups 1, 2, and 3 are equivalent. 
 
Null hypothesis (H0): GMT(Gi) / GMT(Gj) ≤ 1/2 or GMT(Gi) / GMT(Gj) ≥ 2 for 
any i ≠ j  
Alternative hypothesis (H1): 1/2 < GMT(Gi) / GMT(Gj) < 2 for all i ≠ j 
GMT(Gi) and GMT(Gj) are the GMTs of antibodies against the meningococcal 
serogroups A, C, Y, and W for the ith and jth lots, respectively. Each of the 
antigens of A, C, Y, and W serogroups will be tested separately. If the 2-
sided 95% confidence interval (CI) of the ratio of the GMTs is > 1/2 and < 2 
for each antigen, the non-equivalence assumption will be rejected. 
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Primary Objective 2 
Non-inferiority of MenACYW conjugate vaccine compared to Menactra® in 
terms of hSBA vaccine seroresponse 
 
Thirty days after the administration of MenACYW conjugate vaccine or 
Menactra®, the percentages of subjects who achieve an hSBA vaccine 
seroresponse* for meningococcal serogroups A, C, Y, and W in Groups 1, 2, 
and 3 combined are non-inferior to the corresponding percentages in 
Group 4. 
 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
Alternative hypothesis (H1): p(G123) - p( G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA 
vaccine seroresponse in Groups 1 - 3 pooled and Group 4, respectively. 
Each of the serogroups A, C, Y, and W will be tested separately. If the lower 
limit of the 2-sided 95% CI of the difference between the 2 proportions is > 
-10%, the inferiority assumption will be rejected. 
 
Secondary Objective 1 
Non-inferiority of MenACYW conjugate vaccine compared to Menactra® in 
terms of hSBA vaccine seroresponse in the adult population (18 to 55 years 
old) 
Thirty days after the administration of MenACYW conjugate vaccine or 
Menactra®, the percentages of subjects who achieve an hSBA vaccine 
seroresponse* for meningococcal serogroups A, C, Y, and W in Groups 1b, 
2b, and 3b combined are non-inferior to the corresponding percentages in 
Group 4b. 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
Alternative hypothesis (H1): p(G123) - p(G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA 
vaccine seroresponse in Groups 1b, 2b, and 3b pooled and Group 4b, 
respectively. Each of the serogroups A, C, Y, and W will be tested 
separately. If the lower limit of the 2-sided 95% CI of the difference 
between the 2 proportions is > -10%, the inferiority assumption will be 
rejected. 
 
* hSBA vaccine seroresponse for serogroups A, C, Y, and W is defined as: 
• 
For a subject with a pre-vaccination titer < 1:8, the post-
vaccination titer must be ≥ 1:16. 
• 
For a subject with a pre-vaccination titer ≥ 1:8, the post-
vaccination titer must be at least 4-fold greater than the pre-
vaccination titer.  
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Secondary Objective 2 
Non-inferiority of MenACYW conjugate vaccine compared to Menactra® in 
terms of hSBA vaccine seroresponse in the adolescent population (10 to 
17 years old) 
Thirty days after the administration of MenACYW conjugate vaccine or 
Menactra®, the percentages of subjects who achieve an hSBA vaccine 
seroresponse* for meningococcal serogroups A, C, Y, and W in Groups 1a, 
2a, and 3a combined are non-inferior to the corresponding percentages in 
Group 4a 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
 
Alternative hypothesis (H1): p(G123) - p(G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA 
vaccine seroresponse in Groups 1a, 2a, and 3a pooled and Group 4a, 
respectively. Each of the serogroups A, C, Y, and W will be tested 
separately. If the lower limit of the 2-sided 95% CI of the difference 
between the 2 proportions is > -10%, the inferiority assumption will be 
rejected. 
 
Secondary Objective 3 
Comparison of 3 MenACYW conjugate vaccine lots in terms of hSBA 
vaccine seroresponse 
The difference in percentages of subjects who achieve an hSBA vaccine 
seroresponse* 30 days after the administration of MenACYW conjugate 
vaccine for meningococcal serogroups A, C, Y, and W in Groups 1, 2, and 3 
will be calculated for each comparison and 95% CI will be provided. 
* hSBA vaccine seroresponse for serogroups A, C, Y, and W is defined as:  
• 
For a subject with a pre-vaccination titer < 1:8, the post-
vaccination titer must be ≥ 1:16. 
• 
For a subject with a pre-vaccination titer ≥ 1:8, the post-
vaccination titer must be at least 4-fold greater than the pre-
vaccination titer. 
 
Secondary Objective 4 
Comparison of MenACYW conjugate vaccine to Menactra® in terms of 
hSBA GMTs 
The ratio of GMTs of meningococcal serogroups A, C, Y, and W between 
the MenACYW conjugate vaccine Groups 1- 3 pooled (Lots 1, 2, and 3 
combined) and the Menactra® Group 4 30 days after the administration of 
vaccine will be calculated and 95% CI will be provided. 
 
Observational Objectives 
Immunogenicity 
Descriptive statistics will be provided for the antibody titers against 
meningococcal serogroups contained in each lot of MenACYW conjugate 
vaccine and Menactra®.  
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  
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approximation assuming they are log-normally distributed. Reverse 
cumulative distribution curve (RCDC) figures will be provided for the 
antibody titers against meningococcal serogroups. 
 
In summary, descriptive analyses on A, C, Y, and W serogroups will include 
but not be limited to: 
• 
hSBA GMTs and 95% CI at each time point for each group 
• 
hSBA titer distribution and RCDC 
 
• 
Proportion of subjects with hSBA titer ≥ 1:4 and ≥ 1:8 and 95% CI 
at D0 and D30 for each group 
• 
Proportion of subjects with hSBA titer ≥ 4-fold rise from pre-
vaccination to post-vaccination, and 95% CI 
• 
rSBA GMTs and 95% CI at each time point in a subset of 
100 subjects in each group 
• 
rSBA titer distribution and RCDC 
• 
Proportion of subjects with rSBA titer ≥ 1:8 and ≥ 1:128 and 95% 
CI at D0 and D30 in a subset of 100 subjects in each group 
 
• 
Proportion of subjects with rSBA titer ≥ 4-fold rise from pre-
vaccination to post-vaccination and 95% CI 
• 
Vaccine seroresponse* against meningococcal serogroups A, C, Y, 
and W measured by rSBA and 95% CI 
* 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 all study groups. The main 
parameters for the safety endpoints will be described by 95% CIs (based on 
the Clopper-Pearson method). 
 
Calculations of Sample Size 
 
 
 
 
 
 
 
 
 
 
 
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Table of Study Procedures 
Phase III Trial, 2 Visits, 1 Vaccination, 2 Blood Samples, 2 Telephone Calls,  
180 Days Duration Per Subject 
Visit/Contact 
Visit 1 
Telephone  
Call 1 
Visit 2 
Telephone  
Call 2 
Trial timelines (days) 
Day 0 
Day 8 
Day 30 
Day 180 
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), 10 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 
Visit 1 to Visit 2 
 
Diary card reviewed and collected 
 
 
X 
 
Recording of MAAEs‡‡ 
 
 
 
After Visit 2 to TC2 
Reporting of SAEs 
To be reported throughout the study period 
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 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 1 dose of MenACYW conjugate vaccine or Menactra® 
**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 / 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 / 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. 
§§The MA is used for the recording of SAEs and MAAEs. The site staff will make a telephone call to the subject/subject’s 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) 
AE 
adverse event 
AR 
adverse reaction 
BL 
blood sampling 
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  
hSBA 
serum bactericidal assay using human complement 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IM 
intramuscular(ly) 
IMD 
invasive meningococcal disease 
IND 
investigational new drug (application) 
IOM 
Institute of Medicine 
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IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LCLS 
last contact, last subject 
LLOQ 
lower limit of quantitation 
LLT 
lowest level term 
MA 
memory aid 
MAAE 
medically-attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter(s) 
NSAID 
non-steroidal anti-inflammatory drug 
PPAS 
Per-Protocol Analysis Set 
PS 
polysaccharide(s) 
PSO 
Product Safety Officer 
R&D 
Research and Development 
RCDC 
reverse cumulative distribution curve 
RMO 
Responsible Medical Officer 
rSBA 
serum bactericidal assay using baby rabbit complement 
SAE 
serious adverse event 
SafAS 
Safety Analysis Set 
SAP 
statistical analysis plan 
SMT 
Safety Management Team 
TMF 
Trial Master File 
UAR 
unexpected adverse reaction 
ULOQ 
upper limit of quantitation 
UTN 
Universal Trial Number 
WHO 
World Health Organization 
 
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1 
Introduction 
1.1 
Background 
This trial will evaluate the immune lot consistency of Meningococcal Polysaccharide (Serogroups 
A, C, Y, and W) Tetanus Toxoid Conjugate Vaccine (hereafter referred to as MenACYW 
conjugate vaccine), evaluate the immune non-inferiority versus Menactra®, and describe the 
safety and additional immunogenicity of study vaccines in adolescents and adults 10 to 55 years 
of age. 
Invasive meningococcal disease (IMD) is a serious illness caused by the bacterium Neisseria 
meningitidis (N. meningitidis), a Gram-negative diplococcus found exclusively in humans. 
Symptoms may include intense headache, fever, nausea, vomiting, photophobia, stiff neck, lethargy, 
myalgia, and a characteristic petechial rash (1). At least 12 distinct meningococcal serogroups have 
been classified based on the immunochemistry of the capsular polysaccharides (PS). Some strains 
are more likely than others to cause infection (1) (2) (3). Worldwide, most cases of 
meningococcal disease are caused by serogroups A, B, C, X, Y, and W (2) (3) (4). Serogroup B is 
responsible for endemic disease and some outbreaks, while serogroup C is responsible for large 
outbreaks (5). Serogroup A is the main cause of epidemics in the world, and is especially 
dominant in Africa and Asia. Serogroup W has been seen in Africa, as well as in the United 
Kingdom in residents who participated in the Hajj pilgrimage to the Kingdom of Saudi Arabia (4) 
(6) (7) and more recently in Chile (8), Turkey (9) (10), China (11) (12), Argentina (13), and Brazil 
(14) (15) and in other parts of the world. Serogroup X causes substantial meningococcal disease 
in parts of Africa but rarely causes disease in other parts of the world (2) (16). Serogroup Y has 
not been associated with outbreaks, but its frequency as a cause of sporadic cases has gradually 
increased in the US and more recently in Canada and Europe (17) (18) (19). This serogroup is 
commonly associated with meningococcal pneumonia, particularly in older adults > 65 years of 
age (20). Outbreaks of serogroup B meningococcal disease have also been reported on college 
campuses in the US during the last five-year period: a prolonged outbreak of serogroup B on a 
university campus in Ohio from 2008-2010 and 2 universities in New Jersey and California in 
2013 (21) (22). 
The epidemiology of N. meningitidis can be described as complex, unpredictable, geographically 
variable, and changing over time. Meningococcal disease occurs worldwide in both endemic and 
epidemic forms with seasonal variation. In Europe, the incidence rate of IMD has remained stable 
over the last 5 to 10 years, with the highest peak occurring in the population less than 4 years of 
age and a smaller peak in the 15- to 19-year-old group. The highest incidence rate in Europe is 
caused by serogroup B, followed by C (23). 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 IMD cases in earlier years (24). A gradual increase 
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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 target age groups.  
1.2 
Background of the Investigational Product 
1.2.1 
Non-clinical Safety 
 
 
 
 
 
1.2.2 
Clinical 
The MenACYW conjugate vaccine formulation was finalized based on data provided by 
2 studies: MET28, a Phase I study in infants, toddlers, and adults 18 to 55 years of age; and 
MET32, a Phase I/II study in toddlers. 
The formulation has been evaluated in over 650 subjects (infants, toddlers, and adults > 55 years 
of age) in MET39 and MET44. Both Phase II studies are discussed below. In addition, the vaccine 
has been evaluated in another Phase II study in 10 to 17 year olds in the US (MET50). The 
MET50 study evaluated the safety and immune response of the MenACYW conjugate vaccine 
when administered alone or along with Tdap and HPV vaccine administered concurrently as 
compared to a licensed vaccine (MENVEO®). A total of 895 subjects received the MenACYW 
conjugate vaccine in this study. The follow up of this study has been completed; however, 
analysis is still ongoing. No safety concerns or signals were identified in this study. 
The MenACYW conjugate vaccine was found to be well tolerated and no unanticipated or new 
significant safety concerns have been identified in the clinical trials completed to date. 
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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®, 
Pentacel®, ROTARIX® or RotaTeq®, hepatitis B vaccine, M-M-R® II, and VARIVAX®. 
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 vaccine 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. 
1.3 
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 
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that the vaccine is well tolerated, and no safety issues have been detected to date. In all, the data 
support further evaluation of the MenACYW conjugate vaccine in humans. 
Subjects who receive Menactra® 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 Menactra® may not protect 100% of 
individuals against the diseases they are designed to prevent. 
1.3.2 
Potential Risks to Subjects 
Like other vaccines, vaccination with MenACYW conjugate vaccine or Menactra® may cause 
injection site reactions such as pain, swelling, and erythema, or certain systemic events such as 
fever, headache, malaise, or myalgia.  
Other common reactions after Menactra® in the studied age group include injection site 
induration, fatigue, arthralgia, appetite lost, and diarrhea. 
There may be a rare possibility of an allergic reaction which could be severe. Prior to any vaccine 
injection, all known precautions should be taken to prevent hypersensitivity reactions. This 
includes a review of the subject’s prior vaccination history with respect to possible 
hypersensitivity to the vaccine or similar vaccines. Epinephrine injection (1:1000) and other 
appropriate agents used for the control of immediate allergic reactions must be available to treat 
unexpected reactions (e.g., anaphylaxis). 
There may be other risks for MenACYW conjugate vaccine which are not yet known. 
The following additional adverse events have been very rarely reported during post-approval use 
of Menactra®: Guillain-Barré syndrome (GBS), transverse myelitis, acute disseminated 
encephalomyelitis, vasovagal syncope, facial palsy, dizziness, paraesthesia, convulsion, and 
hypersensitivity reactions such as anaphylactic / anaphylactoid reaction, wheezing, difficulty 
breathing, upper airway swelling, urticaria, erythema, pruritus, and hypotension. Because these 
events were reported voluntarily from a population of uncertain size, it is not possible to reliably 
estimate their frequency or to establish a causal relationship to Menactra® exposure. 
GBS has been reported mostly in persons aged 11 to 19 years who had symptom onset within 
6 weeks of administration of Menactra® (29). A retrospective cohort study carried out in the US 
using healthcare claims data found no evidence of increased GBS risk following Menactra® 
vaccination. 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. 
 
 
 
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2 
Trial Objectives 
2.1 
Primary Objectives 
1) To demonstrate the immune lot consistency of the antibody responses to meningococcal 
serogroups A, C, Y, and W following the administration of a single dose of MenACYW 
conjugate vaccine with respect to serum bactericidal assay using human complement (hSBA) 
geometric mean titers (GMTs) 
2) To demonstrate the non-inferiority of the antibody responses to meningococcal serogroups A, 
C, Y, and W following the administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the administration of a single dose 
of Menactra® 
The endpoints for the primary objectives are presented in Section 9.1.1.1. 
2.2 
Secondary Objectives 
1) To demonstrate the non-inferiority of the antibody responses to meningococcal serogroups A, 
C, Y, and W following the administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the administration of a single dose 
of Menactra® in the adult population (18 to 55 years old) 
2) To demonstrate the non-inferiority of the antibody responses to meningococcal serogroups A, 
C, Y, and W following the administration of a single dose of MenACYW conjugate vaccine 
(pooled Lots 1 to 3) compared to those observed following the administration of a single dose 
of Menactra® in the adolescent population (10 to 17 years old) 
3) To compare the hSBA vaccine seroresponses of meningococcal serogroups A, C, Y, and W 
for each of 3 lots of MenACYW conjugate vaccine 30 days (+14 days) after vaccination 
4) 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 Menactra® 
The endpoints for the secondary objectives are presented in Section 9.2.1.1. 
2.3 
Observational Objectives 
Immunogenicity 
To describe the antibody responses to the meningococcal serogroups A, C, Y, and W before and 
30 days (+14 days) after vaccination with MenACYW conjugate vaccine or Menactra® 
Safety 
To describe the safety profile of MenACYW conjugate vaccine and that of the licensed 
Menactra® 
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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 study to evaluate immune lot consistency of MenACYW conjugate vaccine, evaluate the 
immune non-inferiority versus Menactra®, and describe the safety and additional immunogenicity 
of these study vaccines in adolescents and adults aged 10 to 55 years in the United States. 
Healthy, meningococcal-vaccine naïve adolescents and adults will be randomized in a 
3:3:3:2 ratio to the following groups: 
• Group 1: MenACYW conjugate vaccine (Lot 1) 
• 
Group 1a: 400 subjects 10 to 17 years of age 
• 
Group 1b: 500 subjects 18 to 55 years of age 
• Group 2: MenACYW conjugate vaccine (Lot 2) 
• 
Group 2a: 400 subjects 10 to 17 years of age 
• 
Group 2b: 500 subjects 18 to 55 years of age 
• Group 3: MenACYW conjugate vaccine (Lot 3) 
• 
Group 3a: 400 subjects 10 to 17 years of age 
• 
Group 3b: 500 subjects 18 to 55 years of age 
• Group 4: Menactra® 
• 
Group 4a: 300 subjects 10 to 17 years of age 
• 
Group 4b: 300 subjects 18 to 55 years of age 
All subjects will provide blood samples for immunogenicity assessment at baseline (pre-
vaccination) and at 30 to 44 days post-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 from D0 through D180 (+14 days) after vaccination.  
Medically-attended adverse events (MAAEs) will be collected throughout the study from Visit 1 
to 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 
The purpose of MET43 is to demonstrate the immune lot consistency of the antibody responses to 
meningococcal serogroups A, C, Y, and W following the administration of a single dose of 
MenACYW conjugate vaccine. Additionally, MET43 has the purpose of demonstrating the non-
inferiority of the antibody responses to meningococcal serogroups A, C, Y, and W following the 
administration of a single dose of MenACYW conjugate vaccine compared to those observed 
following the administration of a single dose of Menactra®.  
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This study will be the only study to generate immune lot consistency data in the US and would be 
an additional study (to MET56) to generate immune non-inferiority data versus Menactra® in age 
groups 15 to 55 years. Lot consistency is best measured by GMTs of each lot, while the 
performance of the vaccine is best measured by vaccine seroresponse rate. 
This trial is modified double-blind, which means that both the subject and the Investigator remain 
unaware of the treatment assignments throughout the trial. An un-blinded 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. 
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 MenACYW conjugate vaccine (from 1 of the 3 lots 
[Lot 1, Lot 2, or Lot 3]) or Menactra® on 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). 
A, C, Y, and W antigens of MenACYW conjugate vaccine (Groups 1, 2, and 3) and Menactra® 
(Group 4) will be measured by hSBA for all subjects, and by rSBA for a subset of 100 subjects 
per treatment group. 
Collection of safety data 
• All subjects will be observed for 30 minutes after vaccination, and any unsolicited systemic 
AEs occurring during that time will be recorded as immediate unsolicited systemic AEs in the 
electronic case report form (CRF). 
• The subject or 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 or the subject’s parent / guardian will record information about any possible SAEs 
and MAAEs in a memory aid (MA) from Visit 2 until the 6 month (+14 days) telephone call. 
• In addition, the subject or subject’s parent / guardian will be asked to notify the site 
immediately about any potential SAEs at any time during the trial. 
• Staff will contact the subject or 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 and/or the subject’s parent / 
guardian at Visit 2. 
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• Staff will contact the subject or the subject’s parent / guardian by telephone at 6 months 
(+14 days) after vaccination to review the MA and identify the occurrence of any MAAEs, as 
well as SAEs that may have not been reported. 
5.1.4 
Visit Procedures 
Medical procedures (examinations, injections, etc.) must be conducted by appropriately licensed 
or credentialed study site staff working within the scope of their license/credentials. At Visit 1 
(D0), visit procedures will be performed in the order listed below. 
Visit 1 (D0): Inclusion, Randomization, Blood Sample, and Vaccination 
1) Subjects aged 10 to < 18 years: Give the subject and the subject’s parent / guardian 
information about the trial, answer any questions, obtain signed assent from subjects and the 
written informed consent from the subject’s parent /guardian, and give him / her a signed 
copy of each. 
2) Subject aged 18 years and older: Give the subject information about the trial, answer any 
questions, obtain written informed consent from the subject, and give him / her a signed copy 
of the ICF. 
3) Check inclusion and exclusion criteria for eligibility (see Section 5.2.4 and Section 5.2.5, 
respectively). 
4) Collect relevant demographic information. 
5) Perform urine pregnancy test (if applicable). 
6) Obtain verbal medical history about the subject. 
7) 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). 
8) Connect to the Interactive Web Response System (IWRS) for subject identification number 
and randomization (see Section 6.5 for instructions). 
9) Obtain the 10-mL pre-vaccination blood sample (see Section 7 for detailed instructions 
regarding the handling of blood samples). If attempts to obtain the first blood draw are 
unsuccessful (3 attempts), Visit 1 can be rescheduled to a later date at which point informed 
consent and inclusion/exclusion criteria have to be re-validated. If the first blood draw cannot 
be obtained, the subject will be withdrawn from the trial without being vaccinated. 
10) Administer the appropriate study vaccine to the subject in the deltoid muscle. The vaccine 
must be administered according to the assigned study group on the side opposite to that of the 
blood sampling: 
 
Group 1 = MenACYW conjugate vaccine (Lot 1) 
 
Group 2 = MenACYW conjugate vaccine (Lot 2) 
 
Group 3 = MenACYW conjugate vaccine (Lot 3) 
 
Group 4 = Menactra® 
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11) Keep the subject under observation for 30 minutes, and record any AE in the source 
document. 
12) Give the subject or the subject’s parent / guardian a diary card, a thermometer, and a ruler, 
and go over the instructions for their use. 
13) Remind the subject or 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. 
14) Remind the subject or the subject’s parent / guardian to notify the site in case of an SAE. 
15) Complete the relevant CRF pages for this visit. 
Telephone Call 1 (8 to 10 days after Visit 1) 
Note: If Day 08 falls on a weekend or a holiday, the telephone call may be made on the following 
business day. If the subject or 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 or 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 (30 days [+14 days] after Visit 1): Collection of Safety Information and Blood Sample 
1) Review the pages of the diary card with the subject or the subject’s parent / guardian, 
including any AEs, medications, or therapy that occurred since vaccination. The subject or 
subject’s parent / guardian must return the diary card. 
2) Review the temporary contraindications for blood sampling (see Section 5.2.8). 
3) Obtain the blood sample (see Section 7 for detailed instructions regarding the handling of 
blood samples). 
4) Give the subject or the subject’s parent / guardian an MA. 
5) Complete the termination record of the CRF. 
6) If the subject or 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 or the subject’s parent / 
guardian by telephone. During the telephone call, the subject or 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 or the subject’s parent / guardian with 3 attempts, the study personnel will follow 
instructions given in Section 5.2.10. 
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Safety Follow-up Telephone Call 2 (180 days [+14 days] after Visit 1): Collection of SAEs and 
MAAEs 
Review the MA and ask the subject or the subject’s parent / guardian if the subject has 
experienced any SAE in the time since the vaccination that has not been reported to the study 
personnel and / or any 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. 
SAEs and AEs That Are Related to Vaccination or That Led to Discontinuation: 
At any time during the study, a subject who experiences an SAE or an AE must be followed if 
either of the following is true: 
• The SAE or AE is considered by the Investigator to be related to vaccination, and is not 
resolved by the end of the subject’s participation in the trial 
• The subject has been discontinued from the trial because of the SAE or AE 
Any such subject must be followed until the condition resolves, becomes stable, or becomes 
chronic. 
5.1.5 
Planned Trial Calendar 
The following dates are approximate. The actual dates may differ as, for example, the trial will 
not start until all the appropriate regulatory and ethical approvals have been obtained. 
Planned trial period - FVFS (first visit, first subject)  
to LCLS (last contact, last subject):   
 
15 July 2016 to 30 June 2017 
Planned inclusion period - FVFS to FVLS  
(first visit, last subject): 
 
 
 
15 July 2016 to 30 December 2016 
Planned vaccination period:  
 
 
15 July 2016 to 30 December 2016 
Planned end of trial (LCLS):  
 
 
30 June 2017 
Planned date of final clinical study report:  
31 January 2018 
Telephone call 2 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 
Investigators, the IECs/IRBs, and the regulatory authorities of the reason for termination or 
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suspension. If the trial is prematurely terminated for any reason, the Investigator will promptly 
inform the trial subjects or the subjects’ parents / guardian and should assure appropriate therapy 
and follow-up. 
5.2 
Enrollment and Retention of Trial Population 
5.2.1 
Recruitment Procedures 
Before the start of the trial, the Investigator and / or study staff may contact an appropriate pool of 
potential subjects or 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 potential subject who comes to a trial site for a routine visit may be invited to enroll 
in the trial, or a parent who brings a child to the trial site for a routine visit may be invited to 
enroll the child 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 /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 < 18 years of age on the day of enrollment 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 parent / 
guardian. 
In accordance with GCP, prior to signing and dating the consent form, the subject or the subject’s 
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 and dating the assent form, subjects < 18 years of age on the day of enrollment 
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 who cannot read, or a subject whose parent / guardian cannot read will not be included 
in the trial. 
The actual ICF used at each center may differ, depending on local regulations and IEC / IRB 
requirements. However, all versions must contain the standard information found in the sample 
ICF provided by the Sponsor. Any change to the content of the ICF must be approved by the 
Sponsor and the IEC / IRB prior to the form being used. 
If new information becomes available that may be relevant to the subject’s or the subject’s 
parent’s / guardian’s willingness to continue participation in the trial, this will be communicated 
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to him / her in a timely manner. Such information will be provided via a revised ICF or an 
addendum to the original ICF. 
ICFs will be provided in duplicate, or a photocopy of the signed consent will be made. The 
original will be kept by the Investigator, and the copy will be kept by the subject or the 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 10 to 55 years on the day of inclusiona 
2) Informed consent form has been signed and dated by the subject (aged 18 to 55 years) or 
assent form has been signed and dated by the subject and informed consent form has been 
signed and dated by the parent(s) or guardian (for subjects aged 10 to < 18 years).  
3) Subject (≥ 18 years) or subject (10 to < 18 years) 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 (to be considered of non-
childbearing potential, a female must be pre-menarche or post-menopausal for at least 1 year, 
surgically sterile, or using an effective method of contraception or abstinence from at least 
4 weeks prior to vaccination until at least 4 weeks after vaccination)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 pandemic influenza vaccines and multivalent influenza vaccines 
                                                 
a  “10 to 55” means from the day of the 10th birthday to the day before the 56th birthday 
b  For pre-menarche females, the young female patients will declare by themselves if they have not yet started 
menstruation. If a young female patient 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 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 substances 
10) Verbal report of thrombocytopenia, as reported by the subject or the subject’s parent / 
guardian, 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 within 10 years of the proposed study vaccination 
14) Deprived of freedom by an administrative or court order, or in an emergency setting, or 
hospitalized involuntarily 
15) Current alcohol abuse or drug addiction  
16) Chronic illness that, in the opinion of the investigator, is at a stage where it might interfere 
with trial conduct or completiona 
17) Moderate or severe acute illness/infection (according to investigator judgment) on the day of 
vaccination or febrile illness (temperature ≥ 100.4°F). A prospective subject should not be 
included in the study until the condition has resolved or the febrile event has subsided 
18) Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw 
19) Identified as an Investigator or employee of the Investigator or study center with direct 
involvement in the proposed study, or identified as an immediate family member (i.e., parent, 
                                                 
a  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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spouse, natural or adopted child) of the Investigator or employee with direct involvement in 
the proposed study 
If agreeable to the subject or the subject’s parent / guardian (as indicated in the ICF), if the subject 
has a primary physician who is not the Investigator, the site must contact this physician with the 
subject’s or parent’s / guardian’s consent to inform him / her of the subject’s participation in the 
study. In addition, the site should ask this primary physician to verify exclusion criteria relating to 
previous therapies, such as receipt of blood products or previous vaccines. 
5.2.6 
Medical History 
Prior to enrollment, subjects will be assessed for pre-existing conditions and illnesses, both past 
and ongoing. Any such conditions will be documented in the source document. Significant 
medical history (reported as diagnosis) including conditions for which the subject is or has been 
followed by a physician or conditions that could resume during the course of the study or lead to 
an SAE or to a repetitive outpatient care will be collected in the CRF. The significant medical 
history section of the CRF contains a core list of body systems and disorders that could be used to 
prompt comprehensive reporting, as well as space for the reporting of specific conditions and 
illnesses. 
For each condition, the data collected will be limited to: 
• Diagnosis (this is preferable to reporting signs and symptoms) 
• Presence or absence of the condition at enrollment 
The reporting of signs and symptoms is strongly discouraged. 
Dates, medications, and body systems are not to be recorded, and the information collected will not 
be coded. Its purpose is to assist in the later interpretation of safety data collected during the trial. 
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 Visit 2 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 (72 hours) 
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 
Subjects / parents / guardians will be informed that they have the right to withdraw / withdraw 
their child from the trial at any time.  
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A subject may be withdrawn from the study: 
• At the discretion of the Investigator or Sponsor due to safety concerns (withdrawal) without 
the subject’s permission 
• At the request of the subject or the subject’s parent / guardian (dropout)  
The following will result in automatic withdrawal or exclusion of a subject from the study: 
• Significant non-compliance with the protocol, based on the Investigator’s judgment 
The reason for a withdrawal or dropout should be clearly documented in the source documents 
and on the CRF.  
The Investigator must determine whether voluntary withdrawal is due to safety concerns (in 
which case, the reason for discontinuation will be noted as “SAE” or “other AE” as appropriate) 
or for another reason. 
Withdrawn subjects will not be replaced. 
5.2.10 Lost to Follow-up Procedures 
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(s) 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). However, no additional vaccination will be administered.  
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 or the trial subjects’ parents / guardians 
and assure appropriate therapy and / or follow-up for them. 
6 
Vaccines Administered 
6.1 
Identity of the Investigational Products 
6.1.1 
Identity of Trial Product 
MenACYW conjugate vaccine: Meningococcal Polysaccharide (Serogroups A, C, Y, and W) 
Tetanus Toxoid Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Form:  
Liquid solution 
Dose:  
0.5 milliliter (mL) 
Route:  
IM 
Batch number: 3 Lots (UD18368, UD18364, UD18365) 
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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 components: 
Meningococcal capsular polysaccharides: 
Serogroup A...................................................................................................................... 10 µg 
Serogroup C ...................................................................................................................... 10 µg 
Serogroup Y...................................................................................................................... 10 µg 
Serogroup W ..................................................................................................................... 10 µg 
Tetanus toxoid protein carrier ........................................................................ approximately 65 µg 
6.1.1.2 
Preparation and Administration 
MenACYW conjugate vaccine is supplied in single-dose (0.5 mL) vials. 
Prior to administration, all study products must be inspected visually for cracks, broken seals, 
correct label content (see Section 6.3.1), 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. 
One dose (0.5 mL) of MenACYW conjugate vaccine will be administered IM into the deltoid 
muscle of the arm. The site of injection should be prepared with a suitable antiseptic. After 
administration of the vaccine, the used syringe and needle will be disposed of in accordance with 
currently established guidelines. 
Subjects must be kept under observation for 30 minutes after vaccination to ensure their safety, 
and any reactions during this period will be documented in the CRF. Appropriate medical 
equipment and emergency medications, including epinephrine (1:1000), must be available on site 
in the event of an anaphylactic or other immediate allergic reaction. 
6.1.1.3 
Dose Selection and Timing 
Subjects in Group 1 will receive 1 dose of MenACYW conjugate vaccine, Lot 1 on D0. 
Subjects in Group 2 will receive 1 dose of MenACYW conjugate vaccine, Lot 2 on D0. 
Subjects in Group 3 will receive 1 dose of MenACYW conjugate vaccine, Lot 3 on D0. 
6.1.2 
Identity of Control Product 
Menactra®: Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid 
Conjugate Vaccine (Sanofi Pasteur Inc., Swiftwater, PA, USA) 
Form: 
 
Solution for injection 
Dose: 
 
0.5 mL 
Route: 
 
IM 
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Batch number: 
 
U5462AB (provided by the Sponsor) 
6.1.2.1 
Composition 
Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium 
chloride solution to contain the following ingredients: 
Serogroup A............................................................................................................................. 4 µg 
Serogroup C ............................................................................................................................. 4 µg 
Serogroup Y............................................................................................................................. 4 µg 
Serogroup W-135 .................................................................................................................... 4 µg 
Diphtheria toxoid protein carrier ................................................................... approximately 48 µg 
6.1.2.2 
Preparation and Administration 
Menactra® is supplied in single-dose (0.5 mL) vials. One dose of Menactra® will be administered 
IM into the deltoid muscle of the arm. 
See the Menactra® package insert (34). The procedures for preparing and administering 
Menactra® are the same as those described for the trial product in Section 6.1.1.2. 
6.1.2.3 
Dose Selection and Timing 
Subjects in Group 4 will receive 1 dose of Menactra® 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” 
A commercial lot of Menactra® in single-dose (0.5 mL) vials will be supplied by Sanofi Pasteur 
Inc., with commercial labeling on the vial and investigational packaging. 
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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 
qualified staff member to assume this responsibility. 
At the site, products must be kept in a secure place with restricted access. Vaccines will be stored 
in a refrigerator at a temperature ranging from +2°C to +8°C. The vaccines must not be frozen. 
The temperature must be monitored and documented (see the Operating Guidelines) for the entire 
time that the vaccine is at the trial site. In case of accidental freezing or disruption of the cold 
chain, vaccines must not be administered and must be quarantined, and the Investigator or 
authorized designee should contact the Sanofi Pasteur representative for further instructions. 
6.3.2.3 
Product Accountability 
The person in charge of product management at the site will maintain records of product delivery 
to the trial site, product inventory at the site, the dose(s) given to each subject, and the disposal of 
or return to the Sponsor of unused doses. 
The necessary information on the product labels is to be entered into the source document and the 
CRF. If applicable, information may also be entered into the subject’s vaccination card. 
The Sponsor’s monitoring staff will verify the trial site’s product accountability records against 
the record of administered doses in the CRFs and the communication from the IWRS (if 
applicable). 
In case of any expected or potential shortage of product during the trial, the Investigator or an 
authorized designee should alert the Sanofi Pasteur representative as soon as possible, so that a 
shipment of extra doses can be arranged. 
6.3.3 
Replacement Doses 
If a replacement dose is required (e.g., because the syringe broke or particulate matter was 
observed in the syringe), the site personnel must either connect to the IWRS to receive the new 
dose allocation, or follow the instructions given in the Operating Guidelines. 
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6.3.4 
Disposal of Unused Products 
Unused or wasted products will be returned to the Sponsor in accordance with the instructions in 
the Operating Guidelines. Product accountability will be verified throughout the trial period. 
6.3.5 
Recall of Products 
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 both the subject and the Investigator 
remain unaware of the treatment assignments throughout the trial. An un-blinded 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.  
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 
On the day of enrollment, subjects who meet the inclusion/exclusion criteria and sign the ICF 
(subjects aged 18 to 55 years) or sign the assent form and whose parent / guardian signs the ICF 
                                                 
a  according to local regulations 
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(subjects aged 10 to 17 years) will be randomly assigned to Groups 1 through 4 in a 3:3:3:2  ratio, 
stratified according to age such that Groups 1, 2, and 3 will have approximately 900 subjects 
(400 subjects 10 to 17 years old and 500 subjects 18 to 55 years old) and Group 4 will have 
approximately 600 subjects (300 subjects 10 to 17 years old and 300 subjects 18 to 55 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 “-”). For example, Subject 001-
00001is the first subject enrolled in center number 1. Subject numbers should not be reassigned 
for any reason. 
6.6 
Treatment Compliance 
The following measures will ensure that the vaccine doses administered comply with those planned, 
and that any non-compliance is documented so that it can be accounted for in the data analyses: 
• All vaccinations will be administered by qualified trial personnel 
• The person in charge of product management at the site will maintain accountability records 
of product delivery to the trial site, product inventory at the site, dose(s) given to each subject, 
and the disposal of unused or wasted doses 
6.7 
Concomitant Medications and Other Therapies 
At the time of enrollment, ongoing medications including other therapies e.g., blood products, 
should be recorded in the source document as well as new medications prescribed for new 
medical conditions / AEs during trial participation.  
Documentation in the CRF of concomitant medication will be limited to specific categories of 
medication of interest beginning on the day of vaccination. This may include medications of 
interest that were started prior to the day of vaccination. 
Reportable medications will be collected in the CRF from the day of vaccination to the end of the 
solicited and unsolicited follow-up period (e.g., 30 day safety follow-up) as they may impact the 
response to the vaccination and impact the consistency of the information collected on 
concomitant medications at any vaccination. 
The “reportable” medications are distributed according to 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. 
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• 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. 
7.1 
Sample Collection 
At Visits 1 and 2, 10 mL of blood will be collected in tubes provided by or recommended by the 
Sponsor. Immediately prior to the blood draw, the staff member performing the procedure will 
verify the subject’s identity; will verify the assigned subject’s number on the pre-printed label that 
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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.  
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 or 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 
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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 (including Assent forms), 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, and digital thermometers. 
The means for performing EDC will be defined by Sanofi Pasteur. If a computer is provided by 
Sanofi Pasteur, it will be retrieved at the end of the trial. 
The Investigator will supply all vaccination supplies, phlebotomy, and centrifugation equipment, 
including biohazard and / or safety supplies. The biohazard and safety supplies include needles 
and syringes, examination gloves, laboratory coats, sharps disposal containers, and absorbent 
countertop paper. The site will ensure that all biohazard wastes are autoclaved and disposed of in 
accordance with local practices. The Investigator will also supply appropriate space in a 
temperature-monitored refrigerator for the storage of the products and for the blood samples, and 
appropriate space in a temperature-monitored freezer for serum aliquots. 
In the event that additional supplies are required, study staff must contact Sanofi Pasteur, 
indicating the quantity required. Contact information is provided in the Operating Guidelines. 
They must allow approximately 1 week for an order to be filled and to have the supplies sent to 
their site. 
9 
Endpoints and Assessment Methods 
9.1 
Primary Endpoints and Assessment Methods 
9.1.1 
Immunogenicity 
9.1.1.1 
Immunogenicity Endpoints 
The primary endpoints for the evaluation of immunogenicity are: 
1) Geometric mean titer ratios (GMTRs) of antibodies against meningococcal serogroups A, C, 
Y, and W measured by hSBA 30 days (+14 days) after vaccination between lots for immune 
lot consistency 
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2) Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by hSBA 
assessed at baseline (D0, before vaccination) and 30 days (+14 days) after vaccination for 
immune non-inferiority between MenACYW conjugate vaccine and Menactra® (Groups 1 - 3 
pooled versus Group 4) 
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. 
9.2 
Secondary Endpoints and Assessment Methods 
9.2.1 
Immunogenicity 
9.2.1.1 
Immunogenicity Endpoints 
The secondary endpoints for immunogenicity are: 
1) Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by hSBA 
assessed at baseline (D0, before vaccination) and 30 days (+14 days) after vaccination for 
immune non-inferiority between MenACYW conjugate vaccine and Menactra® adult study 
participants (Groups 1b, 2b, and 3b pooled versus Group 4b) 
2) Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by hSBA 
assessed at baseline (D0, before vaccination) and 30 days (+14 days) after vaccination for 
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immune non-inferiority between MenACYW conjugate vaccine and Menactra® adolescent 
study participants (Group 1, 2a, and 3a pooled versus Group 4a) 
3) Vaccine seroresponse of meningococcal serogroups A, C, Y, and W measured by hSBA 
30 days (+14 days) following the administration of MenACYW conjugate vaccine (Groups 1, 
2, and 3) 
4) GMTRs of antibodies against meningococcal serogroups A, C, Y, and W measured by hSBA 
for the groups that received MenACYW conjugate vaccine (Groups 1 - 3 pooled) and 
Menactra® (Group 4) 
9.2.1.2 
Immunogenicity Assessment Methods 
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: 
Antibody titers against meningococcal serogroups A, C, Y, and W measured by hSBA and serum 
bactericidal assay using baby rabbit complement (rSBA) assessed at baseline (D0, before 
vaccination) and 30 days (+14 days) after vaccination in a subset of subjects for all groups 
9.3.1.2 
Immunogenicity Assessment Method 
 
 
 
 
 
 
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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 
• 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. 
                                                 
a  T60: Time of incubation duration of 60 minutes 
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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). 
(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: 
                                                 
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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• 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. 
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.  
                                                 
a  All injection site AEs are considered to be related to vaccination and are therefore all injection site reactions. 
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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 or parent / guardian about any 
solicited reactions and unsolicited AEs recorded in the diary card, as well as about any other AEs 
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. 
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9.3.2.3.2 
Reactogenicity (Solicited Reactions From Day 0 to Day 07 After Vaccination) 
After vaccination, subjects or 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 subject or parent / 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 or 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 
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: No interference with activity 
Grade 2: Some interference with activity 
Grade 3: Significant; prevents daily activity 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
Grade 1: ≥ 25 to ≤ 50 mm 
Grade 2: ≥ 51 to ≤ 100 mm 
Grade 3: > 100 mm 
* 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: 
Subjects or 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 oral. 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, subjects or 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 subject or parent / 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) 
3:  Health care provider contact and prescription of a new medication (health care provider 
instructed subject to take a new medication, either an over-the-counter medication or one 
requiring a written prescription) 
                                                 
a The stop date of all related AEs will be actively solicited. For other events, the investigator will provide the stop 
date when it becomes available. AEs for which no stop date was obtained during the course of the trial will be 
considered as ongoing at the end of the trial. 
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• Whether the AE led to discontinuation 
• Whether the AE was related to vaccination (for unsolicited systemic AEs) 
9.3.2.3.4 
Serious Adverse Events 
Information on SAEs will be collected and assessed throughout the trial, from inclusion until 
180 days (+14 days) after vaccination. 
Any SAE occurring at any time during the trial will be reported by the Investigator through the 
EDC system and according to the completion guidelines provided by the Sponsor. All information 
concerning the SAE is to be reported, either as part of the initial reporting or during follow-up 
reporting if relevant information became available later (e.g., outcome, medical history, results of 
investigations, copy of hospitalization reports. The Investigator will assess the causal relationship 
between the SAE and the investigational product as either “Not related” or “Related”, as 
described in Section 10.4. 
See Section 10 for further details on SAE reporting. 
9.3.2.3.5 
 
Not applicable. 
9.3.2.3.6 
Medically-Attended Adverse Events 
MAAE information will be collected throughout the study. MAAEs that occur from Visit 1 (D0) 
to Visit 2 (D30[+14days]) will be recorded as unsolicited AEs on the diary card as part of all 
unsolicited AEs collected for this post-vaccination period. MAAEs that occur from Visit 2 
(D30 [+14 days]) to D180 (+14 days) will be recorded as such in the MA. A 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) 
                                                 
a  ICH Guidelines, Clinical Safety Data Management E2A 
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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 
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 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): 
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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. 
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. 
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SAE Data Management  
During the trial, data pertaining to SAEs reported on eSAE Forms will be integrated into the 
Sponsor’s centralized GPV database. 
Upon receipt of an eSAE Form, the data will be entered into the GPV database after a duplicate 
check. Each SAE case will be assigned a case identification number. Each case will be entered in 
the GPV database and assessed by the case management platform or its delegate before being 
reported to the relevant authorities as necessary. Assessment of related cases will be done in 
collaboration with the PSO and the RMO. Follow-up information concerning a completed case 
will be entered into the GPV database, and a new version of the case will be created. 
The information pertaining to SAEs in the GPV database will be reconciled with that in the 
clinical database. 
11.3 Data Review 
A 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. 
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 Objectives 
12.1.1.1 Primary Objective 1  
Equivalence of 3 MenACYW Conjugate Vaccine Lots in Terms of hSBA GMTs 
Thirty days after the administration of the MenACYW conjugate vaccine, GMTs of antibodies 
against meningococcal serogroups A, C, Y, and W in Groups 1, 2, and 3 are equivalent. 
Null hypothesis (H0): GMT(Gi) / GMT(Gj) ≤ 1/2 or GMT(Gi) / GMT(Gj) ≥ 2 for any i ≠ j  
Alternative hypothesis (H1): 1/2 < GMT(Gi) / GMT(Gj) < 2 for all i ≠ j  
GMT(Gi) and GMT(Gj) are the GMTs of antibodies against the meningococcal serogroups A, C, Y, 
and W for the ith and jth lots, respectively. Each of the antigens of A, C, Y, and W serogroups 
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will be tested separately. If the 2-sided 95% confidence interval (CI) of the ratio of the GMTs is 
> 1/2 and < 2 for each antigen, the non-equivalence assumption will be rejected. 
Assuming that log10 transformation of the data follows a normal distribution, the log10 (data) will 
be used for the statistical analysis, then antilog transformations will be applied to the results of 
calculations, in order to provide the results in terms of GMTs. 
For each of the equivalence hypotheses using the GMT ratios, the statistical methodology will be 
based on the use of the 2-sided 95% CI of difference in means of post-vaccination log10 
transformed titers between the 2 groups with normal approximation. 
12.1.1.2 Primary Objective 2 
Non-inferiority of MenACYW Conjugate Vaccine Compared to Menactra® in Terms of hSBA 
Vaccine Seroresponse 
Thirty days after the administration of MenACYW conjugate vaccine or Menactra®, the 
percentages of subjects who achieve an hSBA vaccine seroresponsea for meningococcal 
serogroups A, C, Y, and W in Groups 1, 2, and 3 combined are non-inferior to the corresponding 
percentages in Group 4. 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
Alternative hypothesis (H1): p(G123) - p( G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA vaccine seroresponse 
in Groups 1 - 3 pooled and Group 4, respectively. Each of the serogroups A, C, Y, and W will be 
tested separately. If the lower limit of the 2-sided 95% 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  
(35). The overall non-inferiority of this objective will be demonstrated if all 4 individual null 
hypotheses are rejected. 
                                                 
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.  
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12.1.2 Hypotheses and Statistical Methods for Secondary Objectives 
12.1.2.1 Secondary Objective 1 
Non-inferiority of MenACYW Conjugate Vaccine Compared to Menactra® in Terms of hSBA 
Vaccine Seroresponse in the Adult Population (18 to 55 Years Old) 
Thirty days after the administration of MenACYW conjugate vaccine or Menactra®, the 
percentages of subjects who achieve an hSBA vaccine seroresponsea for meningococcal 
serogroups A, C, Y, and W in Groups 1b, 2b, and 3b combined are non-inferior to the 
corresponding percentages in Group 4b. 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
Alternative hypothesis (H1): p(G123) - p( G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA vaccine seroresponse 
in Groups 1b, 2b, and 3b pooled and Group 4b, respectively. Each of the serogroups A, C, Y, and 
W will be tested separately. If the lower limit of the 2-sided 95% 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  
(35). The overall non-inferiority of this objective will be demonstrated if all 4 individual null 
hypotheses are rejected. 
12.1.2.2 Secondary Objective 2 
Non-inferiority of MenACYW Conjugate Vaccine Compared to Menactra® in Terms of hSBA 
Vaccine Seroresponse in the Adolescent Population (10 to 17 Years Old) 
Thirty days after the administration of MenACYW conjugate vaccine or Menactra®, the 
percentages of subjects who achieve an hSBA vaccine seroresponsea for meningococcal 
serogroups A, C, Y, and W in Groups 1a, 2a, and 3a combined are non-inferior to the 
corresponding percentages in Group 4a. 
Null hypothesis (H0): p(G123) - p(G4) ≤ -10% 
Alternate hypothesis (H1): p(G123) - p(G4) > -10% 
where p(G123) and p(G4) are the percentages of subjects who achieve an hSBA vaccine seroresponse 
in Groups 1a, 2a, and 3a pooled and Group 4a, respectively. Each of the serogroups A, C, Y, and 
W will be tested separately. If the lower limit of the 2-sided 95% CI of the difference between the 
2 proportions is > -10%, the inferiority assumption will be rejected. 
                                                 
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.  
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For the 4 non-inferiority hypothesis using the seroresponse rates, the CI of the difference in 
proportions will be computed using the Wilson Score method without continuity correction (35). 
The overall non-inferiority of this objective will be demonstrated if all 4 individual null 
hypotheses are rejected. 
12.1.2.3 Secondary Objective 3 
Comparison of 3 MenACYW Conjugate Vaccine Lots in Terms of hSBA Vaccine Seroresponse 
The difference in percentages of subjects who achieve an hSBA vaccine seroresponsea 30 days 
after the administration of MenACYW conjugate vaccine for meningococcal serogroups A, C, Y, 
and W in Groups 1, 2, and 3 will be calculated for each comparison and 95% CI will be provided. 
The CI of the difference in proportions will be computed using the Wilson Score method without 
continuity correction (35). 
12.1.2.4 Secondary Objective 4 
Comparison of MenACYW Conjugate Vaccine to Menactra® in Terms of hSBA GMTs 
The ratio of GMTs of meningococcal serogroups A, C, Y, and W between the MenACYW 
conjugate vaccine Groups 1- 3 pooled (Lots 1, 2, and 3 combined) and the Menactra® Group 4 
30 days after the administration of vaccine will be calculated and 95% CI will be provided. 
Assuming that log10 transformation of the data follows a normal distribution, the log10 (data) will 
be used for the statistical analysis, then antilog transformations will be applied to the results of 
calculations, in order to provide the results in terms of GMTs. 
For each of the GMT ratios, the statistical methodology will be based on the use of the 2-sided 
95% CI of difference in means of post-vaccination log10 transformed titers between the 2 groups 
with normal approximation. 
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 each lot of MenACYW conjugate vaccine and in Menactra®.  
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) 
                                                 
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.  
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for percentages (36). 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. 
In summary, descriptive analyses on A, C, Y, and W serogroups will include but not be limited to: 
• hSBA GMTs and 95% CI at each time point for each group 
• hSBA titer distribution and RCDC 
• Proportion of subjects with hSBA titer ≥ 1:4 and ≥ 1:8 and 95% CI at D0 and D30 for each 
group 
• Proportion of subjects with hSBA titer ≥ 4-fold rise from pre-vaccination to post-
vaccination, and 95% CI 
• rSBA GMTs and 95% CI at each time point in a subset of 100 subjects in each group 
• rSBA titer distribution and RCDC 
• Proportion of subjects with rSBA titer ≥ 1:8 and ≥ 1:128 and 95% CI at D0 and D30 in a 
subset of 100 subjects in each group 
• Proportion of subjects with rSBA titer ≥ 4-fold rise from pre-vaccination to post-
vaccination and 95% CI 
• Vaccine seroresponsea against meningococcal serogroups A, C, Y, and W measured by 
rSBA and 95% CI  
12.1.3.2 Safety 
Safety results will be described for subjects in all study groups. The main parameters for the 
safety endpoints will be described by 95% CIs (based on the Clopper-Pearson method). 
The frequency and percentage of subjects who had solicited injection site and systemic reactions 
and their 95% CIs will be provided. These events will be tabulated by type of reactions and 
intensity for each study group, as well as by other categories specified in the endpoints. 
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 other categories specified in the 
endpoints. 
12.2 Analysis Sets 
Three analysis sets will be used: the Full Analysis Set (FAS), the PPAS, and the Safety Analysis 
Set (SafAS). 
                                                 
a  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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12.2.1 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 blood sample result. All subjects will be analyzed according to 
the treatment group to which they were randomized. 
12.2.2 Safety Analysis Set 
The SafAS is defined as those subjects who have received at least one dose of the study vaccine 
and have any safety data available. All subjects will have their safety analyzed according to the 
vaccine they actually received. 
If the vaccine received by a subject does not correspond to any study group, the subject will be 
excluded from the SafAS. The corresponding safety data will be presented in separate listings. 
12.2.3 Per-Protocol Analysis Set 
The PPAS is a subset of the FAS. The subjects presenting with at least one of the following 
relevant protocol deviations will be excluded from the PPAS: 
• Subject did not meet all protocol-specified inclusion criteria or met at least one of the 
protocol-specified exclusion criteria 
• Subject did not receive vaccine 
• Subject received a vaccine other than the one that he / she was randomized to receive 
• Preparation and / or administration of vaccine was not done as per-protocol 
• Subject did not receive vaccine in the proper time window 
• Subject did not provide post-dose serology sample in the proper time window or a post-dose 
serology sample was not drawn.  
• Subject received a protocol-prohibited Category 2 or Category 3 therapy / medication / 
vaccine 
• Subject’s serology sample did not produce a valid test result 
• Subject had other protocol violations that affected the subject’s immune response, as 
determined by the clinical team before locking the database. 
12.2.4 Populations Used in Analyses 
The primary immunogenicity analyses will be performed on the PPAS, and will be confirmed 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. 
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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. 
12.4 Interim / Preliminary Analysis 
No interim / preliminary analyses are planned. 
12.5 Determination of Sample Size and Power Calculation 
 
 
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13 Ethical and Legal Issues and Investigator / Sponsor Responsibilities 
13.1 Ethical Conduct of the Trial / Good Clinical Practice 
The conduct of this trial will be consistent with the standards established by the Declaration of 
Helsinki and compliant with the ICH guidelines for GCP as well as with all local and / or national 
regulations and directives. 
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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 
Food and Drug Administration (FDA), require direct access to all study records, and will treat 
these documents in a confidential manner. 
In the event a subject’s medical records are not at the investigational site, it is the responsibility of 
the investigator to obtain those records if needed. 
13.4 Monitoring, Auditing, and Archiving 
13.4.1 Monitoring  
Before the start of the trial (i.e., before the inclusion of the first subject in the first center), the 
Investigators and the Sponsor’s staff or a representative will meet at the site-initiation visit to 
discuss the trial protocol and the detailed trial procedures. Emphasis will be placed on inclusion 
and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE 
reporting procedures, CRF completion, and the handling of samples and products. The Sponsor’s 
                                                 
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 
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Trial Agreement (CTA). In no event, should study personnel destroy or permit the destruction of 
any trial documents upon less than 90 days advance written notification to the Sponsor. In 
addition, trial documents should continue to be stored, at Sponsor’s sole expense, in the event that 
the Sponsor requests in writing that such storage continues for a period of time that exceeds that 
required by any applicable law or regulation or the CTA. The Investigator will inform Sanofi 
Pasteur of any address change or if they will no longer be able to house the trial documents. 
Archived data may be held on electronic records, provided that a back-up exists and that a hard 
copy can be obtained if required. The protocol, documentation, approvals, and all other 
documents related to the trial, including certificates attesting that satisfactory audit and inspection 
procedures have been carried out, will be kept by the Sponsor in the Trial Master File (TMF). 
Data on AEs are included in the TMF. All data and documents will be made available if requested 
by relevant authorities. 
13.5 Financial Contract and Insurance Coverage 
A CTA will be signed by all the parties involved in the trial’s performance, if relevant. The 
Sponsor has an insurance policy to cover any liabilities that may arise from use of the product  
and / or the study protocol. 
13.6 Stipends for Participation 
The subject or 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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28 
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