A Phase IV, Open-Label, Multi-Center Study to Evaluate the Safety and the 1-year Persistence of Antibody Response Among Children Who Received 4 Doses of the GSK MenACWY Conjugate Vaccine at 2, 4, 6 and 12 Months of Age in South Korea
Phase: PHASE4
Conditions: Infections, Meningococcal
Sponsor: GlaxoSmithKline

Novartis Vaccines 
Confidential 
Protocol V59_75 
10 DEC 14 Final Protocol Version #1 
 
 
Page 1 of 74 
 
 
 
 
CLINICAL STUDY PROTOCOL V59_75 Version # 1 
 
 
A Phase IV, Open-Label, Multi-Center Study to Evaluate the Safety and the 1-year 
Persistence of Antibody Response Among Children Who Received 4 Doses of the 
Novartis MenACWY Conjugate Vaccine at 2, 4, 6 and 12 Months of Age in South 
Korea 
 
 
 
 
Evaluation of Antibody persistence following 4 MenACWY vaccinations 
 
 
 
 
 
 
Property of Novartis Pharma Services AG 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of Novartis Pharma Services AG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol V59_75 
Page 2 of 74 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................... 2 
PROTOCOL SYNOPSIS V59_75 VERSION 1 ................................................................. 8 
LIST OF ABBREVIATIONS ............................................................................................ 19 
1.0 
BACKGROUND AND RATIONALE .................................................................. 20 
1.1 
Background ........................................................................................................ 20 
1.2 
Rationale ............................................................................................................ 21 
2.0 
OBJECTIVES ........................................................................................................ 22 
2.1 
Primary Objective(s) .......................................................................................... 22 
2.1 
Secondary Objective(s) ...................................................................................... 22 
3.0 
STUDY DESIGN ................................................................................................... 23 
3.1 
Overview of Study Design ................................................................................. 23 
3.2 
Study Period ....................................................................................................... 24 
3.3 
Blinding Procedures ........................................................................................... 24 
3.4 
Data Collection .................................................................................................. 24 
3.4.1 
Data Collected from Subjects .................................................................... 24 
3.4.2 
Tools Used for Data Collection ................................................................. 25 
3.5 
Collection of Clinical Specimens ....................................................................... 26 
3.6 
Stopping/Pausing Guidelines ............................................................................. 27 
3.7 
Data Monitoring Committee .............................................................................. 27 
3.8 
Premature Withdrawal from Study .................................................................... 27 
3.9 
End of Study ...................................................................................................... 29 
4.0 
SELECTION OF STUDY POPULATION ........................................................... 30 
4.1 
Inclusion Criteria ............................................................................................... 30 
4.2 
Exclusion Criteria .............................................................................................. 30 
4.3 
Criteria for Delay of Vaccination ...................................................................... 31 
5.0 
STUDY PROCEDURES ....................................................................................... 32 
5.1 
Pre-vaccination Clinic Visit(s) ........................................................................... 32 
5.1.1 
Informed Consent/Assent ........................................................................... 32 
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5.1.2 
Screening .................................................................................................... 33 
5.1.3 
Enrolment ................................................................................................... 34 
5.1.4 
Randomization ........................................................................................... 34 
5.2 
Vaccination Clinic Visit(s) ................................................................................ 35 
5.2.1 
Post-vaccination Procedures ...................................................................... 35 
5.2.2 
Post-vaccination Reminder Calls ............................................................... 36 
5.3 
Post-vaccination Visit(s) .................................................................................... 36 
5.3.1 
Follow-up Clinic Visit(s) ........................................................................... 36 
5.3.2 
Safety Follow-up Calls ............................................................................... 37 
5.4 
Unscheduled Visits ............................................................................................ 37 
5.5 
Study Termination Visit ..................................................................................... 37 
5.5.1 
Early Termination Visit ............................................................................. 38 
6.0 
TREATMENT OF SUBJECTS ............................................................................. 40 
6.1 
Study Vaccine(s) ................................................................................................ 40 
6.2 
Non-Study Vaccines .......................................................................................... 41 
6.3 
Vaccine Preparation and Administration ........................................................... 41 
6.4 
Vaccine Administration Error or Overdose of Vaccine ..................................... 42 
6.5 
Prior and Concomitant Medications and Vaccines ............................................ 43 
6.6 
Vaccine Supply, Labeling, Storage and Tracking .............................................. 43 
7.0 
ASSESSMENTS .................................................................................................... 46 
7.1 
Safety Assessment .............................................................................................. 46 
7.1.1 
Solicited Adverse Events ........................................................................... 46 
7.1.2 
Unsolicited Adverse Events ....................................................................... 48 
7.1.3 
Evaluation of Adverse Events .................................................................... 48 
7.1.4 
Serious Adverse Events ............................................................................. 49 
7.1.4.1 
Adverse Events of Special Interest ........................................................ 51 
7.1.5 
Methods for Recording Adverse Events and Serious Adverse Events ...... 51 
7.1.5.1 
Post-Study Events .................................................................................. 52 
7.1.6 
Pregnancies ................................................................................................ 52 
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7.1.7 
Safety Laboratory Measurements ............................................................... 52 
7.2 
Efficacy Assessment .......................................................................................... 52 
7.3 
Immunogenicity Assessment ............................................................................. 52 
8.0 
STATISTICAL CONSIDERATIONS ................................................................... 54 
8.1 
Endpoints ........................................................................................................... 54 
8.1.1 
Primary Endpoint(s) ................................................................................... 54 
8.1.1.1 
Primary Safety Endpoint(s) .................................................................... 54 
8.1.1.2 
Primary Efficacy Endpoint(s) ................................................................ 54 
8.1.1.3 
Primary Immunogenicity Endpoint(s) ................................................... 54 
8.1.2 
Secondary Endpoint(s) ............................................................................... 54 
8.1.2.1 
Secondary Safety Endpoint(s) ................................................................ 54 
8.1.2.2 
Secondary Efficacy Endpoint(s)............................................................. 55 
8.1.2.3 
Secondary Immunogenicity Endpoint(s) ................................................ 55 
8.1.3 
Exploratory Endpoint(s) ............................................................................. 55 
8.1.3.1 
Exploratory Safety Endpoint(s) .............................................................. 55 
8.1.3.2 
Exploratory Efficacy Endpoint(s) .......................................................... 55 
8.1.3.3 
Exploratory Immunogenicity Endpoint(s) ............................................. 55 
8.2 
Success Criteria .................................................................................................. 56 
8.2.1 
Success Criteria for Primary Objective(s).................................................. 56 
8.2.1.1 
Success Criteria for Primary Safety Objective(s) .................................. 56 
8.2.1.2 
Success Criteria for Primary Efficacy Objective(s) ............................... 56 
8.2.1.3 
Success Criteria for Primary Immunogenicity Objective(s) .................. 56 
8.2.2 
Success Criteria for Secondary Objective(s) .............................................. 56 
8.2.2.1 
Success Criteria for Secondary Safety Objective(s) .............................. 56 
8.2.2.2 
Success Criteria for Secondary Efficacy Objective(s) ........................... 56 
8.2.2.3 
Success Criteria for Secondary Immunogenicity Objective(s) .............. 56 
8.3 
Analysis Sets ...................................................................................................... 56 
8.3.1 
All Enrolled Set .......................................................................................... 56 
8.3.2 
All Exposed Set .......................................................................................... 57 
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8.3.3 
Safety Set ................................................................................................... 57 
8.3.4 
Full Analysis Set (FAS) Efficacy/Immunogenicity Set ............................. 58 
8.3.5 
Per Protocol (PP) Set Efficacy/Immunogenicity Set ................................ 58 
8.3.6 
Other Analysis Sets .................................................................................... 59 
8.3.7 
Subgroups .................................................................................................. 59 
8.3.8 
Protocol Deviations .................................................................................... 59 
8.4 
Statistical Analysis Plan ..................................................................................... 59 
8.4.1 
Analysis of Demographic and Baseline Characteristics ............................ 59 
8.4.2 
Analysis of Primary Objective(s) ............................................................... 59 
8.4.2.1 
Analysis of Primary Safety Objective(s) ................................................ 59 
8.4.2.1.1 
Analysis of Extent of Exposure ....................................................... 59 
8.4.2.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events. 59 
8.4.2.1.3 
Analysis of Unsolicited Adverse Events ......................................... 60 
8.4.2.1.4 
Analysis of Safety Laboratory Values ............................................. 61 
8.4.2.2 
Analysis of Primary Efficacy Objective(s) ............................................ 61 
8.4.2.2.1 
Statistical Hypotheses ........................................................................ 61 
8.4.2.2.2 
Analysis Sets ...................................................................................... 61 
8.4.2.2.3 
Statistical Methods .......................................................................... 61 
8.4.2.3 
Analysis of Primary Immunogenicity Objective(s) ............................... 61 
8.4.2.3.1 
Statistical Hypotheses ..................................................................... 61 
8.4.2.3.2 
Analysis Sets ................................................................................... 61 
8.4.2.3.3 
Statistical Methods .......................................................................... 62 
8.4.3 
Analysis of Secondary Objective(s) ........................................................... 62 
8.4.3.1 
Analysis of Secondary Safety Objective(s) ............................................ 62 
8.4.3.1.1 
Analysis of Extent of Exposure ....................................................... 62 
8.4.3.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events. 62 
8.4.3.1.3 
Analysis of Unsolicited Adverse Events ......................................... 62 
8.4.3.1.4 
Statistical Hypotheses ..................................................................... 62 
8.4.3.1.5 
Analysis Sets ................................................................................... 63 
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8.4.3.1.6 
Statistical Methods .......................................................................... 63 
8.4.3.2 
Analysis of Secondary Efficacy Objective(s) ........................................ 63 
8.4.3.2.1 
Statistical Hypotheses...................................................................... 63 
8.4.3.2.2 
Analysis Sets ................................................................................... 63 
8.4.3.2.3 
Statistical Methods .......................................................................... 63 
8.4.3.3 
Analysis of Secondary Immunogenicity Objective(s) ........................... 63 
8.4.3.3.1 
Statistical Hypotheses...................................................................... 63 
8.4.3.3.2 
Analysis Sets ................................................................................... 63 
8.4.3.3.3 
Statistical Methods .......................................................................... 63 
8.4.4 
Analysis of Exploratory Objectives ........................................................... 64 
8.4.4.1 
Analysis of Exploratory Safety Objective(s) ......................................... 64 
8.4.4.2 
Analysis of Exploratory Efficacy Objective(s) ...................................... 64 
8.4.4.3 
Analysis of Exploratory Immunogenicity Objective(s) ......................... 64 
8.5 
Sample Size and Power Considerations of Primary and Secondary Objectives 64 
8.6 
Interim Analysis ................................................................................................. 65 
9.0 
SOURCE DOCUMENTATION, STUDY MONITORING AND AUDITING .... 66 
9.1 
Source Documentation ....................................................................................... 66 
9.2 
Study Monitoring, Auditing and Source Data Verification ............................... 67 
10.0 
DATA MANAGEMENT ....................................................................................... 68 
10.1 
Data Entry and Management .............................................................................. 68 
10.2 
Data Clarification ............................................................................................... 68 
10.3 
Data Protection ................................................................................................... 68 
11.0 
RECORD RETENTION ........................................................................................ 69 
12.0 
USE OF INFORMATION AND PUBLICATION ................................................ 70 
13.0 
ETHICAL CONSIDERATIONS ........................................................................... 71 
13.1 
Regulatory and Ethical Compliance ................................................................... 71 
13.2 
Informed Consent Procedures ............................................................................ 71 
13.3 
Responsibilities of the Investigator and IRB/EC ............................................... 72 
13.4 
Protocol Amendments ........................................................................................ 73 
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14.0 
REFERENCE LIST ............................................................................................... 74 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS V59_75 VERSION 1 
 
Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
Title of Study: 
A Phase IV, Open-Label, Multi-center study to evaluate the Safety and the 1-year 
persistence of antibody response among children who received 4 doses of the Novartis 
MenACWY Conjugate Vaccine at 2, 4, 6 and 12 months of age in South Korea. 
Study Period: The duration of study 
participation for each subject is 
approximately 22 months. 
Clinical Phase: Phase IV 
Background and Rationale: 
The purpose/aim of this study is to evaluate the persistence of the antibody response in 
children approximately 24 months of age who receive 4 doses of Menveo® at 2, 4, 6,12 
months of age. 
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis worldwide, 
(Rouphael and Stephens 2012, Al-Tawfiq et al 2010, Hill et al 2010, Deasy and Read 
2011) capable of causing outbreaks and epidemics of invasive disease. Meningococcal 
disease causes high rates of morbidity and mortality even among patients who receive 
early antibiotic treatment. Based on antigenic differences in their capsular 
polysaccharide, 13 serogroups of N. meningitidis have been identified. Virtually all 
disease-associated isolates are encapsulated, with serogroups A, B, C, Wand Y being 
responsible for the large majority of invasive meningococcal infections worldwide. 
Novartis developed a quadrivalent meningococcal vaccine against serogroups A, C, W 
and Y (MenACWY-CRM, Menveo® ) which is licensed in more than 60 countries. 
Recently this vaccine was approved for use in infants as young as 2 months of age in the 
US, Argentina, South Korea and other countries. MenACWY-CRM is given to infants as 
a 4-dose series at 2, 4, 6, and 12 months of age; children 7 to 23 months of age should 
receive a 2-dose series, with the second dose administered in the second year of life. 
Previous studies have shown that MenACWY-CRM is immunogenic and well tolerated 
 
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Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
when administered at 2, 4, 6 and 12-13 months of age, or when administered to toddlers 
as 1 or 2 doses in the second year of life. Limited data are available about long-term 
persistence of bactericidal antibodies following a 4-dose vaccination series in infants. 
Novartis MenACWY ( Menveo® has been approved for use in people 2 months through 
55 years of age in the United State and in people 2 years up to 55 in Europe and other 
countries, including the Republic of South Korea. In South Korea, the indication was 
extended in May 2014 to infants 2 months of age up to 55, however, the Ministry of 
Food and Drug Safety (MFDS) of the Republic of South Korea have requested data on 
immunogenicity persistence in the Korean children who received 4 doses of Menveo® at 
2, 4, 6, and 12 months of age. 
Study Objectives: 
Primary Objective(s): 
1. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose 
infant vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as 
measured by hSBA titers ≥8. 
2. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose 
infant vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as 
measured by rSBA titers ≥8 and ≥128. 
Secondary Objective(s): 
1. To describe hSBA titers ≥8 and hSBA GMTs against N. meningitidis serogroups A, 
C, W and Y 1 month after a full vaccination series at 2,4,6 and 12 months of age. 
2. To describe rSBA titers ≥8 and ≥128 and rSBA GMTs against N. meningitidis 
serogroups A, C, W and Y 1 month after a full vaccination series at 2,4,6 and 12 
months of age. 
3. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose 
 
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Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
infant vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as 
measured by hSBA GMTs and rSBA GMTs. 
Safety Objective(s) 
To assess the safety and tolerability of MenACWY administered at 2-4-6 and12 months 
of age. 
Study Design: 
This is Phase IV, Open label, Multicenter study. Subject’s parents and/or legal guardian 
will be provided information about the trial. If interested and if eligible, they will then be 
asked to provide signed informed consent. The initial study visit can occur immediately 
after signed informed consent has been obtained. Approximately 135 subjects will be 
enrolled to receive 4 doses of intramuscular MenACWY vaccine at 2, 4, 6 and 12 
months of age. 
A total of two blood samples (up to approx. 5 mL per draw) will be obtained at 13 and 
24 months of age. 
Table 1: 
Overview of the Study design 
Table 2: 
Safety Assessment 
Medical history: 
Any significant past (see details in Section 4.2 and 6.2 
of the protocol) 
From birth 
 
 
 
 
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No Subjects 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
2-Months 
4-Months 
6-Months 
12-Months 
13- Months 
24- Months 
135 
Menveo® 
Menveo® 
Menveo® 
Menveo® 
Blood 
draw 
Blood 
draw 

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Protocol V59_75 
Page 11 of 74 
 
 
Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
Vaccination history: 
Will be checked to determine subject’s eligibility 
criteria. 
From birth 
Immediate reactions: 
Subjects will be assessed for immediate reactions 
For 30 minutes after each 
Men ACWY vaccination 
Body Temperature: Body Temperature (tympanic is 
recommended, but axillary, rectal route is allowed if 
temperature cannot be taken by tympanic route) and 
antipyretic/analgesic use will be recorded. 
From Day 1 to Day 7 after 
each Men ACWY 
vaccination 
Solicited local adverse events: Injection site erythema, 
injection site induration, injection site tenderness. 
From Day 1 to Day 7 after 
each Men ACWY 
vaccination 
Solicited systemic adverse events: Change in eating 
habits, sleepiness, irritability, vomiting, diarrhea, fever. 
From Day 1 to Day 7 after 
each Men ACWY 
vaccination 
Unsolicited Adverse Events: All medically-attended 
unsolicited AEs and AEs leading to premature 
withdrawal will be collected verbally during all clinical 
visits 
From Day 1 of the study to 
Visit 6 (24 months of age) 
Serious AEs (SAEs): All SAEs will be monitored until 
resolution and/or the cause is identified (if a SAE 
remains unresolved at study termination, a clinical 
assessment will be made by the investigator and the 
Novartis medical monitor to determine whether 
continued follow up of the SAE is warranted). 
From Day 1 of the study to 
Visit 6 (24 months of age) 
Medications: Medications used to treat any medically- 
attended AE, AEs leading to premature withdrawal and 
SAE, verbally during all clinical visits 
From Day 1 of the study to 
Visit 6 (24 months of age) 
 
 
 
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Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
Number of Subjects planned: Approximately 135 subjects will be enrolled in this 
study. 
Study Population and Subject Characteristics: 
The list of inclusion and exclusion criteria is included in protocol section 4.0, Selection 
of Study Population. 
Study Procedures: 
Visit 1 (Age 2 months) (Day 1). Informed consent must be obtained from the subject's 
parent(s) or legally acceptable representative(s) prior to the performance of any study 
related procedures. After receiving the 1st vaccination, subjects will be observed for at 
least 30 minutes for any immediate reactions. The subjects’ parents/legal guardian will 
be instructed to complete a subject diary daily, reporting solicited local and systemic 
adverse events (AEs) occurring from Day 1 to Day 7after vaccination with MenACWY. 
At Day 3 after vaccination a telephone call will be made to remind the subjects’ 
parents/legal guardian to complete the subject diary . 
Visit 2 (Age 4 Months) (60 days after Visit 1 +/- 7 days). The subject diary will be 
collected and reviewed with all subject’s parents/legal guardian. After receiving the 2nd 
vaccination, subjects will be observed for at least 30 minutes for any immediate 
reactions. The subjects’ parents/legal guardian will be instructed to complete a subject 
diary daily, reporting solicited local and systemic adverse events (AEs) occurring from 
Day 1 to Day 7 after vaccination with MenACWY. 
At Day 3 after vaccination a telephone call will be made to remind the subjects’ 
parents/legal guardian to complete the subject diary. 
Visit 3 (Age 6 months) (60 days after Visit 2 +/- 7 days). The subject diary will be 
collected and reviewed with all subject’s parents/legal guardian. After receiving the 3rd 
vaccination, subjects will be observed for at least 30 minutes for any immediate 
reactions. The subjects’ parents/legal guardian will be instructed to complete a subject 
diary daily, reporting solicited local and systemic adverse events (AEs) occurring from 
 
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Protocol V59_75 
Page 13 of 74 
 
 
Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
Day 1 to Day 7 after vaccination with MenACWY. 
At Day 3 after vaccination a telephone call will be made to remind the subjects’ 
parents/legal guardian to complete the subject diary. 
Visit 4 (Age 12 Months) (Inclusive + 14 days). The subject diary will be collected and 
reviewed with all subject’s parents/legal guardian. 
After receiving 4th vaccination, subjects will be observed for at least 30 minutes for any 
immediate reactions. The subjects’ parents/legal guardian will be instructed to complete 
a subject diary daily, reporting solicited local and systemic adverse events (AEs) 
occurring from Day 1 to Day 7 after vaccination with MenACWY. 
At Day 3 after vaccination a telephone call will be made to remind the subjects’ 
parents/legal guardian to complete the subject diary. 
Visit 5 (Age 13 Months) (30 days after Visit 4;-7, +14 days). The subject diary will be 
collected and reviewed with all subject’s parents/legal guardian. A blood sample of 
approximately 5ml will be collected to evaluate the level of bactericidal antibodies. 
Visit 6 will be appointed for when subject reaches 24 months of age (+/-60 days). 
Visit 6 (24 months of age; +/- 60 days). A blood sample of approximately 5ml will be 
collected to evaluate the level of bactericidal antibodies. Any symptoms or medical 
events that are new or changed since previous visit, such as SAEs, medically attended 
AEs or AEs leading to premature withdraw, and medications used to treat them. 
All blood draws should be delayed in case the subjects received oral or parenteral 
antibiotic treatment in the 7 days prior to the scheduled blood draw. 
Study Vaccines: 
The study Novartis MenACWY vaccine is obtained by extemporaneous mixing just 
before injection of the lyophilized Men A component to be re-suspended with the liquid 
Men CWY component. After reconstitution the MenACWY vaccine will have the 
following composition per 0.5 mL of injectable solution: 
 
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Protocol V59_75 
Page 14 of 74 
 
 
Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
Table 3: 
Composition of Novartis MenACWY Conjugate Vaccine 
Primary Endpoint(s): Immunogenicity Endpoint(s). 
No specific criteria are established to assess adequacy of the antibody persistence. All 
analyses will be run descriptively. 
• Percentage of subjects with hSBA ≥ 8 at Visits 5 and 6 
• hSBA GMTs at Visits 5 and 6 
• Percentage of subjects with rSBA ≥ 8 at Visits 5 and 6 
• Percentage of subjects with rSBA ≥ 128 at Visits 5 and 6 
 
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Name of Ingredients 
Quantity per dose 
CRM197-MenA conjugate 
10 µg MenA, 12.5 – 33 µg CRM197 
CRM197-MenC conjugate 
5 µg MenC, 6.5 - 12.5 µg CRM197 
CRM197-MenW conjugate 
5 µg MenW, 3.3 – 10 µg CRM197 
CRM197-MenY conjugate 
5 µg MenY, 3.3 – 10 µg CRM197 
Sodium chloride 
4.5 mg 
Sucrose 
12.5 mg 
Sodium phosphate buffer 
10 mM 
Potassium dihydrogen phosphate 
5 mM 
Water for injection 
qS to 0.5 mL 

Novartis Vaccines 
10 DEC 14 Final Protocol Version #1 
Confidential 
Protocol V59_75 
Page 15 of 74 
 
 
Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
• rSBA GMTs at Visits 5 and 6 
Safety Endpoint(s): 
Percentage of subjects with: 
• Immediate reactions reported within 30 minutes after vaccination. 
• Solicited local and systemic adverse events from Day 1 to Day 7 following each 
vaccination 
• Medically-attended unsolicited AEs and AEs leading to premature withdraw 
from Day 1 to Visit 6 (at 24 months of age) 
• SAEs from Day 1 to Visit 6 (at 24 months of age) 
Statistical Analyses: 
There is no statistical hypothesis associated with the immunogenicity objective. All 
analyses will be run descriptively. 
The primary objective is to evaluate the persistence of the antibody response against N. 
meningitidis serogroups A, C, W and Y at approximately 1 year after completion of a 4- 
dose infant vaccination. This persistence will be summarized as the percentage of 
subjects with a titer ≥8 (hSBA) or with a titer ≥ 8 and ≥128 (rSBA) along with 
associated two-sided 95% Clopper-Pearson confidence intervals. 
The antibody titers will be summarized using GMTs with two-sided 95% confidence 
intervals constructed by exponentiation (base 10) of the means and confidence limits of 
the logarithmically transformed (base 10) antibody titer. Moreover the geometric mean 
ratios (GMR) between visit 6 (1 year after full vaccination) and visit 5 (1 month after 
full vaccination) will be provided along with the 2-sided 95% confidence intervals. 
Approximately 135 subjects will be enrolled in this study providing approximately 100 
evaluable subjects, assuming a 25% drop-out. The sample size is based on the number of 
subjects requested and agreed with South Korean Health Authorities for this persistence 
 
 
 
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Name of Sponsor: 
Novartis Pharma 
Services AG 
Protocol number: 
V59_75 
Generic name of study vaccine(s): 
MenACWY-CRM (Menveo®) is a 
Meningococcal (Groups A, C, Y and W- 
135), Oligosaccharide Diphtheria 
CRM197 Conjugate Vaccine. 
study. 
With 100 evaluable subjects, the 95% confidence limits of the observed percentages of 
subjects with hSBA titer ≥8 or rSBA titer titer ≥ 8 or ≥128 will be as presented in the 
following table. 
Table 4: 
Calculated 95% Confidence Interval, Associated With Different 
Observed Percentages of Subjects 
Dependent on the point estimate, the length of the confidence interval will be 12% - 
20%. 
The analyses will be done on the Full Analysis Set (FAS population). 
Additional details will be described in the statistical analysis plan. 
Interim Analysis: 
The interim analysis is not applicable in this study. 
Data Monitoring Committee: 
The Data Monitoring Committee is not Applicable for this study. 
 
 
 
 
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Observed percentage 
95% confidence interval 
(Menveo® N=100) 
50% 
40%- 60% 
60% 
50%-70% 
70% 
61%-79% 
80% 
72%-88% 
90% 
84%-96% 

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Time and Events Table – Treatment Period 
 
Visit Type 
Clinic Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
1 
3 
61 
63 
121 
123 
301 
304 
331 
661 
Study Day 
Visit Window (Days) 
n/a 
-1/+1 
+/-7 
n/a 
+/-7 
-1/+1 
+14 
-1/+1 
-7/+14 
+/-60 
Months of age 
2 
4 
6 
12 
13 
24 
Visit Number 
1 
2 
3 
4 
5 
6 
Study Event 
References 
Study Treatment 
Vaccination 
Section 5.2 
X 
X 
X 
X 
Screening and Safety 
Inform Consent * 
Section 5.1.1 
Xa 
Medical History 
Section 5.1.2 
X 
Physical Exam 
Section 5.1.2 and 5.3.1 
Xb 
X 
X 
X 
•
X 
X 
Exclusion/Inclusion Criteria 
Section 4.0 
Xc 
X 
X 
X 
X 
X 
30 Minutes Post Injection 
Assessment 
Section 5.2.1 
X 
X 
X 
X 
Subject Diary 
Dispensed/Training 
Section 5.2.1 
X 
X 
X 
X 
Subject Diary Reminder Call 
Section 5.2.2 
X 
X 
X 
X 
Subject Diary Review/ Collect 
Section 5.3.1 
X 
X 
X 
X 
Assess all solicited AEs 
Section 7.1.1 and 7.1.3 
Xd 
Xd 
Xd 
Xd 
Xd 
 
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Visit Type 
Clinic Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
1 
3 
61 
63 
121 
123 
301 
304 
331 
661 
Study Day 
Visit Window (Days) 
n/a 
-1/+1 
+/-7 
n/a 
+/-7 
-1/+1 
+14 
-1/+1 
-7/+14 
+/-60 
Months of age 
2 
4 
6 
12 
13 
24 
Visit Number 
1 
2 
3 
4 
5 
6 
Study Event 
References 
Assess SAEs 
Section 7.1.4 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Medically attended AEs, AEs 
leading to withdrawal 
Section 7.1.4.1 and 7.1.3 
Xc 
Xc 
Xc 
Xe 
Xe 
Immunogenicity 
Serology blood draw 
Section 3.5. 
X 
X 
 
Notes: 
a. 
Confirm consent form(s) signed prior to any procedures. * May be collected up to 5 days prior to vaccination on day 1. 
b. 
Physical examination must be performed by a qualified healthcare professional. 
c. 
Procedures to be performed prior to vaccination. 
d. 
Only solicited adverse event (AE) occurred during the day of each vaccination and for the following 6 days will be reported by the subject on a subject diary. 
e. 
SAEs, medically attended AE and AEs leading to study or vaccine withdrawal will be collected through Day 661. Please see section 6.6 for greater detail regarding 
methods for SAE and AEs leading to study or vaccine withdrawal collection 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BCDM 
Biostatistics and Clinical Data Management 
BLA 
Biologic License Application 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDT 
Electronic Data Transfer 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GMT 
hSBA 
Geometric Mean Titer 
Human Complement Serum Bactericidal Assay 
rSBA 
Rabbit Complement Serum Bactericidal Assay 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IM 
Intramuscular 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MFDS 
Ministry of Food Drugs and Safety 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SDA 
Source Data Agreement 
SOP 
TV 
Standard Operating Procedure 
Termination visit 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Background 
Meningococcal disease is caused by a gram-negative diplococcus, Neisseria meningitidis. 
Invasive infection by N. meningitidis usually results in bacteremia and/or meningitis, and 
can be complicated by purpuric rash (meningococcemia), arthritis, myocarditis, 
pericarditis, endophthalmitis, or pneumonia. This disease often cannot be distinguished 
clinically from other forms of acute bacterial meningitis and sepsis caused by 
Haemophilus influenzae or Streptococcus pneumoniae. The signs of meningococcal 
meningitis in adults include headache, stiff neck, fever, chills, malaise, and prostration. 
Asymptomatic colonization of the upper respiratory tract by encapsulated N. meningitidis 
is common, yet only a small percentage of colonized persons develop disease. 
Transmission is thought to be via droplets of respiratory tract secretions. 
Novartis Vaccines and Diagnostics has developed a quadrivalent conjugate vaccine aimed 
at preventing disease in infants and older age groups due to Neisseria meningitidis 
serogroups A, C, W, and Y. Serogroup prevalence varies with geography, time of year, 
and age group. Currently, serogroup B and C strains are most prevalent in Europe, and 
serogroup B, C and Y strains are most prevalent in North America.1 
 
N meningitidis serogroup A strains are responsible for large epidemics of bacteremia and 
meningitis in sub-Saharan Africa, with attack rates as high as 500 to 1000 per 100,000 
population.2 Outbreaks due to serogroup W have also recently been reported in the same 
geographic location and among Hajj pilgrims. 
 
Meningococcal vaccines containing polysaccharides of serogroups A, C, W and Y were 
licensed to control meningococcal epidemics, but their use is limited by poor immune 
response and protection for young children, especially those younger than 2 years of age 
(the group that is generally at highest risk of disease). The available polysaccharide 
vaccines also do not induce immunologic memory and may trigger immunologic hypo 
responsiveness, even in older individuals. 
 
Novartis’ meningococcal C conjugate vaccine (Men C, Menjugate), has been licensed in 
over 30 countries worldwide and has been successfully used in immunization campaigns 
in response to serogroup C meningococcal outbreaks in the United Kingdom and Quebec, 
Canada (Trotter C, Lancet 2004: 364: 365-367). 12 The development program for 
Novartis’ Meningococcal ACWY conjugate vaccine (Novartis MenACWY, Menveo®) 
builds upon this experience and includes manufacturing methods similar to those 
employed for Menjugate. In brief, the vaccine synthesis involves production of sized 
oligosaccharides from each of the four meningococcal serogroups (A, C, W, and Y) and 
their individual conjugation to the protein carrier, CRM197. Therefore, the intent of this 
 
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program is to provide a meningococcal conjugate vaccine with broad serogroup coverage, 
protecting persons across all age groups, from infants through adults. 
 
In 2010, Menveo®, (Meningococcal ACWY Conjugate Vaccine) was licensed for use in 
adolescents and adults, 11 years of age and older in the United States. 
 
On October 27, 2010, the Advisory Committee on Immunization Practices (ACIP) 
approved updated recommendations for the use of quadrivalent meningococcal conjugate 
vaccines in adolescents and persons at high risk for meningococcal disease 
(Recommendations of the Advisory Committee on Immunization Practices (ACIP). 
Morbidity and Mortality Weekly Report (MMWR). The two new recommendations 
approved are: (1) a booster dose at age 16 years in subjects immunized at 11 to 12 years 
of age and (2) a 2-dose primary series administered 2 months apart for persons aged 2 
through 54 years with persistent complement component deficiency (e.g., C5--C9, 
properidin, factor H, or factor D) and functional or anatomic asplenia, and for adolescents 
with human immunodeficiency virus (HIV) infection. 
 
Supplementary BLAs (sBLAs) for an expanded age indication in children (2 10 years of 
age) and infants (2-23 months of age) were approved in US in January 2011 and August 
2013, respectively. In EU two variations for the same extensions were submitted in 
August 2011. The variation to expand age indication in children (2-10 years of age) was 
approved in April 2012. Currently MenACWY vaccine is registered for vaccination of 
adolescents and adults in more than 60 countries; many of these countries have also 
approved use in children (2 10 years of age) and infants (2-23 months of age). 
 
1.2 
Rationale 
 
Novartis MenACWY (Menveo®) has been approved for use in people 2 months through 
55 years of age in the United State and in people of 2 years and above in Europe and other 
countries, including the Republic of South Korea. In South Korea, the indication was 
extended in May 2014 to infants 2 months of age to 55 years, and as post commitment of 
indication change, the Regulatory Authorities of the Republic of South Korea, (MFDS) 
have requested data on immunogenicity persistence in the Korean children who received 
4 doses of Menveo® at 2-4-6-12 months of age. 
 
 
 
 
 
 
 
 
 
 
 
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2.0 
OBJECTIVES 
 
2.1 
Primary Objective(s) 
Primary Safety Objective(s) 
To assess the safety and tolerability of MenACWY administered at 2-4-6 and12 months 
of age. 
 
Primary Immunogenicity Objective(s) 
1. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose infant 
vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as measured 
by hSBA titers ≥8. 
2. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose infant 
vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as measured 
by rSBA titers ≥8 and ≥128. 
 
2.1 
Secondary Objective(s) 
Secondary Immunogenicity Objectives 
1. To describe hSBA titers ≥8 and hSBA GMTs against N. meningitidis serogroups A, 
C, W and Y 1 month after a full vaccination series at 2,4,6 and 12 months of age 
2. To describe rSBA titers ≥8 and ≥128 rSBA and GMTs against N. meningitidis 
serogroups A, C, W and Y 1 month after a full vaccination series at 2,4,6 and 12 
months of age 
3. To evaluate the persistence of the antibody response against N. meningitidis 
serogroups A, C, W and Y at approximately 1 year after completion of a 4-dose infant 
vaccination series (2, 4, 6 and 12 months of age) of MenACWY vaccine as measured 
by hSBA GMTs and rSBA GMTs 
 
 
 
 
 
 
 
 
 
 
 
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3.0 
STUDY DESIGN 
 
3.1 
Overview of Study Design 
This is a Phase IV multicenter open label, post marketing committement study to evaluate 
the persistence of antibody response in approximately 135 children 1 year after 
completion of series of Menveo® vaccination at 2-4-6-12 month vaccination. The study 
foresees 6 clinical visits, 2 blood draws (at 13 and 24 months) and 4 reminder phone calls. 
The subjects study participation is approximately 22 months. 
 
Table 3.1-1 
Overview of the study design 
 
N Subjects 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
2-Months 
4-Months 
6-Months 
12-Months 
13- Months 
24- Months 
135 
Menveo® 
Menveo® 
Menveo® 
Menveo® 
Blood draw 
Blood draw 
 
The informed consent will be obtained prior to any study-related procedures and subjects 
will be enrolled only after their eligibility for participation is confirmed by the 
investigator. All participants will receive 4 doses of Menveo® in an open label fashion. A 
total of two blood samples will be drawn from all subjects for immunogenicity evaluation 
at the following time points: 1 month after the fourth and last dose of Menveo® vaccine, 
(Visit 5, 13 months of age) and one during the last clinical visit (Visit 6, 24 months of 
age). 
 
After each vaccination, all subjects will remain under medical supervision at the study 
site for at least 30 minutes to be monitored in case of a hypersensitivity reaction. 
Furthermore, subject’s parent/legal guardian will be instructed on the completion of a 
subject diary, to record solicited local and systemic AEs and other solicited events 
(including body temperature and use of analgesics/antipyretics for prophylaxis or 
treatment), for 7 days, starting on the day of vaccination and continuing during each of 
the 6 days following vaccination. They will also be instructed to call the site if they 
develop any adverse event(s) of concern including those which require admission to a 
hospital or an emergency room or a visit to/by a doctor. In order to ensure proper 
completion of the subject diary four reminder calls will be carried out by the site staff 2 
days after each vaccination visit (e.g. on Day 3). 
 
Subject diary will be collected by study staff at the next clinical study visits until visit 5. 
The safety information obtained by study personnel will be recorded on the appropriate 
web based system referred to as Electronic Data Capture (EDC). 
 
Site staff will record the following selected safety measures in the EDC: 
 
 
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• Solicited local adverse events: Injection site erythema, injection site induration, 
injection site tenderness (from Day 1 to Day 7 after each Men ACWY 
vaccination) 
• Solicited systemic adverse events: Change in eating habits, sleepiness, irritability, 
vomiting, diarrhea, fever (from Day 1 to Day 7 after each Men ACWY 
vaccination). 
• Unsolicited Adverse Events: All medically-attended unsolicited AEs and AEs 
leading to premature withdrawal will be collected (From Day 1 of the study and 
orally during the last clinical visit) 
• Serious AEs: All SAEs will be collected from day 1 to end of study. SAEs will be 
monitored until resolution and/or the cause is identified (if a SAE remains 
unresolved at study termination, a clinical assessment will be made by the 
investigator and the Novartis medical monitor to determine whether continued 
follow up of the SAE is warranted) Medications used to treat any medically- 
attended AE and SAE will be collected from Day 1 of the study and during the 
last clinical visit. 
• Note that all medically-attended unsolicited AEs, AEs leading to premature 
withdraw and all the medication used to treat them, these data will be captured by 
interviewing the subject and/or subjects’ parents/guardian (as applicable) during 
clinic visits. 
 
3.2 
Study Period 
Each subject should expect to participate in the study for 22 months, from the time of 
enrolment through the last study visit. 
 
3.3 
Blinding Procedures 
 
The trial is designed as an open label study; therefore blinding procedures are not 
applicable. 
 
3.4 
Data Collection 
 
3.4.1 
Data Collected from Subjects 
 
The following data will be collected from each subject over the duration of their study 
participation: 
• Demographic Information (Date of Birth, Sex, Weight, Height) 
 
 
 
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• Adverse Events Seriousness, Date of Onset, Date of Resolution, Frequency, 
Severity, Actions Taken, Outcome, Relationship to Study Vaccine 
• Medical History that may be relevant to subject eligibility for study participation 
such as prior vaccinations 
• Concomitant Medications 
• Vaccination record (Pre-Vaccination Body Temperature, Date of Vaccination, 
Injection Site) 
• Study termination (Reason(s) for ending study participation or Reason(s) for early 
termination) 
 
All data collected must only be identified using the Novartis Subject ID, as described in 
section 5.1.4, Randomization. 
 
3.4.2 
Tools Used for Data Collection 
 
Data will be recorded in the Subject Diary and collected on Case Report Forms (CRFs). 
 
Subject Diary 
 
Paper Diaries (pDiaries) hereafter referred to as Subject Diaries will be the only source 
document allowed for solicited local and systemic adverse events (including body 
temperature measurements), starting after the initial 30 minute post-vaccination period at 
the clinic. The following additional rules apply to documentation of safety information 
collected in the Subject Diary. 
 
1. No corrections or additions to the information recorded by the subject within the 
Subject Diary will be allowed after it is delivered to the site. 
2. Any blank or illegible fields on the Subject Diary must be described as missing in the 
CRF. 
 
Case Report Forms 
 
This study utilizes Case Report Forms (CRFs) to collect study-related data from each 
subject. A qualified site staff member(s) is required to enter subject data in the CRFs in 
English based on the medical information available in each subject’s source record. 
 
Data should be entered into the CRF in a timely fashion following each subject’s clinic 
visit, study procedure, or phone call. Each subject’s CRF casebook will be compared with 
the subject’s source records by a Novartis-approved study monitor (or designee) over the 
duration of the study in order to ensure data collection accuracy. 
 
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The following additional rules apply to documentation of Subject Diary information 
collected in the CRFs: 
 
1. The site must enter all readable entries in the Subject Diary into the CRF, including 
those values that may be biologically implausible (e.g. body temperature: 400°C). 
2. Any illegible or implausible data should be reviewed with the parent(s)/legal 
guardian(s). If an underlying solicited or unsolicited adverse event is described on 
review with the subject, this should be described in the source document and reported 
as an unsolicited adverse event in the Adverse Event CRF (e.g., if the subject above 
confirms body temperature of 40°C on the day in which body temperature: 400°C was 
written into his/her Subject Diary, this fever of 40°C should be recorded in the 
Adverse Event CRF). 
3. Any newly described safety information (including a solicited adverse event) must not 
be written into the Subject Diary and must be described in the study file as a verbally 
reported adverse event. Any adverse event reported in this fashion must be described 
as an unsolicited adverse event and therefore entered on the Adverse Event CRF. 
 
3.5 
Collection of Clinical Specimens 
During the study will be collected 2 blood draws approximately at 13 and 24 months 
(Visit 5 and Visit 6). Detailed information about the laboratory assays is to be provided in 
section 7.0, Assessments. 
 
Processing of each specimen should be completed by a qualified site member and in 
accordance with the study-specific Clinical Specimen Laboratory Manual. Testing of 
clinical specimens will be performed by a Novartis or designated laboratory. Refer to the 
study-specific Clinical Specimen Laboratory Manual for additional details. 
 
Blood Specimens 
 
An approximately 5 mL sample of blood will be drawn from all subjects at visits 5 and 6; 
a 5 mL sample of blood will provide the necessary serum volume for the serology 
assays (approximately half of the blood draw volume). The blood volume will not exceed 
5 mL at each time point. 
 
The blood will be used for immunological assays See section 7.0, Assessments for 
additional details. 
 
The total amount of blood collected over the study period per subject will be 10 mL. 
 
 
 
 
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3.6 
Stopping/Pausing Guidelines 
 
There are no predetermined stopping rules other than circumstances for which subjects 
may not be eligible for additional study vaccinations as described in section 4.0, Selection 
of Study Population or may be withdrawn from the study according to the best interests of 
the subject as described in section 3.8, Premature Withdrawal from Study. 
 
3.7 
Data Monitoring Committee 
Not applicable for this study. 
 
3.8 
Premature Withdrawal from Study 
Subjects may withdraw at any time, or be dropped from the study at the discretion of the 
investigator should any untoward effects occur and/or for safety reasons. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if he/she violates the study 
plan or for administrative reasons. The investigator or study coordinator must notify the 
Sponsor immediately when a subject has been withdrawn due to an adverse event. 
 
The circumstances above are referred to as premature withdrawal from the study, and the 
reason for premature withdrawal should be clearly documented and detailed in the source 
documentation. The investigator should make every attempt to evaluate the subject’s 
safety, including resolution of ongoing AEs, at the time of premature withdrawal. If a 
subject wants to withdraw from the study before all doses are administered or prior to the 
last planned study visit, the subject will be asked to be followed for safety for the duration 
of the study. When a subject withdraws, or is withdrawn, from the study, the procedures 
described in section 5.5.1, Early Termination Visit should be completed if possible. 
 
The reasons for premature withdrawal from the study include: adverse event, death, 
withdrawal of consent, lost to follow-up, administrative reason, and protocol deviation. 
These reasons are described in greater detail below. 
 
Adverse Event 
For any subject withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the reason for 
discontinuing the study. This AE must be identified on the AE CRF page by indicating 
“Withdrawn from study due to AE”. Any ongoing AEs at the time of study withdrawal 
must be followed until resolution or stabilization. 
 
Subjects who develop a serious adverse event (SAE) judged to be possibly or probably 
related to the study vaccine, including hypersensitivity reactions, should not receive 
subsequent vaccination. 
 
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Death 
 
For any subject withdrawn from study participation due to death, this should be noted on 
the Study Termination CRF page and the associated SAE that led to the death must be 
reported. 
 
Withdrawal of consent 
 
The subject parent(s)/legal guardian(s) can withdraw consent for participation in the study 
at any time without penalty or loss of benefit to which the subject is otherwise entitled. 
Reason for early termination should be deemed as “withdrawal of consent” if the subject 
withdraws from participation due to a non-medical reason (i.e., reason other than AE). If 
the subject parent(s)/legal guardian(s) intends to withdraw consent from the study, the 
investigator should clarify if the subject will withdraw completely from the study or if the 
subject will continue study participation for safety, or a subset of other study procedures. 
If the subject requests complete withdrawal from the study, no further study interventions 
will be performed with the subject. 
 
Lost to Follow-Up 
 
For subjects who fail to show up for final visits (clinic or telephone contacts), or for three 
consecutive visits, study staff are encouraged to make at least three documented attempts 
to contact the subject by telephone and at least one documented written attempt to contact 
the subject parent(s)/legal guardian(s) to encourage the completion of study termination 
procedures. These efforts to contact the subject should be recorded in the source 
document. The termination date for the subject to be captured on the Study Termination 
CRF page is the date of the last successful contact (clinic visit or telephone) with the 
subject. 
 
Administrative Reason 
 
Examples for subjects withdrawn from the study due to administrative reason can include: 
Sponsor decision to terminate the study, subject meeting a pre-specified withdrawal 
criterion, subject discontinuation for insurance issues, moving, no time, etc. This reason 
should be noted in the Study Termination CRF page and any ongoing AEs at the time of 
study withdrawal must be followed until resolution/stabilization. 
 
If the clinical study is prematurely terminated by the Sponsor, the investigator is to 
promptly inform the study subjects and local EC/IRB and should assure appropriate 
therapy and follow up for the subjects. All procedures and requirements pertaining to the 
archiving of study documents should be followed. All other study materials (study 
medication/vaccines, etc.) must be returned to the Sponsor. 
 
 
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For subjects who are withdrawn from the study due to receipt of an excluded 
medication/vaccination or due to significant protocol non-compliance, this reason should 
be noted in the Study Termination CRF page. 
 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. In general, subjects associated with protocol deviations 
may remain in the study unless continuation in the study jeopardizes the subject’s health, 
safety, or rights. 
 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring 
the study to request approval of a protocol deviation, as no authorized deviations are 
permitted. If the investigator feels a change to the protocol would improve the conduct of 
the study this must be considered a protocol amendment, and unless such an amendment 
is agreed upon by Novartis and approved by the IRB/EC and health authorities it cannot 
be implemented. 
 
3.9 
End of Study 
 
Most clinical trials intended to support the efficacy/immunogenicity and safety of an 
Investigational Product proceed to full completion of planned sample size accrual. 
 
Evaluation of the primary and/or secondary immunogenicity/efficacy objectives requires 
the testing of biological samples from the study subjects, which can only be completed 
after all samples are collected. The last samples for the analysis of the primary and/or 
secondary objectives will be taken at visit 6. For the purpose of this protocol, end of study 
is defined as the completion of the testing of such biological samples, to be achieved no 
later than 8 months after collection of the last biological sample visit 6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.0 
SELECTION OF STUDY POPULATION 
 
4.1 
Inclusion Criteria 
In order to participate in this study, all subjects must meet ALL of the inclusion criteria 
described. 
 
1. Healthy male and female 2 month-old infants (55 – 89 days) on the day of consent. 
2. Infants whose parents or legal guardians have voluntary given written informed 
consent after the nature of the study has been explained according to local regulatory 
requirements, prior to study entry. 
3. Infants whose parents or legal guardians can comply with study procedures including 
follow-up 
 
Prior to receipt of study vaccination, subjects must be evaluated to confirm that they are 
eligible for subsequent vaccination. If subjects do not meet any of the original inclusion 
criteria listed above, they should not receive additional vaccinations. 
 
4.2 
Exclusion Criteria 
Each subject must not have/have been: 
 
1. previously received any meningococcal A, C, W and Y vaccines. 
2. previous confirmed or suspected disease caused by N. meningitidis or who have had 
household contact with and/or intimate exposure to an individual with laboratory 
confirmed N. meningitidis infection at any time since birth. 
3. progressive, unstable or uncontrolled clinical conditions. 
4. a history of anaphylactic shock, asthma, urticaria or other allergic reaction after 
previous vaccinations or known hypersensitivity to any vaccine component, such as 
latex allergy. 
5. experienced significant acute or chronic infection within the previous 7 days or have 
experienced fever (temperature ≥ 38.0°C [100.4°F]) within the previous 3 days. 
6. any confirmed or suspected immunosuppressive or immunodeficient condition, based 
on medical history and physical examination. 
7. received treatment with systemic administration corticosteroids (PO/IV/IM) for more 
than 14 consecutive days from birth. 
 
 
 
 
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8. ever received blood, blood products and/or plasma derivatives or any parenteral 
immunoglobulin preparation (including Hepatitis B immune globulin) at any time 
since birth and for the full length of the study. 
9. any bleeding disorder which is considered as a contraindication to intramuscular 
injection or blood draw. 
10. any condition which, in the opinion of the investigator, might interfere with the results 
of the study or pose additional risk to the subject due to participation in the study. 
11. received or are planning to receive any investigational or non-registered medicinal 
product from birth and throughout the study. 
12. received oral or parenteral antibiotic treatment in the 3 days prior to the scheduled 
blood draw (topical antibiotics are acceptable, including antibiotic eye drops). 
13. relatives of site research staff working on this study. 
 
Prior to receipt of study vaccination, subjects must be evaluated to confirm that they are 
eligible for subsequent vaccination. At subsequent vaccinations, if subjects meet any of 
the original exclusion criteria listed above (with exception exclusion criteria 1, previous 
received the study vaccine), they should not receive additional vaccinations. 
 
4.3 
Criteria for Delay of Vaccination 
There may be instances when individuals meet all eligibility criteria for vaccination yet 
have a transient clinical circumstance which may warrant delay of vaccination: 
 
• experienced significant acute or chronic infection within the previous 7 days or 
have experienced fever (temperature ≥ 38.0°C [100.4°F]) within the previous 3 
days 
• or use of antipyretics and/or analgesic medications within 24 hours prior to 
vaccination. 
 
Under such circumstances, a subject may be considered eligible for study enrolment after 
the appropriate window for delay has passed and inclusion/exclusion criteria have been 
rechecked, and if the subject is confirmed to be eligible. 
 
 
 
 
 
 
 
 
 
 
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5.0 
STUDY PROCEDURES 
 
The sections that follow provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following subjects who participate in this clinical study. Visits 
can be either clinic visits or safety follow-up telephone calls, as specified in the Table 
below and in the Time and Events Table. 
 
Table 5.0-1 
Study Procedures 
 
Visit Category 
Procedures 
Pre-vaccination Clinic Visit(s) 
Section 5.1. describes procedures to be followed 
prior to study vaccination: informed consent/assent, 
screening, enrolment, and randomization 
Vaccination Clinic Visit(s) 
Section 5.2 describes procedures to be followed 
during each clinic visit involving vaccination: 
vaccination, post-vaccination procedures, and post- 
vaccination reminder calls 
Post-vaccination Visit(s) 
Section 5.3 describes follow-up clinic visits and 
safety follow-up calls 
Unscheduled Visit(s) 
Section 5.4 describes possible procedures to be 
followed at unscheduled clinic visit 
Study Termination Visit 
Section 5.5 describes procedures to be followed at 
the last study visit for a subject (may include early 
termination visit) 
 
5.1 
Pre-vaccination Clinic Visit(s) 
This section describes the procedures that must be performed for each potential subject 
prior to vaccination, including obtaining informed consent/assent, screening, enrolment 
and randomization. 
 
5.1.1 
Informed Consent/Assent 
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, and 
without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and potential 
benefits, and the requirements of the research to be able to make an informed decision. 
 
Informed consent following local IRB/EC guidance must be obtained before conducting 
any study-specific procedure (i.e., all of the procedures described in the protocol). The 
 
 
 
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process of obtaining informed consent should be documented in the subject source 
document in addition to maintaining a copy of the signed and dated informed consent. 
 
Informed consent of the parent(s)/legal guardian(s) and assent of subject following local 
IRB/EC guidance must be obtained before conducting any study-specific procedures (i.e., 
all of the procedures described in the protocol). The process of obtaining informed 
consent and assent should be documented in the subject source document in addition to 
maintaining a copy of the signed and dated informed consent. Additional specifics 
regarding the informed consent and assent processes are located in section 13.2, Informed 
Consent Procedures. 
 
If a subject parent(s)/legal guardian(s) is unable to read, an impartial witness should be 
present during the entire informed consent discussion. An impartial witness is defined as 
a person who is independent from study conduct, who cannot be unfairly influenced by 
those involved with the study, who attends the informed consent process if the subject or 
the subject's legally acceptable representative cannot read, and who reads the informed 
consent form and any other written information supplied to the subject. After the written 
informed consent form and any other written information to be provided to subjects, is 
read and explained to the subject parent(s)/legal guardian(s) and after the subject 
parent(s)/legal guardian(s) has verbally consented to the subject’s participation in the 
study and, if capable of doing so, has signed and personally dated the informed consent 
form, the witness should sign and personally date the consent form. By signing the 
consent form, the witness attests that the information in the consent form and any other 
written information was accurately explained to, and apparently understood by, the 
subject parent(s)/legal guardian(s) and that informed consent was freely given by the 
subject parent(s)/legal guardian(s). 
 
5.1.2 
Screening 
After an individual has consented to participate in the study and informed is signed, that 
individual will be given a unique Screening Number manually created by the investigator. 
The subject’s unique Screening Number will be documented in the Screening and 
Enrolment log. The eligibility of the subject will be determined based on the inclusion 
and exclusion criteria listed in section 4.0, Selection of Study Population and evaluated 
during this screening procedure. 
 
Prior to study enrolment, demographic data will be collected from the subject, including: 
age, sex, race, height, weight and ethnicity. Medical history will also be collected, 
including but not limited to any medical history that may be relevant to subject eligibility 
for study participation such as prior vaccinations, concomitant medications, and previous 
and ongoing illnesses or injuries. Relevant medical history can also include any medical 
history that contributes to the understanding of an adverse event that occurs during study 
 
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participation, if it represents an exacerbation of an underlying disease/pre-existing 
problem. 
 
Review of systems is a structured interview that queries the subject parent(s)/legal 
guardian(s) as to any complaints the subject has experienced across each organ system. 
This will be performed before enrolment and used to guide physical examination. 
 
If applicable, prior and concomitant medications or vaccinations taken prior to start of 
study should be collected (refer to section 6.5, Prior and Concomitant Medications and 
Vaccines for further details). 
 
Collect vital signs, including heart rate, temperature (this data is to be recorded in the 
source documents only). Vital signs measurements can be performed by a trained health 
care professional. 
 
A general physical examination is to be performed by a qualified health care practitioner. 
“Qualified health care practitioner” refers to any licensed health care professional who is 
permitted by institutional policy to perform physical examinations and who is identified 
within the Study Staff Signature Log. 
 
These data will be written in the source document (see section 9.1, Source 
Documentation). Should the physical assessment reveal any abnormal values or events, 
these must be documented in the CRF Adverse Events Form. 
 
In the event that the individual is determined ineligible for study participation, he/she is 
considered a screen failure. The reason for screen failure must be documented in the 
Screening and Enrolment log. If the individual is determined to be eligible for the study, 
he/she will be enrolled into the study. 
 
5.1.3 
Enrolment 
After signing the informed consent form, if an individual is determined to be eligible for 
study participation, the investigator will enroll the subject and enter the Screening 
Number into the EDC system. 
 
5.1.4 
Randomization 
This is a non-randomized study. Enrolled subjects will be manually assigned a unique 
Subject ID. The Subject ID will be the subject’s unique identification number for all 
CRFs and associated study documentation that will be used for duration of the study. The 
Screening Number ceases to be used and remains in the Screening and Enrolment Log 
only. 
 
 
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If for any reason, after enrolment the subject fails to undergo the study procedures, this is 
an Early Termination and the reason should be recorded in source document as specified 
in the Source Data Agreement. The information on these Early Termination subjects 
should be kept distinct in the source documentation from subjects who are screen failures, 
as described in section 5.1.2, Screening. 
 
5.2 
Vaccination Clinic Visit(s) 
Vaccination will be performed on day 1, day 61, day 121 and day 301. For studies which 
have visits for concomitant vaccinations or treatments, see section 6.5, Prior and 
Concomitant Medications and Vaccines for those visit procedures. 
 
After completing the pre-vaccination procedures on day 1, administer the vaccine to the 
subject according to the procedures described in section 6.3, Vaccine Preparation and 
Administration. Prior to administration of each vaccination, confirm that the subject is 
eligible for additional study vaccinations and does not meet any criteria for delaying 
additional study vaccinations as described in section 4.0, Selection of Study Population. 
 
5.2.1 
Post-vaccination Procedures 
 
The following post-vaccination procedures will be performed on day 1, day 61, day 121 
and day 301. 
 
After vaccination, the subject will be observed for at least 30 minutes including 
observation for, solicited adverse events, and body temperature measurement. Record all 
safety data collected during this time in the subject’s source document. 
 
A Subject Diary will be used in this study to document solicited adverse events. The 
Subject Diary is the only source for collection of these data; therefore, it is critical that the 
subject parent(s)/legal guardian(s) completes the Subject Diary correctly. The subject 
parent(s)/legal guardian(s) should be trained on how and when to complete each field of 
the Subject Diary. 
 
The subject parent(s)/legal guardian(s) should be trained on how to measure local 
solicited adverse events and body temperature. The measurement of solicited local 
adverse events is to be performed using the ruler provided by the site. 
 
The subject parent(s)/legal guardian(s)] should be instructed how to perform body 
temperature measurement using the thermometer provided by the site. If the subject feels 
unusually hot or cold during the day, the subject parent(s)/legal guardian(s) should check 
body temperature. If the subject has fever, the highest body temperature observed that day 
should be recorded in the Subject Diary. 
 
 
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Subject Diary training should be directed at the individual(s) who will perform the 
measurements of adverse events and who will enter the information into the Subject 
Diary. This individual may not be the subject parent(s)/legal guardian(s), but if a person 
other than the subject parent(s)/legal guardian(s) enters information into the Subject 
Diary, this person’s identity must be documented in the Subject Diary and in the subject’s 
source record. Any individual that makes entries into the Subject Diary must receive 
training on completion of the Subject Diary at the time of the visit. This training must be 
documented in the subject’s source record. 
 
The site should schedule the next clinic visit with the subject parent(s)/legal guardian(s). 
 
The subject parent(s)/legal guardian(s) should be reminded of the next planned study 
activity. The subject parent(s)/legal guardian(s) will be reminded to complete the Subject 
Diary and to contact the site if there are any questions, and to contact the site immediately 
(or as soon as the subject is medically stable) if the subject has a medical condition that 
leads to a hospitalization or an emergency room visit or to a visit to/by a doctor or is of 
concern. 
 
5.2.2 
Post-vaccination Reminder Calls 
Subject Diary reminder calls will be performed on day 3 after each vaccination. The 
purpose of this call is to remind the subject parent(s)/legal guardian(s) about completion 
of the Subject Diary. The call follows the Subject Diary Reminder Telephone Call Script 
provided to the site. The subject parent(s)/legal guardian(s) should be reminded to contact 
the site via the telephone number provided in the informed consent to discuss medical 
questions. 
 
5.3 
Post-vaccination Visit(s) 
Post-vaccination visits will be performed on day 331 and on day 661. 
 
5.3.1 
Follow-up Clinic Visit(s) 
During the follow-up clinic visit, the Subject Diary will be reviewed. No changes to the 
information recorded within the Subject Diary are permissible. For details on the Subject 
Diary see sections 3.4.2, Tools Used for Data Collection and 5.2.1, Post-vaccination 
Procedures. The subject parent(s)/legal guardian(s)] will be interviewed to determine if 
any unsolicited adverse events occurred and if any concomitant medications or vaccines 
were taken/received in the time since the last clinic visit. The healthcare professional 
reviewing these data will discuss the symptoms (if any) reported by the subject and will 
determine if any additional diagnoses and/or adverse events are present. Adverse events 
reported by the subject parent(s)/legal guardian(s) at this follow-up clinic visit must be 
 
 
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recorded in the subject's source document and on an Adverse Events CRF, as specified in 
section 7.1, Safety Assessment. 
 
Perform a brief symptom-directed physical examination if necessary according to 
symptoms the subject has reported. This is a physical examination that will include an 
examination of organ systems that are relevant to the investigator based on review of the 
subject’s reported adverse events, concomitant medication and body temperature. The 
physical assessment must be performed by the investigator or designee of the investigator, 
who is qualified to perform a physical assessment in accordance with their institutional 
policy. Corresponding information is documented in the subject’s source document and 
CRF(s). 
 
A blood sample will be collected at Visit 5 and Visit 6, as specified in section 3.5. 
 
The site should schedule the next clinic visit (if applicable) with the subject and 
parent(s)/legal guardian(s). 
 
The subject parent/legal guardian(s) will receive a written reminder of the next planned 
study activity. The subject parent(s)/legal guardian(s) will be reminded to complete the 
Subject Diary and to contact the site if there are any questions and to contact the site 
immediately (or as soon as the subject is medically stable) if the subject has a medical 
condition that leads to a hospitalization or an emergency room visit. 
 
5.3.2 
Safety Follow-up Calls 
There are no safety follow up calls in this study. 
 
5.4 
Unscheduled Visits 
An unscheduled visit describes a non-routine study visit triggered by a specific event. 
These could include anticipated or unanticipated adverse events or interventions. 
 
5.5 
Study Termination Visit 
 
The study termination visit will occur on day 661. The termination visit may be a clinic 
visit or a telephone call. The date of termination is the date of the last contact (clinic visit 
or telephone call) in which the subject’s health status was assessed or, in cases where the 
subject does not agree to any further safety follow-up, it is the date consent is withdrawn. 
This date should be recorded on the termination CRF page. For visit procedures to be 
performed for a subject whose planned study participation ends prematurely, please see 
section 5.5.1, Early Termination Visit. 
 
 
 
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At the clinic visit or during the telephone call, the following procedures will be 
performed: 
• Review of the safety information that includes review of Subject Diary, review of 
systems, interview of subject parent(s)/legal guardian(s) to collect any medically 
attended adverse events, AEs leading to withdrawal, SAEs 
• Interview of subject parent(s)/legal guardian(s) to collect concomitant 
medications/ vaccinations associated with the AEs listed above, Symptom- 
directed physical assessment is to be performed as needed (including 
measurement of vital signs, body temperature and a check of general appearance) 
• Collection of the last blood sample as specified in section 3.5 and section 4.3. 
• The site will review with the subject parent(s)/legal guardian(s) the plan of when 
information relating to the subject’s participation in the study may be available 
(e.g., study results, treatment assignments). It will also be discussed how 
information relating to the subject’s participation in the study will be shared with 
the subject’s healthcare provider, if the subject parent(s)/legal guardian(s) chooses 
to share this information 
 
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study. 
 
5.5.1 
Early Termination Visit 
 
When a subject is withdrawn from treatment or withdraws from the study, the investigator 
will notify the Sponsor and, when possible, will perform the procedures listed below. The 
reason(s) for the early termination will be included in the subject’s source documentation. 
If the Early Termination Visit is a telephone call, collect as much information as possible. 
Early Termination Visits include subjects who were enrolled but not treated. 
 
At the clinic visit or during the telephone call, the following procedures will be 
performed: 
 
• Review of the safety information that includes review of Subject Diary (if 
applicable), review of systems, interview of subject and/or parent(s)/legal 
guardian(s) to collect unsolicited adverse events occurring within 30 days of 
vaccination, medically attended adverse events, AEs leading to withdrawal, SAEs. 
• Interview of subject and/or parent(s)/legal guardian(s) to collect concomitant 
medications/ vaccinations associated with the above AEs. 
• Symptom-directed physical assessment is to be performed as needed (including 
measurement of vital signs, body temperature and a check of general appearance). 
 
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The site will review with the subject parent(s)/legal guardian(s) the plan of when 
information relating to the subject’s participation in the study may be available (e.g., 
study results, treatment assignments). It will also be discussed how information relating to 
the subject’s participation in the study will be shared with the subject’s healthcare 
provider, if the subject parent(s)/legal guardian(s) chooses to share this information. 
 
The site will complete the termination CRF page and this will mark the completion of the 
subject’s participation in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.0 
TREATMENT OF SUBJECTS 
 
All vaccines associated with this study are to be stored separately from other vaccines and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All vaccines associated with this study must be checked for expiration 
date prior to use. Expired vaccines must not be administered to subjects. 
 
6.1 
Study Vaccine(s) 
The term ‘study vaccine’ refers to those vaccines provided by the Sponsor, which will be 
evaluated as part of the study objectives. The study vaccines specific to this study are 
described below. Novartis MenACWY is licensed in South Korea in people from 2 years 
up to 55 years but Korean MFDS has recently extended the indication also in infants of 2 
months of age. 
 
Novartis MenACWY is provided in the form of: 
• MenA conjugate component: One vial containing a lyophilized powder of the drug 
substance, MenA-CRM, as well as sucrose and potassium dihydrogen phosphate 
• MenCWY conjugate component: One vial containing the drug substances MenC- 
CRM, MenW-CRM, and MenY-CRM conjugates, as well as sodium chloride, 
sodium phosphate buffer, and water for injection (WFI). 
 
The vaccine is prepared by reconstituting the lyophilized MenA component with the 
liquid MenCWY component. The final formulation contains 10-5-5-5 µg per 
oligosaccharide of N. meningitidis serogroups A, C, W, and Y respectively, without 
adjuvant. The vaccine must be administered immediately after reconstitution. Novartis 
MenACWY is intended for storage at +2°C to +8°C and should not be frozen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 6.1-1: Composition of Reconstituted Novartis MenACWY for 0.5 mL/Dose of 
Injectable Solution 
 
Name of Ingredient 
Quantity Per Dose (0.5 mL) 
Function 
Active Substances* 
MenA-CRM 
10 μg MenA + 16.7 to 33 μg CRM 
Antigen + carrier protein 
MenC-CRM 
5 µg MenC + 7.1 to 12.5 µg CRM 
Antigen + carrier protein 
MenW-CRM 
5 μg MenW + 3.3 to 8.3 μg CRM 
Antigen + carrier protein 
MenY-CRM 
5 μg MenY + 5.6 to 10 μg CRM 
Antigen + carrier protein 
Excipients 
Sodium chloride 
4.5 mg 
Tonicity modifying agent 
Sodium phosphate buffer 
Sodium dihydrogen 
phosphate 
Disodium hydrogen 
phosphate dihydrate 
10 mM 
2.5 mM 
(0.345 mg/mL) 
7.5 mM 
(1.335 mg/mL) 
pH buffering agent 
Potassium dihydrogen 
phosphate 
5 mM (0.68 mg/mL) 
pH buffering agent 
Sucrose 
12.5 mg 
Lyophilization bulking, 
tonicity modifying agent and 
stabilizer 
WFI 
Qs to 0.5 mL 
Solvent 
 
6.2 
Non-Study Vaccines 
 
The term ‘non-study vaccine’ refers to those vaccines which will be intentionally given to 
study subjects but not formally included in the analysis of study objectives. The Sponsor 
will not provide any non-study vaccines. 
 
6.3 
Vaccine Preparation and Administration 
 
The investigator or designee will be responsible for oversight of the administration of 
vaccine to subjects enrolled in the study according to the procedures stipulated in this 
study protocol. All vaccines will be administered only by personnel who are qualified to 
perform that function under applicable local laws and regulations for the specific study 
site. 
 
Detailed vaccine preparation and administration instructions will be provided to 
investigators in the Protocol Ancillary Document prior to study start. 
 
 
 
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PRECAUTIONS TO BE OBSERVED IN ADMINISTERING STUDY VACCINE: 
 
Prior to vaccination, subjects must be determined to be eligible for study vaccination and 
it must be clinically appropriate in the judgment of the investigator to vaccinate. 
Eligibility for vaccination prior to first study vaccine administration is determined by 
evaluating the entry criteria outlined in protocol sections 4.1, Inclusion Criteria and 4.2, 
Exclusion Criteria. 
 
Eligibility for subsequent study vaccination is determined by following the criteria 
outlined in section 4.3, Criteria for Delay of Vaccination. 
 
Eligibility for non-study vaccines should be determined by the investigator, pending the 
review of the package insert of the relevant vaccine. 
 
Study vaccines should not be administered to individuals with known hypersensitivity to 
any component of the vaccines. 
 
Standard immunization practices are to be observed and care should be taken to 
administer the injection intramuscularly. Before administering vaccine, the vaccination 
site is to be disinfected with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. 
DO NOT inject intravascularly or intragluteally. 
 
As with all injectable vaccines, trained medical personnel and appropriate medical 
treatment should be readily available in case of anaphylactic reactions following vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other 
medications for treating anaphylaxis should be available. 
 
6.4 
Vaccine Administration Error or Overdose of Vaccine 
Vaccine administration error is defined as receiving a dose of study vaccine that was not 
reconstituted as instructed or administered by a different route from the intended route of 
administration. An overdose of study vaccine (whether accidental or intentional) is 
defined when a dosage higher than the recommended dosage is administered in one dose 
of study vaccine of Menveo®. 
An overdose would also occur if two doses of the study vaccine are administered within 
half the time of the recommended interval between doses, as defined in the protocol. 
 
Any vaccine administration error or overdose of study vaccine detailed in this protocol 
must be reported as an adverse event, and if the vaccine administration error or overdose 
is associated with a serious adverse event, it must be reported as such within 24 hours to 
the Sponsor. 
 
 
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6.5 
Prior and Concomitant Medications and Vaccines 
 
All medications, vaccines and blood products taken or received by the subject within 60 
days prior to the start of the study are to be recorded on the Prior and Concomitant 
Medications and Blood Products CRF. 
 
In addition, the following are considered prior medications for this protocol: all 
medication/vaccines described in the inclusion and exclusion criteria of this protocol 
including: 
 
1. 
Subjects treated with systemic administration corticosteroids (PO/IV/IM) for more 
than 14 consecutive days from birth. 
 
2. 
Subjects who received oral or parenteral antibiotic treatment in the 3 days prior to 
the scheduled blood draw 
 
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination 
must be identified and the reason for their use (prophylaxis versus treatment) must be 
described in the source document and Concomitant Medications CRF. 
 
Medications taken for prophylaxis are those intended to prevent the onset of symptoms. 
Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
 
Concomitant medications taken by/administered to the subject to treat any medically- 
attended AE and SAE and all vaccines at and after enrolment and must be documented on 
the Concomitant Medications /CRF. 
 
When recording concomitant medications/vaccines, they should be checked against the 
study entry and continuation criteria in section 4.0, Selection of Study Population to 
ensure that the subject should be enrolled/continue in the study. 
 
6.6 
Vaccine Supply, Labeling, Storage and Tracking 
 
The Sponsor will ensure the following: 
▫ Supply the study vaccine(s). 
▫ Appropriate labeling of all study provided that complies with the legal requirements 
of each country where the study is to be performed. 
 
 
 
 
 
 
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The investigator must ensure the following: 
▫ Acknowledge receipt of the study vaccines by a designated staff member at the site, 
including: 
- 
Confirmation that the vaccines were received in good condition 
- 
Confirmation to the Sponsor of the temperature range during shipment from the 
Sponsor to the investigator’s designated storage location 
- 
Confirmation by the Sponsor that the vaccines are authorized for use. 
▫ Proper storage of the study vaccines, including: 
- 
Storage in a secure, locked, temperature-controlled location. 
- 
Proper storage according to the instructions specified on the labels. 
- 
Appropriate record keeping and inventory of the study vaccines, including regular 
documentation of adequate storage temperature. 
▫ Appropriate use of the study vaccines, including: 
- 
Not use of vaccines prior to receipt of authorization for use from the Sponsor. 
- 
Use only in accordance with the approved protocol. 
- 
Proper handling, including confirmation that the vaccine has not expired prior to 
administration. 
- 
Appropriate documentation of administration of vaccines to study subjects 
including: 
▪ 
Date, dosage, batch/lot numbers, expiration dates, unique identifying 
numbers assigned to subjects and study vaccines, and time of vaccine 
administration. This information will be maintained in an accountability log 
that will be reviewed by the site monitor. 
▪ 
Reconciliation of all vaccines received from the Sponsor. Reconciliation is 
defined as maintaining records of which and how many vaccines were 
received, which vaccines were administered to subjects, which vaccines 
were destroyed at the site, and which vaccines were returned to the Sponsor, 
as applicable. 
▫ Proper adherence to the local institutional policy with respect to destruction of study 
vaccines. 
▫ Complete record keeping of vaccine use, wastage, return or destruction, including 
documentation of: 
- 
Copy of the site’s procedure for destruction of hazardous material. 
 
 
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- 
Number of doses destroyed, date of destruction, destruction code (if available), 
method of destruction, and name of individual performing destruction. 
 
Vaccines that have been stored differently from the manufacturer’s indications must not 
be used unless the Sponsor provides written authorization for use. In the event that the use 
cannot be authorized, the Sponsor will make every effort to replace the vaccine supply. 
All vaccines used in conjunction with this protocol must be stored separately from normal 
hospital/practice stocks to prevent unintentional use of study vaccines outside of the 
clinical study setting. 
 
Monitoring of vaccine accountability will be performed by the study monitor during site 
visits and at the completion of the study. 
 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator must ensure that all unused study vaccines, packaging and supplementary 
labels are destroyed locally (upon approval from Sponsor) or returned to the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.0 
ASSESSMENTS 
 
7.1 
Safety Assessment 
The measures of safety used in this study are based on comparable routine clinical 
procedures. They include a close vigilance for, and stringent reporting of, selected local 
and systemic adverse events routinely monitored in vaccine clinical studies as indicators 
of reactogenicity. 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. Therefore, an AE 
can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes intercurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
 
The period of observation for AEs extends from the time the subject’s parent signs 
informed consent until the subject completes the specified safety follow-up period of 
approximately 12 months after the last study vaccination or terminates the study early 
(whichever comes first). 
 
AEs occurring after the informed consent form is signed but prior to receiving study 
vaccine/product will be documented as an adverse event and recorded within source 
document. However, any AEs occurring prior to receipt of any study vaccine will be 
analyzed separately from “treatment emergent” AEs (AEs occurring after administration 
of the first study vaccine). 
 
Adverse events are collected as either solicited or unsolicited adverse events. Solicited 
events are derived from organized data collection systems, such as Subject Diaries or 
interview. 
 
7.1.1 
Solicited Adverse Events 
The term “reactogenicity” refers to solicited signs and symptoms (“solicited adverse 
events”) occurring in the hours and days following a vaccination, to be collected by the 
subject parent(s)/legal guardian(s) for 7 consecutive days starting from the day of each 
study vaccination, using a pre-defined Subject Diary. 
 
The following solicited adverse events are included in the Subject Diary. Each adverse 
event is to be assessed using the scoring system reported in parentheses below 
 
 
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Solicited Local Adverse Events 
 
Injection site erythema, injection site induration, injection site tenderness. 
 
Solicited local adverse events will be collected daily by the subject(s) parent(s)/legal 
guardian(s) for 7 consecutive days starting from the day of each study vaccination. They 
will be recorded in the Subject Diary and entered into the eCRF 
 
Solicited Systemic Adverse Events 
Change in eating habits, sleepiness, irritability, vomiting, diarrhea, fever. Fever is defined 
as body temperature ≥ 38.0°C measured via tympanic route as preferred. 
 
Solicited systemic adverse events will be collected daily by subject(s) parent(s)/legal 
guardian(s) for 7 consecutive days starting from the day of each study vaccination. They 
will be recorded in the Subject Diary and entered into the eCRF. 
 
Other Solicited Adverse Events 
▫ Use of analgesics / antipyretics for treatment (Days 1-7 after each study vaccination) 
▫ Use of analgesics / antipyretics for prophylaxis (Days 1-7 after each study 
vaccination) 
▫ Body temperature (preferably tympanic) 
 
 
Above listed indicators of reactogenicity will be collected daily by the subject(s) 
parent(s)/legal guardian(s) for 7 consecutive days starting from the day of each study 
vaccination. They will be recorded in the Subject Diary and entered into the eCRF. 
 
The study staff must review the data entered into the Subject Diary as described in section 
3.4.2, Tools Used for Data Collection and section 5.3.1, Follow-up Clinic Visit(s). 
 
Note: Any solicited adverse event that meets any of the following criteria must be entered 
into subjects’ source document (see section 9.1, Source Documentation) and also as an 
adverse event on the Adverse Event CRF: 
 
▫ Solicited local or systemic adverse event that continues beyond day 7 after 
vaccination. 
▫ Solicited local or systemic adverse event that leads to a visit to a healthcare provider 
(medically attended adverse event, see section 7.1.3, Evaluation of Adverse Events). 
 
 
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▫ Solicited local or systemic adverse event leading to the subject withdrawing from the 
study or the subject being withdrawn from the study by the investigator (adverse event 
leading to withdrawal, see section 7.1.3, Evaluation of Adverse Events). 
▫ Solicited local or systemic adverse event that otherwise meets the definition of a 
serious adverse event (see section 7.1.4, Serious Adverse Events). 
 
7.1.2 
Unsolicited Adverse Events 
An unsolicited adverse event is an adverse event that was not solicited using a Subject 
Diary and that was spontaneously communicated by a subject parent(s)/legal guardian(s)] 
who has signed the informed consent. 
 
7.1.3 
Evaluation of Adverse Events 
Every effort should be made by the investigator to evaluate safety information reported by 
a subject for an underlying diagnosis and to capture this diagnosis as the event in the AE 
page. In other words, the practice of reporting only symptoms (e.g., “cough” or “ear 
pain”) are better reported according to the underlying cause (e.g., “asthma exacerbation” 
or “otitis media”). 
 
The severity of events reported on the Adverse Events CRF will be determined by the 
investigator as: 
 
Mild: 
transient with no limitation in normal daily activity. 
Moderate: 
some limitation in normal daily activity. 
Severe: 
unable to perform normal daily activity. 
 
The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related to an investigational vaccine if there is evidence that clearly 
indicates an alternative explanation. If the subject has not received the vaccine, the timing 
of the exposure to the vaccine and the onset of the AE are not reasonably related in time, 
or other facts, evidence or arguments exist that reasonably suggest an alternative 
explanation, then the AE is not related. 
 
 
 
 
 
 
 
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2. Possibly Related 
 
The administration of the investigational vaccine and AE are considered reasonably 
related in time and the AE could be explained by exposure to the investigational vaccine 
or by other causes. 
 
3. Probably Related 
 
Exposure to the investigational vaccine and AE are reasonably related in time and no 
alternative explanation has been identified. 
 
The relationship of the study treatment to an unsolicited AE will be determined by the 
investigator. 
 
Note: solicited AEs will not be evaluated for relationship to study treatment. Grading for 
severity of solicited local and systemic AEs is described in section 7.1.1, Solicited 
Adverse Events. 
 
Adverse events will also be evaluated by the investigator for the co-existence of any of 
the other following conditions: 
 
▫ “Medically attended adverse event”: an adverse event that leads to a visit to a 
healthcare provider. 
▫ “New onset of chronic disease” (NOCD): an adverse event that represents a new 
diagnosis of a chronic medical condition that was not present or suspected in a subject 
prior to study enrolment. 
▫ AEs leading to withdrawal: adverse events leading to study or vaccine withdrawal. 
All AEs, regardless of severity, will be monitored until resolution or until the investigator 
assesses them as chronic or stable. All subjects experiencing AEs - whether considered 
associated with the use of the study vaccine or not - must be monitored until symptoms 
subside and any abnormal laboratory values have returned to baseline, or until there is a 
satisfactory explanation for the changes observed, or until death, in which case a full 
pathologist’s report should be supplied, if possible. The investigator’s assessment of 
ongoing Adverse Events at the time of each subject’s last visit should be documented in 
the subject’s medical chart. 
 
7.1.4 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose results in one or more of the following: 
 
 
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▫ Death. 
▫ Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
▫ Required or prolonged hospitalization. 
▫ Persistent or significant disability/incapacity (i.e., the event causes a substantial 
disruption of a person’s ability to conduct normal life functions). 
▫ Congenital anomaly/or birth defect. 
▫ An important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but, based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed above. 
 
Adverse events which do not fall into these categories are defined as non-serious. 
 
It should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event need not, by definition, be severe. 
 
Serious adverse events will be captured both on the Vaccines Serious Adverse Event 
(VSAE) form as well as on the AE CRF. All SAEs will be evaluated by the investigator 
for relationship of the event to study vaccine. SAEs that are judged to be possibly or 
probably related to the study vaccine should be reported to the Sponsor as 
related/suspected events. 
 
The relationship of the study treatment to an SAE will be determined by the investigator 
based on the following definitions: 
 
1. Related/suspected 
 
The SAE is judged by the investigator to be possibly or probably related to the study 
vaccine on the AE CRF page (see section 7.1.3, Evaluation of Adverse Events). 
 
2. Not Related 
 
The SAE is not related if exposure to the study vaccine has not occurred, or the 
occurrence of the SAE is not reasonably related in time, or the SAE is considered 
unlikely to be related to use of the study vaccine, i.e., there are no facts (evidence) or 
arguments to suggest a causal relationship. 
 
The relationship of the study vaccine to an SAE will be determined by the investigator. 
 
 
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In addition, SAEs will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected AE is one that is not listed in the current Summary of Product Characteristics 
or the Investigator’s Brochure or an event that is by nature more specific or more severe 
than a listed event. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the Medical History CRF. If the onset of an event occurred before the subject 
entered the study (e.g., any pre-planned hospitalization for conditions like cosmetic 
treatments or for non-emergency routine visits for a pre-existing condition), the 
hospitalization would not lead to an AE being classified as serious unless, in the view of 
the investigator, hospitalization was prolonged as a result of participation in the clinical 
study or was necessary due to a worsening of the pre-existing condition. 
 
7.1.4.1 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are not assessed during the study. 
 
7.1.5 
Methods for Recording Adverse Events and Serious Adverse Events 
Findings regarding Adverse Events must be reported on an Adverse Events CRF, as 
specified in section 7.1.1, Solicited Adverse Events, and on the VSAE form, if applicable, 
which is part of the Investigator Site File. All findings in subjects experiencing AEs must 
be reported also in the subject's source document. 
 
All SAEs which occur during the course of the study, whether considered to be associated 
with the study vaccination or not, must be reported within 24 hours of the site becoming 
aware of the event to Novartis or its designee. Specific instructions and contact details 
for collecting and reporting SAEs to Novartis will be provided to the investigator. 
 
All SAEs are also to be documented on the Adverse Events CRF. Any medication or 
other therapeutic measures used to treat the AE will be recorded on the appropriate 
CRF(s) in addition to the outcome of the AE. 
 
After receipt of the initial report, representatives of Novartis or its designee will contact 
the investigator if it is necessary to obtain further information for assessment of the event. 
 
All SAEs must be reported by the investigator to his/her corresponding EC or 
applicable regulatory authorities in accordance with institutional policy/regulatory 
requirements and adequate documentation of this notification must be provided to the 
Sponsor. 
 
Novartis or its designee must also comply with the applicable regulatory requirement(s) 
related to the reporting of suspected unexpected serious adverse vaccine reactions (also 
 
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known as SUSARs) to the regulatory authority(ies) and the IRB/EC. If a SUSAR or other 
safety signal relating to use of one of the study vaccines is reported to Novartis or its 
designee, the Sponsor will communicate the information to the investigator and the 
investigator will be responsible for submitting this information to the EC /IRB and other 
relevant authorities. 
 
7.1.5.1 
Post-Study Events 
Any suspected SAE that occurs outside of the protocol-specified follow-up period or after 
the end of the study but considered to be caused by the study vaccine must be reported to 
Novartis or its designee. These SAEs will be processed by Novartis or its designee as 
during the course of the study, until 3 months after last subject last visit. Instructions and 
contact details for collecting and reporting these suspected SAEs will be provided to the 
investigator. 
 
7.1.6 
Pregnancies 
 
Not applicable for this study. 
 
7.1.7 
Safety Laboratory Measurements 
 
Not applicable for this study. 
 
7.2 
Efficacy Assessment 
There is no assessment of efficacy in this study. 
 
7.3 
Immunogenicity Assessment 
The measures of immunogenicity used in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant (able to describe the quality and 
extent of the immune response). 
 
The functional measure of immunogenicity used in this study, the serum bactericidal 
assay using complement (SBA), is a measure of the ability of antibodies, in concert with 
complement, to kill meningococci, and is widely used. 
 
For the human SBA (hSBA) the complement is of human origin and generally recognized 
as the serological correlate of protection. 
 
For the rabbit SBA (rSBA) the complement is derived from baby rabbits. 
 
 
 
 
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For the SBA analyses the serum samples of all subjects from visit 5 and visit 6 will be 
used. 
 
The SBA will be used to measure the induction of functional bactericidal antibodies 
directed against the capsule polysaccharides of the meningococcal serogroups A, C, W 
and Y following study vaccination. 
 
The measures of immunogenicity using this assay will be: 
• hSBA: the percentages of subjects who achieve hSBA titers ≥ 8 and 
• rSBA: the percentages of subjects who achieve titers ≥ 8 and ≥ 128. 
• hSBA and rSBA: GMT’s. 
Testing will be conducted by a Novartis or designated laboratory in a blinded manner 
towards the visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
Endpoints 
 
8.1.1 
Primary Endpoint(s) 
 
8.1.1.1 
Primary Safety Endpoint(s) 
Safety of the study vaccine will be assessed in all subjects in terms of the frequency and 
percentage of reported adverse events (AEs) including: 
• Any solicited AEs reported within 30 minutes after each vaccination; 
• Solicited local (i.e. erythema, induration and tenderness) and systemic (i.e. change 
in eating habits, sleepiness, irritability, vomiting, diarrhea, and fever (body 
temperature ≥ 38°C (100.4°F)) AEs reported from Day 1 to Day 7 after each 
vaccination; 
• All medically-attended unsolicited AEs reported from Day 1 to Visit 6 (24 months 
of age); 
• AEs leading to premature withdrawal reported from Day 1 to Visit 6 (24 months 
of age); 
• SAEs reported from Day 1 to Visit 6 (24 months of age); 
8.1.1.2 
Primary Efficacy Endpoint(s) 
Not Applicable. 
 
8.1.1.3 
Primary Immunogenicity Endpoint(s) 
One year after the full vaccination of 4 doses MenACWY (at 2 months, 4 months, 6 
months and 12 months of age), establish the persistence by: 
• Percentage of subjects with hSBA ≥ 8 for each serogroup. 
• The percentage of subjects with rSBA ≥ 8 and with rSBA ≥ 128 for each 
serogroup. 
 
8.1.2 
Secondary Endpoint(s) 
 
8.1.2.1 
Secondary Safety Endpoint(s) 
Not applicable 
 
 
 
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8.1.2.2 
Secondary Efficacy Endpoint(s) 
 
Not applicable 
 
8.1.2.3 
Secondary Immunogenicity Endpoint(s) 
 
One month after the full vaccination of 4 doses MenACWY (at 2 months, 4 months, 6 
months and 12 months of age), evaluate: 
• Percentage of subjects with hSBA ≥ 8 for each serogroup 
• The percentage of subjects with rSBA ≥ 8 and with rSBA ≥ 128 for each 
serogrouo 
 
One year after the full vaccination of 4 doses MenACWY (at 2 months, 4 months, 6 
months and 12 months of age), establish the persistence by: 
 
• hSBA GMT for each serogroup 
• rSBA GMT for each serogroup 
One month after the full vaccination of 4 doses MenACWY (at 2 months, 4 months, 6 
months and 12 months of age), evaluate: 
• hSBA GMT for each serogroup 
• rSBA GMT for each serogroup 
8.1.3 
Exploratory Endpoint(s) 
Not Applicable 
 
8.1.3.1 
Exploratory Safety Endpoint(s) 
Not Applicable 
 
8.1.3.2 
Exploratory Efficacy Endpoint(s) 
Not Applicable 
 
8.1.3.3 
Exploratory Immunogenicity Endpoint(s) 
Not Applicable 
 
 
 
 
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8.2 
Success Criteria 
 
Not Applicable 
 
8.2.1 
Success Criteria for Primary Objective(s) 
 
Not Applicable 
 
8.2.1.1 
Success Criteria for Primary Safety Objective(s) 
 
Not Applicable 
 
8.2.1.2 
Success Criteria for Primary Efficacy Objective(s) 
 
Not Applicable 
 
8.2.1.3 
Success Criteria for Primary Immunogenicity Objective(s) 
 
Not Applicable 
 
8.2.2 
Success Criteria for Secondary Objective(s) 
 
Not Applicable 
 
8.2.2.1 
Success Criteria for Secondary Safety Objective(s) 
 
Not Applicable 
 
8.2.2.2 
Success Criteria for Secondary Efficacy Objective(s) 
 
Not Applicable 
 
8.2.2.3 
Success Criteria for Secondary Immunogenicity Objective(s) 
Not Applicable 
 
8.3 
Analysis Sets 
 
8.3.1 
All Enrolled Set 
 
All screened subjects who provide informed consent and provide demographic and/or 
baseline screening assessments and received a Subject ID. 
 
 
 
 
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8.3.2 
All Exposed Set 
 
All subjects in the enrolled set who receive a study vaccination. 
 
8.3.3 
Safety Set 
 
Solicited Safety Set (solicited local and systemic adverse events and other solicited 
adverse events) 
 
All subjects in the Exposed Set with any solicited adverse event data and/or indicators of 
solicited adverse events 
 
• Solicited Safety Set vaccination 1 
All subjects in the Exposed Set with any solicited adverse event data and/or 
indicators of solicited adverse events from Day 1 of vaccination 1 and subsequent 
6 days 
 
• Solicited Safety Set vaccination 2 
All subjects in the Exposed Set with any solicited adverse event data and/or 
indicators of solicited adverse events from Day of vaccination 2 and subsequent 6 
days 
 
• Solicited Safety Set vaccination 3 
All subjects in the Exposed Set with any solicited adverse event data and/or 
indicators of solicited adverse events from Day of vaccination 3 and subsequent 6 
days 
 
• Solicited Safety Set vaccination 4 
All subjects in the Exposed Set with any solicited adverse event data and/or 
indicators of solicited adverse events from Day of vaccination 4 and subsequent 6 
days 
 
Unsolicited Safety Set (unsolicited adverse events) 
All subjects in the Exposed Set with unsolicited adverse event data. 
 
Overall Safety Set 
All subjects who are in any of the Solicited Safety Sets and/or Unsolicited Safety Set. 
 
 
 
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8.3.4 
Full Analysis Set (FAS) Efficacy/Immunogenicity Set 
Full Analysis Set Efficacy 
Not Applicable 
 
Full Analysis Set Immunogenicity 
All subjects in the All Enrolled Set who, receive at least one study vaccination and 
provide in treatment immunogenicity. 
 
• FAS hSBA 1 month 
All subjects in the Exposed Set who provide evaluable hSBA immunogenicity 
data at 1 month after last vaccination 
 
• FAS rSBA 1 month 
All subjects in the Exposed Set who provide evaluable rSBA immunogenicity data 
at 1 month after last vaccination 
 
• FAS hSBA 1 year 
All subjects in the Exposed Set who provide evaluable hSBA immunogenicity 
data at 1 year after last vaccination 
 
• FAS rSBA 1 year 
All subjects in the Exposed Set who provide evaluable rSBA immunogenicity data 
at 1 year after last vaccination 
 
8.3.5 
Per Protocol (PP) Set Efficacy/Immunogenicity Set 
 
All subjects in the different FAS populations Immunogenicity who: 
▫ Have no protocol deviations leading to exclusion (see section 8.3.8, Protocol 
Deviations) as defined prior to analysis. 
 
PPS are subsets of FAS and should be always defined even if the objectives do not 
require it. PPS sets will be named corresponding to the FAS populations, PPS hSBA 1 
month, PPS rSBA 1 month, PPS hSBA 1 year and PPS rSBA 1 year. 
 
An example for subjects excluded due to other reason than protocol deviations is when 
subjects withdrew informed consent. 
 
 
 
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8.3.6 
Other Analysis Sets 
 
Not Applicable 
 
8.3.7 
Subgroups 
 
Not Applicable 
 
8.3.8 
Protocol Deviations 
 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a study protocol. A protocol deviation may be a reason to remove data from 
an analysis set at the time of analysis. CSR-reportable protocol deviations will be defined 
as exclusionary from the analysis according to protocol objectives and endpoints, which 
will be specified in the statistical analysis plan. In some cases exclusion of data may be 
due to a reason other than a protocol deviation, e.g. early termination. 
 
8.4 
Statistical Analysis Plan 
 
8.4.1 
Analysis of Demographic and Baseline Characteristics 
 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) for 
age, height and weight at enrolment will be calculated. Distributions of subjects by sex 
and ethnic origin will be summarized. 
 
8.4.2 
Analysis of Primary Objective(s) 
 
8.4.2.1 
Analysis of Primary Safety Objective(s) 
 
8.4.2.1.1 
Analysis of Extent of Exposure 
The number of subjects actually receiving the vaccinations will be summarized. 
 
8.4.2.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events 
Most solicited adverse events will be summarized according to defined severity grading 
scales. 
 
Frequencies and percentages of subjects experiencing each adverse event will be 
presented for each symptom severity. Summary tables showing the occurrence of any 
local or systemic adverse event overall and at each time point will also be presented. 
 
 
 
 
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Post-vaccination solicited adverse events reported from 30 minutes, Day 1 to Day 3, Day 
4 to Day 7 and Day 1 to Day 7 will be summarized by maximal severity. 
 
The severity of solicited local adverse events, including injection site erythema, injection 
site induration, injection site tenderness will be categorized as none, 1 to ≤25 mm, 26 to 
≤50 mm, and >50 mm (severe local reactions). 
 
Injection site pain/tenderness and systemic adverse events (except fever) occurring up to 
7 days after each vaccination will be summarized according to “mild”, “moderate” or 
“severe”. 
 
Each solicited local and systemic adverse event will also be further summarized as “none” 
versus “any”. 
 
Implausible measurements (for further definition see statistical analysis plan) will be left 
out of the analysis. 
 
Use of antipyretics and analgesics will be summarized by frequency by type of use 
(prophylactic versus treatment) and percentage of subjects reporting use.  The influence 
of antipyretics and analgesics use on the occurrence of specific adverse events (e.g., fever, 
pain) will be assessed. 
 
Body temperature will be categorized as <38°C (no fever), 38-38.9°C (Mild), 39-39.9°C 
(Moderate), and ≥40°C (severe). Body temperature will also be summarized by <38°C 
(no fever), 38-38.4°C, 38.5-38.9°C, 39-39.4°C, 39.5-39.9°C, and 40°C (severe). 
8.4.2.1.3 
Analysis of Unsolicited Adverse Events 
 
This analysis applies to all adverse events occurring during the study, judged either as 
probably related, possibly related, or not related to vaccination by the investigator, 
recorded in AE CRF, with a start date on or after the date of first vaccination. AE starting 
prior to the first vaccination will only be listed. The original verbatim terms used by 
investigators to identify adverse events in the CRFs will be mapped to preferred terms 
using the MedDRA dictionary. The adverse events will then be grouped by MedDRA 
preferred terms into frequency tables according to system organ class. 
 
All reported adverse events, as well as adverse events judged by the investigator as at 
least possibly related to study vaccine, will be summarized according to system organ 
class and preferred term within system organ class. These summaries will be presented by 
vaccination group and by interval of study observation. When an adverse event occurs 
more than once for a subject, the maximal severity and strongest relationship to the 
vaccine group will be counted. 
 
 
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Separate summaries will be produced for the following categories: 
• Serious adverse events 
• Adverse events that are possibly or probably related to vaccine 
• Adverse event leading to withdrawal 
• Adverse events leading to a medically attended visit 
Data listings of all adverse events will be provided by subject. In addition, adverse events 
in the categories above will be provided as listed data. 
 
8.4.2.1.4 
Analysis of Safety Laboratory Values 
Not Applicable 
 
8.4.2.2 
Analysis of Primary Efficacy Objective(s) 
Not Applicable 
 
8.4.2.2.1 
Statistical Hypotheses 
Not Applicable 
 
8.4.2.2.2 
Analysis Sets 
Not Applicable 
 
8.4.2.2.3 
Statistical Methods 
Not Applicable 
 
8.4.2.3 
Analysis of Primary Immunogenicity Objective(s) 
 
8.4.2.3.1 
Statistical Hypotheses 
 
Not Applicable 
 
8.4.2.3.2 
Analysis Sets 
 
The primary immunogenicity objective will be run with the FAS population, however the 
analyses will also be run with the PPS population for sensitivity reason. 
 
 
 
 
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8.4.2.3.3 
Statistical Methods 
 
Binary data 
 
The primary objective of the study is the persistence one year after the complete schedule 
of 4 vaccinations, expressed as the number and percentage of subjects with hSBA titer ≥ 8 
or rSBA titer ≥ 8 and ≥128 at Visit 6. 
 
These percentages will be presented along with associated two-sided 95% Clopper- 
Pearson confidence intervals. 
 
Handling of missing values for Immunogenicity Data 
 
For immunogenicity data, it may be reasonable to consider missing immunogenicity 
values as missing completely at random, i.e. not informative. Therefore, the analysis will 
comprise a complete case analysis. 
 
Titers below the limit of detection will be set to half that limit for the purposes of 
analysis. 
 
8.4.3 
Analysis of Secondary Objective(s) 
 
8.4.3.1 
Analysis of Secondary Safety Objective(s) 
 
Not Applicable 
 
8.4.3.1.1 
Analysis of Extent of Exposure 
Not Applicable 
 
8.4.3.1.2 
Analysis of Solicited Local, Systemic and Other Adverse Events 
Not Applicable 
 
8.4.3.1.3 
Analysis of Unsolicited Adverse Events 
Not Applicable 
 
8.4.3.1.4 
Statistical Hypotheses 
Not Applicable 
 
 
 
 
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8.4.3.1.5 
Analysis Sets 
 
Not Applicable 
 
8.4.3.1.6 
Statistical Methods 
 
Not Applicable 
 
8.4.3.2 
Analysis of Secondary Efficacy Objective(s) 
 
8.4.3.2.1 
Statistical Hypotheses 
Not Applicable 
 
8.4.3.2.2 
Analysis Sets 
Not Applicable 
 
8.4.3.2.3 
Statistical Methods 
Not Applicable 
 
8.4.3.3 
Analysis of Secondary Immunogenicity Objective(s) 
 
8.4.3.3.1 
Statistical Hypotheses 
 
Not Applicable 
 
8.4.3.3.2 
Analysis Sets 
 
The analysis population will be the FAS defined in Section 8.3. Immunogenicity analysis 
on the Per Protocol Population will also be performed for sensitivity. 
 
8.4.3.3.3 
Statistical Methods 
 
Log-normal distributed data 
 
The statistical analyses will be performed on the logarithmically (base 10) transformed 
values. Individual titers below detection limit will be set to half that limit. 
 
Geometric mean antibody titers (GMT) and GMRs: 
 
The antibody titers will be summarized using GMTs with two-sided 95% confidence 
intervals. The calculation will be done by an univariate analysis. GMTs and 95% 
 
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confidence intervals will be obtained by exponentiation (base 10) of the logarithmically 
transformed antibody titer and confidence limits. Moreover the geometric mean ratios 
(GMR) will be provided along with the 2-sided 95% confidence intervals. GMRs will be 
calculated between visit 6 (one year after full vaccination) and visit 5 (one month after 
full vaccination). 
 
Median, minimum, and maximum values will be obtained using original titer values. 
 
Binary data 
 
The evaluation at one month after the complete schedule of 4 vaccinations is expressed as 
the number and percentage of subjects with hSBA titer ≥ 8 or rSBA titer ≥ 8 and ≥128 at 
Visit 5. 
 
These percentages will be presented along with associated two-sided 95% Clopper- 
Pearson confidence intervals. 
 
8.4.4 
Analysis of Exploratory Objectives 
 
Not Applicable 
 
8.4.4.1 
Analysis of Exploratory Safety Objective(s) 
 
Not Applicable 
 
8.4.4.2 
Analysis of Exploratory Efficacy Objective(s) 
Not Applicable 
 
8.4.4.3 
Analysis of Exploratory Immunogenicity Objective(s) 
Not Applicable 
 
8.5 
Sample Size and Power Considerations of Primary and Secondary 
Objectives 
 
Approximately 135 subjects will be enrolled in this study providing approximately 100 
evaluable subjects, assuming a 25% drop-out. The sample size is based on the number of 
subjects requested and agreed with South Korean Health Authorities for this persistence 
study. 
 
 
 
 
 
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With 100 evaluable subjects, the 95% confidence limits of the observed percentages of 
subjects with hSBA titer ≥8 or rSBA titer titer ≥ 8 or ≥128 will be as presented in the 
following table. 
 
Table 8.5-1: Calculated 95% Confidence Interval, Associated With Different 
Percentages of Observed Percentages of Subjects 
 
Observed percentage 
95% confidence interval 
(Menveo® N=100) 
50% 
40%- 60% 
60% 
50%-70% 
70% 
61%-79% 
80% 
72%-88% 
90% 
84%-96% 
 
Dependent on the point estimate, the length of the confidence interval will be 12% - 20%. 
 
8.6 
Interim Analysis 
No interim analysis of data from this study is planned. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.0 
SOURCE DOCUMENTATION, STUDY MONITORING AND 
AUDITING 
In order to ensure consistency across sites, study monitoring and auditing will be 
standardized and performed in accordance with the Sponsor’s or delegated contract 
research organization’s (CRO) standard operating procedures and applicable regulatory 
requirements (e.g., FDA, EMA, and ICH guidelines). 
 
Prior to enrolment of the first study subject, Novartis or delegate will train investigators 
and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. CRFs supplied by the Sponsor must 
be completed for each enrolled subject (see section 8.3.1, All Enrolled Set for definition 
of enrolled subject). Documentation of screened but not enrolled subjects must be 
maintained at the site and made available for review by the site monitor. Data and 
documents will be checked by the Sponsor and/or monitor. 
 
9.1 
Source Documentation 
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The kinds 
of documents that will serve as source documents will be agreed between Sponsor or 
delegate and investigator and designees and specified in the SDA prior to subject 
enrolment. 
 
In addition, source documentation must include all of the following: subject identification 
(on each page), eligibility and participation, proper informed consent procedures, dates of 
visits, adherence to protocol procedures, adequate reporting and follow-up of adverse 
events, documentation of prior/concomitant medication/vaccines, study vaccine 
receipt/dispensing/return records, study vaccine administration information, any data 
collected by a telephone conversation with the subject parent(s)/legal guardian(s)] and 
date of completion and reason. 
 
The subject parent(s)/legal guardian(s) must also allow access to the subject’s medical 
records. Each subject parent(s)/legal guardian(s)] must be informed of this prior to the 
start of the study and consent for access to medical records may be required in accordance 
with local regulations. 
 
All safety data reported by subjects must be written down in source documents prior to 
entry of the data into CRFs. If there are multiple sources of information (e.g., Subject 
Diary, verbal report of the subject, telephone contact details, medical chart) supporting 
the diagnosis of an adverse event, these sources must be identified in the source 
documents, discrepancies between sources clarified, the ultimate diagnosis must be 
 
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justified and written in the source documents, and this diagnosis must be captured in the 
Adverse Event CRF (AE CRF). The AE CRF must also capture which source(s) of 
information were used to determine the adverse event (e.g., subject recall, medical chart, 
Subject Diary). 
 
9.2 
Study Monitoring, Auditing and Source Data Verification 
 
Prior to enrolment of the first study subject, Novartis or its designee (e.g., a CRO) will 
develop a Clinical Monitoring Plan to specify how centralized and/or on-site monitoring, 
including clinical specimens reconciliation, will be performed for the study. Study 
progress will be monitored by Novartis or its designee as frequently as necessary to 
ensure: 
 
▫ that the rights and well-being of human subjects are protected, 
▫ the reported study data are accurate, complete, and verifiable from the source 
documents and 
▫ the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements. 
 
Contact details for the Novartis team or its designee involved in study monitoring will be 
provided to the investigator. Study data recorded on CRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol except for those parameters which are specifically 
described in section 7.0, Assessment being entered directly into the EDC system. 
 
Data verification may also be performed through a centralized review of data (e.g., 
checking for outliers or other anomalies). Additional documents such as the investigator 
site file, pharmacy records, and informed consent documentation must also be available 
for review if requested. Arrangements for monitoring visits will be made in advance in 
accordance with the monitoring plan, except in case of emergency. 
 
The investigator and/or site staff must make source documents of subjects enrolled in this 
study available for inspection by Novartis or its representative at the time of each 
monitoring visit and Sponsor audits, when applicable. These documents must also be 
available for inspection, verification and copying, as required by regulations, by officials 
of the regulatory health authorities (e.g., FDA, EMA and others) and/or ECs/IRBs. The 
investigator and study site staff must comply with applicable privacy, data protection and 
medical confidentiality laws for use and disclosure of information related to the study and 
enrolled subjects. 
 
 
 
 
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10.0 
DATA MANAGEMENT 
 
10.1 
Data Entry and Management 
In this study, all clinical data (including, but not limited to, AE/SAEs, concomitant 
medications, medical history, and physical assessments), safety data, and immunogenicity 
data will be entered onto case report forms (CRFs) in a timely fashion by the investigator 
and/or the investigator’s dedicated site staff. Data entered onto CRFs are stored on a 
secure website. The data collected on this secure website are assimilated into an 
electronic data capture (EDC) system, which is compliant with Title 21 Part 11 policies of 
the Code of Federal Regulations (FDA 1997). The data system includes password 
protection and internal quality checks. The EDC system will be designed and validated by 
the Sponsor prior to activation for data entry by sites. The investigator or designated 
delegate must review data entered and electronically sign the CRFs to verify their 
accuracy. 
 
Access to the EDC system for data entry or review will require training and distinct 
individual access code assignments to those site staff members who will be entering study 
data and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access. 
 
10.2 
Data Clarification 
As part of the conduct of the trial, the Sponsor may have questions about the data entered 
by the site, referred to as queries. The monitors and the Sponsor are the only parties that 
can generate a query. All corrections and clarifications will be entered into the EDC 
system and will be identified by the person entering the information, the reason for the 
change, as well as the time of the changes made. If changes are made to a previously and 
electronically signed CRF, the investigator must confirm and endorse the changes. 
 
10.3 
Data Protection 
 
Novartis respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. 
 
 
 
 
 
 
 
 
 
 
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11.0 
RECORD RETENTION 
 
Investigators must retain all study records required by Novartis and by the applicable 
regulations in a secure and safe facility. The investigator must consult a Novartis 
representative before disposal of any study records, and must notify the Sponsor of any 
change in the location, disposition, or custody of the study files. Essential documents 
must be retained for 15 years. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced. These documents should be retained for a longer period, however, if 
required by the applicable national regulatory or institutional requirements. 
 
These principles of record retention will also be applied to the storage of laboratory 
samples, provided that the integrity of the stored sample permits testing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.0 
USE OF INFORMATION AND PUBLICATION 
 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov, and in compliance with current regulations. 
 
Novartis also assures that key results of this clinical study will be posted in a publicly 
accessible database within the required time-frame from the end of study as defined in 
section 3.9, End of Study. 
 
In accordance with standard editorial, ethical practices and current guidelines of Good 
Publication Practice (Graf 2009), Novartis will generally support publication of 
multicenter studies only in their entirety and not as individual center data. In this case, a 
coordinating investigator will be designated by mutual agreement prior to the start of the 
study. The coordinating investigator will also sign the clinical study report on behalf of 
the principal investigators (CPMP/EWP/2747/00). Authorship will be determined by 
mutual agreement and in line with International Committee of Medical Journal Editors 
authorship requirements. Any formal publication of the study in which contribution of 
Novartis personnel exceeded that of conventional monitoring will be considered as a joint 
publication by the investigator and the appropriate Novartis personnel. 
 
Novartis must be notified of any intent to publish data collected from the study and prior 
approval from Novartis must be obtained prior to submission for publication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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13.0 
ETHICAL CONSIDERATIONS 
 
13.1 
Regulatory and Ethical Compliance 
The study will be conducted in compliance with the protocol, GCP and applicable 
regulatory requirement(s). 
 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of 
Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), 
Novartis codes on protection of human rights, and with the ethical principles laid down in 
the Declaration of Helsinki (European Council 2001, US Code of Federal Regulations, 
ICH 1997);(59th World Medical Association General Assembly (October 2008) 
 
13.2 
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written informed 
consent or assent, as described in section 5.1.1, Informed Consent/Assent. Before the start 
of the study, the investigator will have the informed consent and any other materials that 
will be provided to the subjects reviewed and approved by the IRB/EC. This review and 
approval will be documented and stored with other study documents. The investigator or 
designee must fully inform the subject or legal guardian of all pertinent aspects of the 
study. A copy of the written informed consent will be given to the subject or the designee. 
The subject/designee must be allowed ample time to ask about the details of the study and 
to make a decision as to whether or not to participate in the study. The subject and/or 
legal guardian(s) must sign the consent form indicating their agreement to participate in 
the study before any study-related procedures are conducted. The informed consent 
process may be conducted up to 5 days prior to vaccination on day 1.  If the subject 
and/or legal guardian(s) is unable to read and write, a witness must be present during the 
informed consent discussion and at the time of informed consent signature. 
 
Prior to the start of the study, Novartis will provide to investigators a proposed informed 
consent form that complies with the ICH GCP guideline and regulatory requirements and 
is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Novartis before submission to the 
IRB/EC and a copy of the approved version must be provided to the Novartis monitor 
after IRB/EC approval. 
 
In addition, the investigator or designee should explain pertinent aspects of the study in an 
age appropriate manner to pediatric subjects who are eligible for informed assent in 
accordance with local policies. The parent(s)/legal guardian(s) must be allowed ample 
 
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time to ask about the details of the study and to make a decision as to whether or not to 
participate in the study. The parent(s)/legal guardian(s)] must sign the consent/assent 
forms indicating their agreement to participate in the study before any study-related 
procedures are conducted. If the parent(s)/legal guardian(s)] are unable to read and write, 
a witness must be present during the informed consent/assent discussion and at the time 
of informed consent/assent signature. 
 
13.3 
Responsibilities of the Investigator and IRB/EC 
 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted IRB/EC before study start. Properly constituted IRB/EC is defined 
in ICH Guideline for Good Clinical Practice E6 (R1), Section 3 (ICH 1997). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/EC must be given to Novartis before study initiation. Prior to study start and at any 
time the protocol is amended during study conduct, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance 
with these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to Novartis monitors, auditors, Novartis 
Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/ECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request 
has been made. 
 
The investigator also responsible for the following: 
 
▫ Maintaining a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties 
▫ Demonstrating the capability of recruiting the required number of suitable subjects 
within the recruitment period 
▫ Demonstrating sufficient time and staffing to properly conduct and complete the study 
within the agreed study period 
▫ Ensuring that all persons assisting with the study are adequately informed about the 
protocol, the investigational product(s), and their study-related duties and functions 
▫ Ensuring that appropriately trained health care professionals are responsible for all 
study-related medical decisions and for ensuring appropriate medical care of subjects 
experiencing any adverse event related to the study 
▫ If permission to do so is given by the subject parent(s)/legal guardian(s)], ensuring 
that the subject’s primary healthcare provider is informed of the subject’s 
participation in the study 
 
 
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The investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favourable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)). In addition, the investigator, or person designated by the investigator, should 
document and explain any deviation from the approved protocol. 
 
The investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/IEC 
approval/favourable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted: 
 
(a) to the IRB/IEC for review and approval/favourable opinion, 
 
(b) to the Sponsor for agreement and, if required, 
 
(c) to the regulatory authority(ies). 
 
13.4 
Protocol Amendments 
An amendment is a written description of change(s) to or formal clarification of a study 
protocol which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect subject safety, including changes of study objectives, study 
design, subject population, sample sizes, study procedures, or significant administrative 
aspects. An administrative change of a study protocol is a minor correction or  
clarification that has no significant impact on the way the clinical study is to be conducted 
and no effect on subject safety (e.g., change of telephone number(s), logistical changes). 
Protocol amendments must be approved by Novartis, health authorities where required, 
and the IRB/EC. In cases when the amendment is required in order to protect the subject 
safety, the amendment can be implemented prior to IRB/EC approval. Notwithstanding, 
the need for formal approval of a protocol amendment, the investigator is expected to take 
any immediate action required for the safety of any subject included in this study, even if 
this action represents a deviation from the protocol. In such cases, Novartis should be 
notified of this action, the IRB/EC at the study site, and, if required by local regulations, 
the relevant health authority) should be informed within 10 working days. 
 
 
 
 
 
 
 
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14.0 
REFERENCE LIST 
 
1. Goldschneider I, Gotschlich EC, Artenstein MS. (1969) Human immunity to the 
meningococcus. I. The role of humoral antibodies. J Exp Med; 129: 1307-1326. 
 
2. Code of Federal Regulations (1997): Food and Drug Administration, U.S. 
Department of Health and Human Services: Title 21, Part 11: Electronic Records 
Electronic Signatures. Federal Register 62: 13464 
 
3. Graf C, Battisti WP, Bridges D (2009). Good publication practice for 
communicating company Sponsored medical research: the GPP2 guidelines. BMJ; 
339: b4330 
 
4. ICH (1998) ICH Harmonised Tripartite ICH Guideline for Statistical Principles 
for Clinical Trials E9. Federal Register, 63 (179): 49583 
 
5. 59th World Medical Association General Assembly (October 2008) Declaration of 
Helsinki - Ethical Principles for Medical Research Involving Human Subjects. 
Seoul, Korea 
 
6. Trotter C, Andrews N, Kaczmarski E, Miller E, Ramsay M. Effectiveness of 
meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet 
2004: 364: 365-367. 
 
7. Rouphael NG and Stephens DS. Neisseria meningitidis: Biology, Microbiology, 
and Epidemiology. Methods Mol Biol. 2012;799:1-20. 
 
8. Al-Tawfiq JA, Clark TA and Memish ZA. Meningococcal disease: the organism, 
clinical presentation, and worldwide epidemiology. J Travel Med 2010; 17 
Suppl:3-8. 
 
9. Deasy A and Read RC. Challenges for development of meningococcal vaccines in 
infants and children. Expert Rev. Vaccines 2011; 10: 335–343. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Novartis 
Document Approval Certificate / 
 
 
The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. PPD 
 
 
 
 
 
 
UserName: PPD 
 
Title: Cluster Physician 
Date: Thursday, 11 December 2014, 14:57 GMT 
Meaning: As an approver, I agree with the content and format of this document. 
================================================ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This signature certificate is only valid when accompanied by all the pages of the document. / 
PPD 
 
PPD 
Doc Number: 68901057 

GLAXOSMITHKLINE BIOLOGICALS S.A 
25 AUG 15 
Clinical Study Protocol Amendment 1 
Page 1 of 2 
Confidential 
 
 
 
 
CLINICAL STUDY PROTOCOL V59_75 
 
 
 
A Phase IV, Open-Label, Multi-Center Study to Evaluate the Safety and the 1-year 
Persistence of Antibody Response Among Children Who Received 4 Doses of the 
GSK MenACWY Conjugate Vaccine at 2, 4, 6 and 12 Months of Age in South Korea 
 
 
 
Amendment Number 1 
 
Revised Protocol version 2.0 issued on 25 August 2015 
 
The present amendment reflects changes to the Protocol version 1.0 
Issued on 10 Dec 14 
Property of GSK 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 2 of 2 
Confidential 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
CHANGE 1 
 
The entire document has been revised to ensure all instances where Novartis is mentioned 
are replaced with GSK. 
 
Rationale for Change: 
 
Due to change of Marketing Authorization Holder from Novartis Vaccines to GSK 
Vaccines, the protocol has been revised to change name of Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
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Novartis 
Document Approval Certificate / 
 
 
The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. PPD 
 
 
 
 
 
 
UserName: PPD 
 
Title: Cluster Physician 
Date: Wednesday, 02 September 2015, 11:31 GMT 
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Doc Number: 74718128 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 1 of 6 
Confidential 
 
 
 
 
CLINICAL STUDY PROTOCOL AMENDMENT 
 
Study Number: V59_75 
 
 
Protocol Title: A Phase IV, Open-Label, Multi-Center Study to Evaluate the Safety 
and the 1-year Persistence of Antibody Response Among Children Who Received 4 
Doses of the GSK MenACWY Conjugate Vaccine at 2, 4, 6 and 12 Months of Age in 
South Korea 
 
 
Amendment Number 2 
 
Revised Protocol version 3 issued on 26 Feb 2016 
 
The present amendment reflects changes to the Revised Protocol version 2.0 issued 
on 25 AUG 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
Property of GSK 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 2 of 6 
Confidential 
 
 
DESCRIPTION OF CHANGE(S) AND RATIONALE: 
 
The present Clinical Study protocol Amendment is considered non-substantial and it is 
being issued to update the range of age of Menveo indication in the countries mentioned 
in the synopsis. 
 
In addition, this amendment aimed to better clarify the visit window in time and events 
table. The visit interval between V3~V4 and V5~V6 were not clear on the current 
protocol. It was added a row called ‘days post injection’ to avoid confusion between 
INVs. 
 
Finally, some changes were implemented to correct minor inconsistencies detected in 
Section # of the Clinical Study Protocol. 
 
CHANGE 1 (Page 9, 23 Background and rationale): 
 
Previously read: 
GSK MenACWY Menveo® has been approved for use in people 2 months through 55 
years of age in the United State and in people 2 years up to 55 in Europe and other 
countries, including the Republic of South Korea. 
 
Now reads: 
GSK MenACWY Menveo® has been approved for use in people 2 months through 55 
years of age in the United States and in children (from 2 years of age), adolescents and 
adults in Europe. 
 
Rationale for Change: 
 
In Europe Menveo is indicated for use in people from 2 years of age without upper age 
limit. 
 
 
CHANGE 2 (Page 12, Paragraph: Study Procedures): 
 
Previously read: 
Visit 2 (Age 4 Months) (60 days after Visit 1 +/- 7 days). At Day 3 after vaccination a 
telephone call will be made to remind the subjects’ parents/legal guardian to complete the 
subject diary. 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 3 of 6 
Confidential 
 
 
Now reads: 
 
At study Day 63 (2 days after the 2nd vaccination) after vaccination a telephone call will 
be made to remind the subjects’ parents/legal guardian to complete the subject diary. 
 
Rationale for Change and Changes #3, #4 and #5 below: 
The visit intervals between V3 toV4 and V5 to V6 were incorrect and caused confusion 
between investigators. Intervals are now described as study days after the relevant 
vaccination for clarity. 
 
 
CHANGE 3 (Page 13, Paragraph: Study Procedures): 
 
Previously read: 
Visit 3 (Age 6 months) (60 days after Visit 2 +/- 7 days). At Day 3 after vaccination a 
telephone call will be made to remind the subjects’ parents/legal guardian to complete the 
subject diary. 
 
Now reads: 
At study Day 123 (2 days after the 3rd vaccination) after vaccination a telephone call will 
be made to remind the subjects’ parents/legal guardian to complete the subject diary. 
 
Rationale for Change: 
Text added for clarification. 
 
 
CHANGE 4 (Page 13, Paragraph: Study Procedures): 
 
Previously read: 
Visit 4 (Age 12 Months) (Inclusive + 14 days). At Day 3 after vaccination a telephone 
call will be made to remind the subjects’ parents/legal guardian to complete the subject 
diary. 
 
Now reads: 
At study day 303 (2 days after the 4th vaccination) after vaccination a telephone call will 
be made to remind the subjects’ parents/legal guardian to complete the subject diary. 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 4 of 6 
Confidential 
 
 
Rationale for Change: 
 
Text added for clarification. 
 
 
CHANGE 5 (Page 18, Time and Events Table – Treatment Period): 
 
Previously read: 
 
Changes highlighted in yellow. 
 
Visit 
Type 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Phone 
Call 
Clinic 
Visit 
Clinic 
Visit 
Study 
Day 
1 
3 
61 
63 
121 
123 
301 
304 
331 
661 
 
Now reads: 
 
Visit 
Type 
Clini 
c  
Visit 
Remind 
er  
Phone 
Call 
Clini 
c  
Visit 
Remind 
er  
Phone 
Call 
Clini 
c  
Visit 
Remind 
er  
Phone 
Call 
Clini 
c  
Visit 
Remind 
er  
Phone 
Call 
Clini 
c  
Visit 
Clini 
c  
Visit 
Study 
Day 
1 
3 
61 
63 
121 
123 
301 
303 
331 
661 
Days 
2 days 
60 
2 days 
post dose 
2 
60 
2 days 
post dose 
3 
180 
2 days 
30day 
330 
Post 
post dose 
days 
days 
days 
post dose 
s post 
days 
Injectio 
1 
post 
post 
post 
4 
dose 
post 
ns 
dose 
dose 
dose 
4 
visit 
1 
2 
3 
5 
 
Rationale for Change # 5: 
A new row titled ‘Days Post injections’ has been inserted to align with text above and to 
better clarify the intervals between visits and the reminder call. 
 
 
 
 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 5 of 6 
Confidential 
 
 
CHANGE 6 (Page 33, 45; Section Exclusion Criteria, Prior and Concomitant 
Medication and Vaccines): 
 
Previously Read: 
 
Received oral or parenteral antibiotic treatment in the 3 days prior to the scheduled blood 
draw (topical antibiotics are acceptable, including antibiotic eye drops). 
 
Now Reads: 
Received oral or parenteral antibiotic treatment in the 7 days prior to the scheduled blood 
draw (topical antibiotics are acceptable, including antibiotic eye drops). 
 
Rationale for Change # 6: 
 
The # of days of delay in case of antibiotics treatment was incorrectly recorded as 3 
instead of 7 days. 
 
 
CHANGE 7 (Page 33, Section 4.3): 
 
Previously Read: 
NA 
 
Now Reads: 
There are clinical circumstances that warrant delay of blood collection for 
immunogenicity assessments in this study. These situations are listed below. In the event 
that a subject meets a criterion for delay of blood collection, blood collection may 
proceed once the window for delay has passed. 
 
Subject has received oral or parenteral antibiotic treatment in the 7 days prior to the 
scheduled blood draw (topical antibiotics are acceptable, including antibiotic eye drops). 
 
Rationale for Change # 7: 
To provide further clarification on criteria for delay in blood draw, aligned with Change 6 
above. 
 
 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

GSK Vaccines 
26 FEB 16 
Clinical Study Protocol V59_75 Amendment 2 
Page 6 of 6 
Confidential 
 
 
CHANGE 8 (Page 45, Section 6.5): 
 
Previously Read: 
All medications, vaccines and blood products taken or received by the subject within 60 
days prior to the start of the study are to be recorded on the Prior and Concomitant 
Medications and Blood Products CRF 
 
Now Reads: 
All medications, vaccines and blood products taken or received by the subject since birth 
are to be recorded on the Prior and Concomitant Medications and Blood Products CRF. 
 
Rationale for Change # 8: 
 
To be aligned with the protocol synopsis. 
 
 
CHANGE 9 (Page 62, Section 8.4.2.1.2): 
 
Previously Read: 
 
The severity of solicited local adverse events, including injection site erythema, injection 
site induration, injection site tenderness will be categorized as none, 1 to ≤25 mm, 26 to 
≤50 mm, and >50 mm (severe local reactions). 
 
Now Reads: 
The severity of solicited local adverse events, including injection site erythema and, 
injection site induration, were summarized according to categories based on linear 
measurement: 1-9 mm (‘none’), 10 to 25 mm (“mild”), 26 to 50 mm (“moderate”), and > 
50 mm (“severe”). 
 
Rationale for Change # 9: 
 
Injection site tenderness is not classified in terms of size and has been deleted. 
Classification of injection site tenderness is already specified in the next paragraph of the 
protocol. 
 
In addition, the ranges for classification of erythema and site induration were updated in 
conformance with the classification used in the latest toddler study for Menveo V59_67. 
 
 
 
PRO-01 TEMP 08 / Atlas No. 293623 
Version No. 2 / Version Date: May 5, 2014 
Doc Number: 78427989 

 
PPD 
Novartis 
Document Approval Certificate / 
 
 
The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. / 
 
 
 
 
UserName: PPD 
 
Title: Cluster Physician 
Date: Tuesday, 22 March 2016, 11:09 GMT 
Meaning: As an approver, I agree with the content and format of this document. 
================================================ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This signature certificate is only valid when accompanied by all the pages of the document. / 
PPD 
 
PPD 
Doc Number: 78427989