Post-licensure Observational Safety Surveillance Study of Quadrivalent Meningococcal ACWY Conjugate Vaccine MenACWY-CRM (MENVEO®) in Children 2 Months Through 23 Months of Age.
Conditions: Meningococcal Disease, Infections, Meningococcal
Sponsor: GlaxoSmithKline

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Title 
Post-licensure observational safety surveillance study 
of quadrivalent meningococcal ACWY conjugate 
vaccine MenACWY-CRM (MENVEO®) in children 2 
months through 23 months of age. 
Protocol version identifier 
V. 2 
Date of last version protocol 11 AUG 16 
EU PAS registry number 
Not applicable. 
Active substance 
Not applicable. 
Medicinal product 
Not applicable. 
Product reference 
Not applicable. 
Procedure number 
Not applicable. 
Marketing authorisation 
holder(s) 
GlaxoSmithKline Biologicals S.A. 
Joint PASS study 
NO 
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Research question and 
objectives 
To describe medical events that require emergency 
room visit or hospitalization in 6 months following 
MenACWY-CRM vaccination in children 2-23 
months of age in a health maintenance organization 
(HMO) in the United States. 
Country(ies) of study 
United States 
Author 
Dr. PPD 
, GSK 
Marketing authorisation 
holder(s) details 
GlaxoSmithKline Biologicals S.A 
Rue de I’Institut, 89 BE-1330 Rixensart. 
Belgium 
MAH contact person 
Dr. PPD 
Clinical and Epidemiology R&D 
GSK 
Amsterdam, The Netherlands 
Email: PPD 
 
 
Property of GlaxoSmithKline Biologicals S.A (hereafter referred to as GSK) 
Confidential 
May not be used, divulged, published or otherwise disclosed without written 
consent of GSK 
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1.0 
TABLE OF CONTENTS 
1.0 
TABLE OF CONTENTS ......................................................................................... 3 
2.0 
LIST OF ABBREVIATIONS .................................................................................. 5 
3.1 
RESPONSIBLE PARTIES ...................................................................................... 6 
3.2 
Main Author(s) of the Protocol ............................................................................ 6 
3.3 
Principal Investigator ........................................................................................... 6 
3.4 
Coordinating Investigator(s) ................................................................................ 6 
3.5 
CRO or Other Service Provider ........................................................................... 6 
4.0 
ABSTRACT ............................................................................................................. 7 
5.0 
AMENDMENTS AND UPDATES ....................................................................... 12 
6.0 
MILESTONES ....................................................................................................... 13 
7.0 
RATIONALE AND BACKGROUND ..................................................................... 14 
8.0 
RESEARCH QUESTION AND OBJECTIVES .................................................... 15 
9.1 
RESEARCH METHODS ....................................................................................... 16 
9.2 
Study Design ...................................................................................................... 16 
9.3 
Setting ................................................................................................................ 16 
9.3.1 
Study Period ............................................................................................... 17 
9.3.2 
Study Subjects ................................................................................................ 17 
9.3.3 
Study Population Selection ........................................................................ 18 
9.4 
Variables ............................................................................................................ 18 
9.4.1 
Exposure of Interest ................................................................................... 18 
9.4.2 
Outcome(s) ..................................................................................................... 20 
9.4.3 
Other Variables .......................................................................................... 20 
9.5 
Data Sources ...................................................................................................... 20 
9.5.1 
Operational Exposure Definition ................................................................ 21 
9.5.2 
Operational Outcome Definition and Identification Process ...................... 21 
9.5.3 
Operational Variable(s) Definition ............................................................. 23 
9.5.4 
Advisory Committee(s) .............................................................................. 23 
9.6 
Study Size ............................................................................................................... 23 
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9.7 
Data Management .............................................................................................. 24 
9.7.1 
Data Processing .......................................................................................... 24 
9.7.2 
Software and Hardware .............................................................................. 24 
9.8 
Data Analysis ..................................................................................................... 24 
9.8.1 
Statistical Hypotheses ................................................................................ 24 
9.8.2 
Analysis of Demographics and Baseline Characteristics ........................... 24 
9.8.3 
Statistical Methods ..................................................................................... 25 
9.8.4 
Statistical Considerations ........................................................................... 26 
9.9 
Quality Control .................................................................................................. 27 
9.9.1 
Validation ................................................................................................... 27 
9.9.2 
Record Retention ........................................................................................ 27 
9.10 
Limitations of the Research Methods ................................................................ 27 
9.11 
Other Aspects ..................................................................................................... 28 
10.1 
PROTECTION OF HUMAN SUBJECTS ............................................................. 29 
10.2 
Regulatory and Ethical Compliance ................................................................... 29 
10.3 
Informed Consent ............................................................................................... 29 
10.4 
Responsibilities of the Investigator and IRB/IEC/REB ..................................... 29 
10.5 
Protocol Adherence ............................................................................................ 29 
11.0 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS ..................................................................................................................... 31 
12.1 
PLANS FOR DISSEMINATING AND COMMUNICATING RESULTS ........... 32 
12.2 
Registration in Public Database(s) ..................................................................... 32 
12.3 
Publications ............................................................................................................ 32 
13.0 
REFERENCES ....................................................................................................... 33 
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2.0 
LIST OF ABBREVIATIONS 
 
ACIP 
Advisory Committee on Immunization Practices 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention 
EMR 
Electronic medical record 
FDA 
Food and Drug Administration 
GSK 
GlaxoSmithKline Biologicals S.A. 
HCP 
Health Care Providers 
HIPAA 
Health Insurance Portability and Accountability Act 
HMO 
Health maintenance organization 
ICD-9 
International Classification of Diseases, Ninth Revision 
ICD-10 
International Classification of Diseases, Tenth Revision 
IRB 
Institutional Review Board 
MAH 
Market authorisation holder 
MenACWY-CRM 
Meningococcal ACWY vaccine conjugated to a carrier 
protein Cross reacting Material 197 (CRM 197) 
PMC 
Post-marketing commitment 
PMS 
Post-marketing study 
KPSC 
Kaiser Permanente Southern California 
RIPC 
Regional Immunization Practice Committee 
RDW 
Research Data Warehouse 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
US 
United States 
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3.1 
RESPONSIBLE PARTIES 
 
3.2 
Main Author(s) of the Protocol 
 
 
GSK 
 
Amsterdam, the Netherlands 
 
 
 
3.3 Principal Investigator 
 
 
Department of Research and Evaluation 
Kaiser Permanente, Southern California 
Pasadena, US 
 
3.4 
Coordinating Investigator(s) 
 
Not applicable. 
 
3.5 
CRO or Other Service Provider 
 
Not Applicable. 
 
3.6 
Advisory Committee 
 
Not Applicable 
PPD 
PPD 
PPD 
3.2 
PPD 
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4.0 
ABSTRACT 
 
Name of Sponsor 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V59_74OB 
Health authority 
study registration 
number(s): 
Date of Protocol 
Abstract: 
11AUG16 
Title of Study: 
Post-licensure observational safety surveillance study of quadrivalent meningococcal 
ACWY conjugate vaccine MenACWY-CRM (MENVEO) among children 2 months 
through 23 months of age. 
Study Period: 
The study will start by December 
2014 and data collection period will 
continue for 3 years. 
Study Type: This study is an observational 
post-marketing safety study required by the 
United States Food and Drug Administration 
(FDA). 
Rationale and Background: 
Meningococcal disease is caused by Neisseria meningitidis. Multiple serogroups are 
responsible for invasive meningococcal disease (groups A, B, C, X, Y, and W-135). The 
relative importance of each serogroup depends on geographic location [1-5], as well as 
other factors, such as age. The overall incidence of meningococcal disease in the US 
during 2005-2011 has been approximately 0.3 cases per 100,000 population. [6] 
MenACWY-CRM (MENVEO) is a Meningococcal (Groups A, C, Y and W-135) 
Oligosaccharide Diphtheria CRM197 Conjugate Vaccine. The safety of Men ACWY- 
CRM has been evaluated in clinical trials in infants and toddlers 2 to 23 months of age. 
No safety concerns were raised.[7] 
In February 2010, MenACWY-CRM was approved for use in persons 11-55 years of 
age in the United States. As of August 2013 MenACWY-CRM was approved for use in 
persons 2 months through 55 years of age in the United States. In infants initiating 
vaccination at 2 months of age, MenACWY-CRM is to be administered as a four-dose 
series at 2, 4, 6, and 12 months of age. Among children 7-23 months of age who have 
not previously received a dose of MenACWY-CRM, MenACWY-CRM is to be 
administered as a two-dose series with the second dose administered in the second year 
of life and at least three months after the first dose. The Centers for Disease Control and 
Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) 
recommends the meningococcal conjugate vaccine MenACWY-CRM for use in infants 
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Name of Sponsor 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V59_74OB 
Health authority 
study registration 
number(s): 
Date of Protocol 
Abstract: 
11AUG16 
and toddlers 2-23 months of age who are at increased risk for meningococcal disease. 
This study will provide additional information to the current safety knowledge of 
MenACWY-CRM in the population 2-23 months of age. 
Research Question and Objectives: 
To describe medical events that require emergency room visit or hospitalization in 6 
months following MenACWY-CRM vaccination in children 2-23 months of age in a 
health maintenance organization (HMO) in the United States. 
Study Design: 
The study is a descriptive observational safety surveillance study. 
Medical events in emergency rooms and inpatient care units in children 2-23 months of 
age who were vaccinated with any dose of MenACWY-CRM vaccine will be described. 
Only medical events that occur within 6 months after a MenACWY-CRM vaccination 
will be captured. Events will be identified from electronic medical records of emergency 
care and inpatient care encounters.  Medical records of these events will be reviewed 
and described. 
Population: 
Children 2-23 months of age who receive at least one dose of MenACWY-CRM 
vaccine at a Kaiser Permanente Southern California (KPSC) facility while enrolled as a 
KPSC health plan member. 
Variables: 
Exposure(s) of interest 
All administered doses of MenACWY-CRM at a KPSC facility are considered as 
exposures of interest in children 2-23 months of age who are KPSC members. The 
exposure of interest is MenACWY-CRM vaccine given as part of routine clinical care in 
all medical centers in KPSC. This study is strictly observational. MenACWY-CRM will 
be the only meningococcal vaccine used in children 2-23 months of age to prevent N. 
meningitidis serogroup A, C, W135 and Y caused meningococcal disease in KPSC. 
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Name of Sponsor 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V59_74OB 
Health authority 
study registration 
number(s): 
Date of Protocol 
Abstract: 
11AUG16 
While health care providers (HCP) are advised to follow the ACIP Recommended 
Childhood Vaccine schedule, vaccination decisions will be determined by the treating 
HCP and the caregivers. MenACWY-CRM vaccine as a N. meningitidis A, C, W135 
and Y vaccine will be used in infants and toddlers 2-23 months of age with high risk 
indications for the vaccine in KPSC. No special labeling will be required for the 
MenACWY-CRM vaccine used in this study. Co-administration of other vaccines may 
occur as consistent with clinical practice. 
▫ Date (s) of MenACWY-CRM vaccination (s): exposure to MenACWY-CRM 
vaccination is defined as a registration of a MenACWY-CRM vaccination in the 
medical records. The date of vaccine administration in the medical records is 
considered as the vaccination date. Age at vaccination will be expressed in number 
of months after birth. 
▫ Observation period: For each individual, the observation period is defined as the 
time from the first dose of MenACWY-CRM vaccination up to 6 months after the 
last dose of MenACWY-CRM vaccination received between 2-23 months of age, 
disenrollment, death, or the end of data collection, whichever occurs sooner. 
Outcome(s) 
Outcomes include medical events that require emergency room visits or hospitalizations 
in children 2-23 months of age following any dose of MenACWY-CRM vaccination. 
Events with a history of the same diagnosis prior to the first dose of MenACWY-CRM 
vaccination will be excluded as a pre-existing condition.  The medical records prior to 
the first dose of MenACWY-CRM will be searched for the same diagnosis code. 
For each identified emergency department or inpatient visit the following information 
will be collected: 
▫ Diagnosis of medical events 
▫ Date of diagnosis: the date of the documented code after any dose of MenACWY- 
CRM vaccination is considered the date of diagnosis. The date of diagnosis is 
expressed as the number of days following the 1st, 2nd, 3rd, or 4th dose of 
MenACWY-CRM vaccination. 
▫ Health care setting: hospitalization or emergency room 
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Name of Sponsor 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V59_74OB 
Health authority 
study registration 
number(s): 
Date of Protocol 
Abstract: 
11AUG16 
Other Variables 
▫ Baseline characteristics: these data will be extracted from patients’ medical records. 
- 
Date of birth, expressed as age at vaccination 
- 
Gender 
▫ Underlying condition of the MenACWY-CRM vaccine indication (i.e., persistent 
complement component deficiencies, asplenia or other), if available. 
▫ Vaccination history 
- 
Concomitant vaccinations (specify) 
- 
History of other vaccinations (specify) 
- 
Vaccinations occurring during the observation period (specify) 
Data Sources: 
Medical events occurring within 6 months following a MenACWY-CRM vaccination 
will be searched in electronic medical records from emergency care and inpatient care 
units. Vaccination information will be searched from vaccination records. Diagnoses 
occurring in any care setting (inpatient, outpatient, or emergency room) prior to the first 
dose of MenACWY-CRM vaccination will be searched in electronic medical records for 
evidence of pre-existing medical events. 
Study Size: 
There is no planned number of vaccinees. The study will include medically attended 
events that require an emergency room visit or hospitalization in the study population. 
Data Analysis: 
This study is descriptive in nature and there will be no hypothesis testing. 
Informed Consent and Ethical Approval: 
Subjects included in this study will be identified among KPSC health plan members. 
Informed consent for receipt of MenACWY-CRM vaccine is not required as it is given 
to eligible KPSC members as part of routine care. KPSC will obtain IRB approval and 
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Name of Sponsor 
GlaxoSmithKline 
Biologicals S.A. 
Protocol number: 
V59_74OB 
Health authority 
study registration 
number(s): 
Date of Protocol 
Abstract: 
11AUG16 
will request waivers for both informed consent and written HIPAA authorization prior 
to initiating data collection. 
Milestones: 
Start of data collection: December 1, 2014 
End of data collection: November 30, 2017 
Final report of study results: November 30, 2018 
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5.0 
AMENDMENTS AND UPDATES 
 
Number 
Date 
Section of the 
study protocol 
Amendment or 
update 
Reason 
1 
11AUG16 
Throughout the text 
of this protocol. 
Amendment 
Main reason: 
To reflect the change 
of Sponsor from 
Novartis Vaccines 
and Diagnostics Inc. 
to GlaxoSmithKline 
Biologicals S.A. 
1 
11AUG16 
Throughout the text 
of this protocol. 
Amendment 
Minor change: 
Name of the vaccine 
(MENVEO) 
has been capitalized. 
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6.0 
MILESTONES 
 
Milestone 
Planned date 
Start of data collection 
December 1, 2014 
End of data collection 
November 30, 2017 
Final report of study results 
November 30, 2018 
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7.0 
RATIONALE AND BACKGROUND 
 
Meningococcal disease is caused by Neisseria meningitidis. Multiple serogroups are 
responsible for invasive meningococcal disease (groups A, B, C, X, Y, and W-135). The 
relative importance of each serogroup depends on geographic location, as well as other 
factors, such as age. Serogroup B and C strains are most prevalent in Europe, and 
serogroups B, C and Y strains are most prevalent in North America. Serogroup A strains 
are rarely isolated in Europe and North America. [1-5]The overall incidence of 
meningococcal disease in the US during 2005-2011has been approximately 0.3 cases per 
100,000 population. [6] Children younger than 1 year of age have the highest incidence of 
meningococcal disease in the United States. 
 
MenACWY-CRM (MENVEO) is a Meningococcal (Groups A, C, Y and W-135) 
Oligosaccharide Diphtheria CRM197 Conjugate Vaccine. Safety of Men ACWY-CRM 
with 2-dose and 4-dose schedules has been primarily evaluated in multiple clinical studies 
in infants and toddlers 2 to 23 months of age. Serious adverse events (SAEs) were similar 
between the MenACWY-CRM and routine paediatric vaccination groups. Rates of severe 
unsolicited adverse events (AEs) reported in subjects who received MenACWY-CRM in 
co-administration with routine childhood vaccination and those who received routine 
childhood vaccination alone are similar. No vaccine related death was reported.[7] 
 
In February 2010, MenACWY-CRM was approved for use in persons 11-55 years of age 
in the United States. As of August 2013 MenACWY-CRM was approved for use in 
persons 2 months through 55 years of age in the United States. In infants initiating 
vaccination at 2 months of age, MenACWY-CRM is to be administered as a four-dose 
series at 2, 4, 6, and 12 months of age. Among children 7-23 months of age who have not 
previously received a dose of MenACWY-CRM, MenACWY-CRM is to be administered 
as a two-dose series, with the second dose administered in the second year of life and at 
least three months after the first dose. The Centers for Disease Control and Prevention's 
(CDC) Advisory Committee on Immunization Practices (ACIP) recommends the 
meningococcal conjugate vaccine MenACWY-CRM for use in infants and toddlers 2-23 
months of age who are at increased risk for meningococcal disease. Children at increased 
risk include those who have persistent complement deficiencies, have functional or 
anatomic asplenia, are at risk during a community outbreak attributable to a vaccine 
serogroup, or travel to or are residents of countries where meningococcal disease is 
hyperendemic or epidemic.[6] 
 
The study is to be conducted in collaboration with Kaiser Permanente Southern California 
(KPSC) in the United States. 
 
This study will add to the current knowledge about the safety of MenACWY-CRM in 
children 2-23 months of age in the setting of routine medical care. 
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8.0 
RESEARCH QUESTION AND OBJECTIVES 
 
To describe medical events that require an emergency room visit or hospitalization in 6 
months following MenACWY-CRM vaccination in children 2-23 months of age in a 
health maintenance organization (HMO) in the United States. 
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9.1 
RESEARCH METHODS 
 
9.2 
Study Design 
 
This is a post marketing commitment (PMC) agreed upon with FDA Center for Biologics 
Evaluation and Research (CBER) to establish an open label, descriptive, epidemiological 
safety surveillance study of MENVEO in children 2 through 23 months of age who 
receive medical care at the site where the study is being conducted. Part I will continue 
for 3 years, or until commencement of Part II, whichever occurs first. Part II of the study 
will be initiated if there is a recommendation by the Advisory Committee on 
Immunization Practices (ACIP) for routine use of meningococcal conjugate vaccine in at 
least one birth cohort within the 2 through 23 months of age range. 
 
Part II will commence with the effective date of the ACIP recommendation, and will 
continue until 20,000 children are enrolled, or until 1 year has elapsed, whichever occurs 
last. If initiated, a final study report for Part II will be submitted 1 year after the last 
subject has completed study Part II. In the event there is no recommendation for routine 
use of meningococcal conjugate vaccine in this age group, Part II will be considered 
fulfilled when Part I is completed. 
 
This study protocol and timelines pertain only to Part I since there is currently no ACIP 
recommendation for routine use of meningococcal conjugate vaccine among children 2 
through 23 months of age. 
 
In Part I, medical events in emergency rooms and inpatient care units in children 2-23 
months of age who were vaccinated with any dose of MenACWY-CRM vaccine will be 
described. Only medical events that occur within 6 months after a MenACWY-CRM 
vaccination will be captured. Events will be identified from electronic medical records of 
emergency care and inpatient care encounters.  Medical records of these events will be 
reviewed and described. 
 
9.3 
Setting 
 
The study will be conducted at Kaiser Permanente Southern California (KPSC), the 
largest managed care organization in Southern California, serving over 3.7 million 
members that are broadly representative of the diverse racial, ethnic and socioeconomic 
background of the source population in Southern California.[8]  The racial/ethnic 
breakdown of the KPSC population is 41% Hispanic, 36% Non-Hispanic White, 11% 
Asian/Pacific Islander, 9% Black, and 3% other. 
 
Prepaid, comprehensive health care is provided to KPSC members at 14 medical centers 
and over 200 satellite clinics. All health care encounters are tracked through electronic 
data systems, with detailed information on diagnoses applied, procedures performed, and 
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immunizations administered, regardless of setting.  KPSC members may seek emergency 
medical care from outside health care providers. For outside providers to be reimbursed 
by the health plan for covered emergency care, claims have to be submitted with 
documentation of the episode of care, and that information is entered into the 
administrative data systems. Thus, the capture of care delivered to KPSC members by 
electronic data is very comprehensive. 
 
KPSC health plan members can enroll through their employer or the employer of a family 
member, through individual and family plans, or through state or federal programs such 
as California Public Employees' Retirement System, MediCal, and Medicare. 
 
The KPSC Regional Immunization Practice Committee (RIPC) makes recommendations 
to ensure appropriate use of vaccination and implementation of new ACIP immunization 
recommendations within KPSC. KPSC has a proactive immunization program that 
includes: 1) alerts in the electronic medical record that indicate which age-appropriate 
routine vaccines are due based on vaccines that the member has already received, 2) a 
policy of vaccinating at all visits, not just well child or physical exam appointments, and 
3) giving immunizations on a walk-in basis without appointment and at no-cost nurse 
visits.  Since there is no charge for immunizations for KPSC members, there is an 
incentive to receive immunizations within the KPSC system. 
 
9.2.1 Study Period 
 
The total study period will be up to 3.5 years, which includes vaccination period and 
observation period. 
 
▫ Vaccination period will start at earliest in May 2014, and at latest in December 2014 
to implement ACIP recommendation on preventing meningococcal serogroups A, C, 
W135 and Y caused meningitis in persons aged 2 through 23 months. 
▫ Observation period: For each individual, the observation period is defined as the time 
from the first dose of MenACWY-CRM vaccination up to 6 months after the last dose 
of MenACWY-CRM vaccination received between 2-23 months of age, 
disenrollment, death, or the end of data collection, whichever occurs sooner. 
 
Pre-existing medical events will be assessed prior to the first dose of MenACWY-CRM 
vaccination. 
 
9.2.2 Study Subjects 
 
According to the ACIP recommended immunization schedule for persons aged 0 through 
18 years, MenACWY-CRM is recommended for children 2-23 months of age with high- 
risk conditions and other persons at increased risk of disease. This population includes: 
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▫ children with anatomic or functional asplenia (including sickle cell disease) 
▫ children with persistent complement component deficiency 
▫ children who travel to or reside in countries in which meningococcal disease is 
hyperendemic or epidemic 
▫ children at risk during a community outbreak attributable to a vaccine serogroup. 
There are approximately 500,000 births per year in California,[9] equivalent to nearly 1 
million infants and toddlers age 2-23 months. There were approximately 38,000 babies 
delivered at KPSC facilities and contracting hospitals in 2012. 
 
There were approximately 122,000 infants and toddlers age 2-23 months enrolled in the 
KPSC health plan in 2013.  Among this population, there were approximately 30 
individuals diagnosed with sickle cell, asplenia, or persistent complement deficiency. 
 
9.2.3 Study Population Selection 
 
Children 2-23 months of age who receive at least one dose of MenACWY-CRM vaccine 
at a KPSC facility while enrolled as a KPSC health plan member are considered as the 
study population. 
 
Inclusion criteria: 
 
▫ children 2-23 months of age at the time of MenACWY-CRM vaccination 
▫ hold KPSC membership at the time of MenACWY-CRM vaccination 
▫ vaccinated with MenACWY-CRM during the study period in KPSC 
There are no exclusion criteria for selection of the study population. 
9.3 
Variables 
 
The sections below describe the theoretical aspects of relevant variables. Data sources 
and operational definitions are discussed in 9.4. 
 
9.3.1 Exposure of Interest 
 
Doses of MenACWY-CRM administered at a KPSC facility are considered as exposures 
of interest in children 2-23 months of age who are KPSC members. The exposure of 
interest is MenACWY-CRM vaccine given as part of routine clinical care in all medical 
centers in KPSC. This study is strictly observational. MenACWY-CRM will be the only 
meningococcal vaccine used in children 2-23 months of age to prevent N. meningitidis 
serogroup A, C, W135 and Y caused meningococcal disease in KPSC.  While HCPs are 
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advised to follow ACIP immunization recommendations, decisions regarding 
vaccinations and vaccination schedule will be determined by the HCP and caregivers. The 
MenACWY-CRM vaccination recommendation will be implemented at all KPSC 
medical centers. 
 
No special labeling will be required for the MenACWY-CRM vaccine used in this study. 
Other vaccines may be co-administered as consistent with clinical practice. 
 
According to the ACIP recommendation, MenACWY-CRM is recommended for infants 
and toddlers 2-23 months of age with high risk of meningococcal disease. The 
recommended meningococcal vaccination schedules for these high risk populations are as 
follows: [10] 
 
▫ Children with anatomic or functional asplenia (including sickle cell disease): 
1. For children younger than 19 months of age, administer a 4-dose infant series of 
MenHibrix or MENVEO at 2, 4, 6, and 12 through 15 months of age. 
2. For children aged 19 through 23 months who have not completed a series of 
MenHibrix or MENVEO, administer 2 primary doses of MENVEO at least 3 months 
apart. 
 
▫ Children with persistent complement component deficiency: 
1. For children younger than 19 months of age, administer a 4-dose infant series of 
either MenHibrix or MENVEO at 2, 4, 6, and 12 through 15 months of age. 
2. For children 7 through 23 months who have not initiated vaccination, two options 
exist depending on age and vaccine brand: 
a. For children who initiate vaccination with MENVEO at 7 months through 23 
months of age, a 2-dose series should be administered with the second dose after 
12 months of age and at least 3 months after the first dose. 
b. For children who initiate vaccination with Menactra at 9 months through 23 
months of age, a 2-dose series of Menactra should be administered at least 3 
months apart. 
 
▫ For children who travel to or reside in countries in which meningococcal disease is 
hyperendemic or epidemic, including countries in the African meningitis belt or the 
Hajj, administer an age appropriate formulation and series of Menactra or MENVEO 
for protection against serogroups A and W meningococcal disease.  Prior receipt of 
MenHibrix is not sufficient for children traveling to the meningitis belt or the Hajj 
because it does not contain serogroups A or W. 
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▫ For children at risk during a community outbreak attributable to a vaccine serogroup, 
administer or complete an age- and formulation-appropriate series of MenHibrix, 
Menactra, or MENVEO. 
Catch-up recommendation of MenACWY-CRM for persons with high-risk conditions is 
as follows: 
 
For children who initiate vaccination with MENVEO at 7 months through 9 months of 
age, a 2-dose series should be administered with the second dose after 12 months of age 
and at least 3 months after the first dose. 
 
9.3.2 Outcome(s) 
 
Outcomes include medical events that require an emergency room visit or hospitalization 
in children 2-23 months of age within 6 months following any dose of MenACWY-CRM 
vaccination. 
 
9.3.3 Other Variables 
 
▫ Baseline characteristics: these data will be extracted from patients’ medical records. 
- 
Date of birth, expressed as age at vaccination 
- 
Gender 
▫ Underlying condition of the MenACWY-CRM vaccine indication (i.e., persistent 
complement component deficiencies, asplenia or other), if available. 
▫ Vaccination history 
- 
Concomitant vaccinations (specify) 
- 
History of other vaccinations (specify) 
- 
Vaccinations occurring during the observation period (specify) 
 
 
9.4 
Data Sources 
 
The study will be conducted using the KPSC Oracle Research Data Warehouse (RDW) 
which supports external and internal research projects conducted in the Department of 
Research & Evaluation, KPSC as well as patient care management programs. The data 
warehouse is an integrated and comprehensive resource. It contains information as far 
back as 1980, including records related to membership, benefits, utilization, pharmacy, 
vital signs, laboratory, vaccines, geocoding, mortality, and procedures. 
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Medical events will be searched in the electronic medical record (EMR). All care 
provided at KPSC is recorded using the EMR. All details of a patient encounter, including 
diagnoses, procedures, and physician’s notes, are entered into the EMR at the point of 
care. All vaccinations are entered into the EMR when they are given, with vaccine, dose, 
manufacturer, and lot number entered at the time of vaccination. 
 
9.4.1 Operational Exposure Definition 
 
Vaccination information will be searched from vaccination records. Documented 
MenACWY-CRM vaccination record is considered as evidence of exposure. 
 
The date of vaccine administration in the medical records is considered as the vaccination 
date. Age at vaccination will be extracted from date of vaccination and date of birth. Age 
at vaccination will be expressed in number of months after birth. 
 
The first dose of MenACWY-CRM vaccination administered at a KPSC facility to a 
KPSC member 2-23 months of age is the starting point of observation period for each 
study individual. 
 
For each individual, the observation period is defined as the time from the first dose of 
MenACWY-CRM vaccination up to 6 months after the last dose of MenACWY-CRM 
vaccination received between 2-23 months of age, disenrollment, death, or the end of data 
collection, whichever occurs sooner. 
 
9.4.2 Operational Outcome Definition and Identification Process 
 
Medical events occurring in emergency and inpatient settings within 6 months following 
a MenACWY-CRM vaccination will be searched in electronic medical records. 
Diagnoses occurring in any care setting (inpatient, outpatient, or emergency room) prior 
to the first dose of MenACWY-CRM vaccination will be searched in electronic medical 
records for evidence of pre-existing medical events. 
 
Events with a history of the same diagnosis prior to the first dose of MenACWY-CRM 
vaccination will be excluded as a pre-existing condition. The medical records prior to the 
first dose of MenACWY-CRM will be searched for the same diagnosis code. As there 
will be a transition from International Classification of Diseases, Ninth Revision (ICD-9) 
to Tenth Revision (ICD-10) coding, in the event that the diagnosis following a 
MenACWY-CRM vaccination is coded using ICD-10, both the same ICD-10 code and an 
equivalent ICD-9 diagnosis code will be searched in the period prior to the first dose. 
 
If a study subject is first seen in the emergency department and subsequently transferred 
to the hospital, this will be treated as a single episode of care. Multiple records of a single 
medical event will be consolidated and treated as 1 report. 
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Medical events are considered as eligible if they occur in eligible study subjects during 
the observation period and are not pre-existing conditions. 
 
For each identified emergency department or inpatient visit the following information 
will be collected: 
 
▫ Diagnosis of medical events 
▫ Date of diagnosis: the date of the documented code after any dose of MenACWY- 
CRM vaccination is considered the date of diagnosis. The date of diagnosis is 
expressed as the number of days following the 1st, 2nd, 3rd, or 4th dose of MenACWY- 
CRM vaccination. 
▫ Health care setting: hospitalization or emergency room visit 
Process of medical events identification 
Eligible medical events identification process is illustrated in Figure 1: 
 
1. Children 2-23 months of age vaccinated with MenACWY-CRM will be identified by 
immunization records in electronic medical records. 
2. Medical events will be searched up to 6 months following MenACWY-CRM 
vaccination in the electronic records of emergency department and inpatient care units 
in all medical centers of KPSC. 
3. Diagnosis codes of medical events from these visits will be identified. 
4. Pre-existing conditions will be excluded by automated search. 
5. Medical charts of identified eligible events will be reviewed and described. 
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Figure 9.4.2-1: Process of eligible medical events identification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.3 Operational Variable(s) Definition 
 
To describe medical events, baseline characteristics, including date of birth, gender, date 
of diagnosis, and underlying condition will be extracted from medical records. 
Vaccination history will be extracted from immunization records. 
 
9.4.4 Advisory Committee(s) 
 
There is no Advisory Committee for this study. 
 
9.5 Study Size 
 
There is no planned number of vaccinees. The study will describe all eligible medically 
attended events that require emergency room visit or hospitalization in the study 
population. 
 
Approximately 245,000 infants and toddlers aged 2-23 months were enrolled in the KPSC 
health plan in the period from 2011 to 2013. Among this population, there were around 
60 children aged 2-23 months old with high risk conditions. It is estimated that the 
number of infants with high risk conditions would likely fall between 60-100 in the study 
Review medical charts of eligible events 
Exclude pre-existing conditions based on searching diagnosis codes 
prior to the first dose 
Identify diagnosis codes of these visits. 
Search for emergency department and inpatient visits up to 6 months 
following MenACWY-CRM vaccination among eligible subjects 
Scheduled computerized searches in HMO electronic immunization 
records to identify eligible vaccine recipients 
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9.6 
Data Management 
 
9.6.1 Data Processing 
 
Data collection and retrieval will be performed using the HMO’s standard procedures in 
agreement with GSK. Quality assurance measures as implemented at the HMO will be 
used. 
 
Blinding 
This study is an open-label study conducted in a routine medical care setting. Reviewers 
are not blinded to the patient identity or vaccination status. All study staff with access to 
protected health information are trained in procedures to protect the confidentiality of 
subject data. 
 
Data linkage 
An important aspect of the KPSC managed care environment is its integrated approach to 
the delivery of medical care. This approach depends on, and therefore facilitates, the 
development and maintenance of a large number of databases, linkable through a unique 
medical record number. These databases include those that track membership, encounters, 
claims, pharmaceuticals dispensed and appointments. They also include test results as 
well as text excerpts of their interpretation. There are also a number of derivative files 
that have been developed for research purposes, including those for disease identification, 
geocoding files and mortality follow-up files. 
 
9.6.2 Software and Hardware 
 
The data analysis in this study will be performed by Research & Evaluation programmers 
and analysts in KPSC. SAS (Enterprise Guide 4.3 or higher) will be used to perform data 
programming and data analysis in the study. Data management will be done in both PC 
and Unix environments. 
 
9.7 
Data Analysis 
 
9.7.1 Statistical Hypotheses 
 
This study is descriptive in nature and there will be no hypothesis testing. 
 
9.7.2 Analysis of Demographics and Baseline Characteristics 
 
Age at vaccination (extracted from date of birth and date of vaccination) will be presented 
by mean, median, standard deviation, minimum and maximum. Gender will be described 
by absolute numbers and percentages. Vaccination history (including vaccine name and 
age or relative timing of vaccination) will be summarized descriptively. 
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9.7.3 Statistical Methods 
 
This descriptive study will analyze collected data to report frequencies of MenACWY- 
CRM exposure and analysis of medical events. The frequencies will be presented as 
absolute numbers and percentages of relevant total. 
 
Frequency of exposure to MenACWY-CRM vaccination 
 
This descriptive study will report the frequency of exposure among infants and toddlers 
2-23 months of age vaccinated at least one dose of MenACWY-CRM during the study 
period. Frequency of exposure will be summarized as follows: 
 
▫ Overall 
▫ 1 dose 
▫ 2 doses 
▫ 3 doses 
▫ 4 doses 
Analysis of medical events 
 
Eligible medical events in the study will be described as follows: 
 
▫ Frequency of individual medical events 
The frequency of medical events is defined as the total number of each individual 
event. The frequency will be described by absolute number of each individual medical 
event and percentage of each individual medical event of total number of captured 
medical events during the observation period. 
 
If the number of medical events allows, captured medical events will be stratified by 
dose. 
 
▫ Rate of medical events 
The rate of medical events is defined as the number of all captured events divided by 
the total person-time following MenACWY-CRM doses administered during the 
study period. 95% confidence interval of the rate of medical events will be calculated. 
Person-time for each dose will begin at the vaccination and end at 6 months following 
vaccination, disenrollment, death, the end of data collection, or receipt of an 
additional dose of MenACWY-CRM, whichever comes first.  If data permit, rate will 
be further stratified by dose. 
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▫ Description of medical events 
Medical events following MenACWY-CRM exposure in children 2-23 months of age 
will be described. Medical events will be reviewed and described, at least including 
age at vaccination, gender, vaccination history, diagnoses, and if available, underlying 
condition. Recurrence of the same medical event after repeated MenACWY-CRM 
vaccination of the same person will be included in the description as well. 
 
9.7.4 Statistical Considerations 
 
Misclassification of diagnosis 
 
As this study focuses on medical events requiring hospitalization and emergency care 
among children 2-23 months of age enrolled as KPSC health plan members, it is unlikely 
that serious and acute outcomes would be missed or misclassified.  Also, due to the ICD- 
9 to ICD-10 transition, both ICD-9 and ICD-10 codes may need to be searched to exclude 
pre-existing conditions.  Some pre-existing conditions may be missed from the automated 
search due to imperfect mapping between ICD-9 and ICD-10. 
 
Misclassification of exposure 
 
Depending on the available data in the medical record database on the recording of a 
vaccination, it may be that not all vaccinations are given through the HMO, resulting in 
not all vaccination data being present in the medical record.  However, loss of these data 
should not affect results because analyses are confined to those individuals with a 
recorded vaccine administration. 
 
Missing Data 
 
No imputation will be performed.  We expect there to be a very low rate of missing data 
regarding population characteristics, such as age and gender, and diagnoses. The study 
uses electronic medical records as the source of information for diagnoses, so events that 
do not result in a medical visit may be missed. Subjects missing the stratification factors 
will be excluded from subgroup analysis where the stratification factor is unknown. We 
expect that most vaccines will be captured by the electronic medical record, with very 
little missing information.  It is possible that some study subjects will have received 
meningococcal vaccine prior to joining the health plan, and these prior doses may not be 
captured. This number is expected to be small and not to have a material impact on the 
results. 
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Handling of Loss to Follow-up 
 
We expect there to be minimal loss to follow-up due to the high retention of KPSC health 
plan members in this age group.  Any loss will be addressed in the data analysis by the 
truncation of person-time in the event rate calculation. 
 
 
9.8 
Quality Control 
 
9.8.1 Validation 
 
Vaccination and medical event data will be extracted directly from the electronic medical 
record, which is the legal record of all medical care received within the KPSC system. 
Records of vaccinations and medical events can only be entered by medical staff, and are 
assumed to be an accurate representation of care received. No validation will be 
performed regarding vaccination.  Medical events will be individually reviewed in order 
to determine the primary reason for the encounter as well as whether the condition pre- 
dated the first receipt of MenACWY-CRM. 
 
All data in the study is extracted and maintained in the electronic database at KPSC. The 
database is maintained on a daily basis, and undergoes quality validations regularly. Only 
authorized study personnel with passwords can access to databases. Validations of data in 
the study database will include range and consistency checks. 
 
9.8.2 Record Retention 
 
The participating HMO’s standard procedures for medical record and data file retention 
will be used for this study. 
 
9.9 
Limitations of the Research Methods 
 
This is a descriptive, observational study conducted in a routine medical care setting. The 
decisions to use MenACWY-CRM and other vaccinations are independently made by 
HCPs and caregivers. 
 
The validity of the study may be limited by several aspects. First, the generalizability will 
be limited by the characteristics of the population covered by KPSC. KPSC has a larger 
proportion of Hispanics compared to the US population, but it is broadly representative of 
the California population. Second, the study may not be able to capture all medical events 
following Men ACWY-CRM vaccination, due to children moving out of the KPSC 
region. Given that the population is relatively stable, it is less likely that the study will be 
affected. Finally, medical events described in the study will be severe due to the nature of 
diseases requiring inpatient and emergency room visits. 
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9.10 
Other Aspects 
 
There are no other aspects of the research method not covered by the previous sections. 
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10.1 
PROTECTION OF HUMAN SUBJECTS 
 
KPSC electronic medical records will be used to conduct the study. Personal information 
is maintained at KPSC with firewall protection. Identifiable data can be only accessed by 
authorized study staff through password protected accounts. Data transmission is through 
encrypted software to assure confidentiality. 
 
GSK respects the subjects’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with applicable laws and regulations. 
 
10.2 
Regulatory and Ethical Compliance 
 
This study was designed and shall be implemented and reported in accordance with Good 
Pharmacoepidemiological Practice, with applicable local regulations and with the ethical 
principles laid down in the Declaration of Helsinki. 
 
10.3 
Informed Consent 
 
Subjects included in this study will be identified among KPSC health plan members. 
Informed consent for receipt of MenACWY-CRM vaccine is not required as it is given to 
eligible KPSC members as part of routine care. KPSC will obtain IRB approval and will 
request waivers for both informed consent and written HIPAA authorization prior to 
initiating data collection. 
 
10.4 
Responsibilities of the Investigator and IRB/IEC/REB 
 
The protocol and waiver of informed consent must be reviewed and approved by a 
properly constituted IRB/IEC/REB before study start. A signed and dated statement that 
the protocol has been approved by the IRB/IEC/REB and waiver of informed consent 
must be given to GSK before study initiation. Prior to study start, 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. If an inspection of the site is requested by a regulatory authority, 
the investigator must inform GSK immediately that this request has been made. 
 
10.5 
Protocol Adherence 
 
Investigators will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact GSK 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 
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is agreed upon by GSK and approved by the IRB/IEC/REB it cannot be implemented. All 
significant protocol deviations will be recorded and reported in the CSR. 
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11.0 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE 
REACTIONS 
 
Adverse reactions reporting is not required, as this is a non-interventional study based on 
secondary use of KPSC electronic records. Vaccination information, medical events and 
pre-existing conditions will be searched in the computer database. SAEs cannot be 
identified spontaneously under the current methodology, so there will not be a general 
tabulation of SAEs that occurred and were reported spontaneously in this study. 
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12.1 
PLANS FOR DISSEMINATING AND COMMUNICATING RESULTS 
 
12.2 
Registration in Public Database(s) 
 
GSK assures that the key design elements of this protocol will be posted in a publicly 
accessible database where applicable and in compliance with current regulations. 
 
GSK also assures that key results of this study will be posted in a publicly accessible 
database within the required time-frame from completion of the data collection where 
applicable and in compliance with current regulations (for study registration numbers see 
title page). 
 
12.3 
Publications 
 
Decisions of publication will be under the agreement of GSK and the study site. 
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13.0 
REFERENCES 
 
1. 
Schwartz, B., P.S. Moore, and C.V. Broome, Global epidemiology of 
meningococcal disease. Clin Microbiol Rev, 1989. 2 Suppl: p. S118-24. 
2. 
Connolly, M. and N. Noah, Is group C meningococcal disease increasing in 
Europe? A report of surveillance of meningococcal infection in Europe 1993-6. 
European Meningitis Surveillance Group. Epidemiol Infect, 1999. 122(1): p. 41-9. 
3. 
Greenwood, B.M., A.K. Bradley, and R.A. Wall, Meningococcal disease and 
season in sub-Saharan Africa. Lancet, 1985. 2(8459): p. 829-30. 
4. 
Berron, S., et al., Increasing incidence of meningococcal disease in Spain 
associated with a new variant of serogroup C. Eur J Clin Microbiol Infect Dis, 
1998. 17(2): p. 85-9. 
5. 
Ramsay, M., et al., Changing patterns of case ascertainment and trends in 
meningococcal disease in England and Wales. Commun Dis Rep CDR Rev, 1997. 
7(4): p. R49-54. 
6. 
Cohn, A.C., et al., Prevention and control of meningococcal disease: 
recommendations of the Advisory Committee on Immunization Practices (ACIP). 
MMWR Recomm Rep, 2013. 62(RR-2): p. 1-28. 
7. 
Novartis Vaccines and Diagnostics, I., MenACWY Investigator’s Brochure. 2013. 
8. 
Koebnick, C., et al., Sociodemographic characteristics of members of a large, 
integrated health care system: comparison with US Census Bureau data. Perm J, 
2012. 16(3): p. 37-41. 
9. 
Hamilton, B.E., J.A. Martin, and S.J. Ventura, Births: preliminary data for 2012. 
Natl Vital Stat Rep, 2013. 62(3): p. 1-20. 
10. 
Akinsanya-Beysolow, I., et al., Advisory Committee on Immunization Practices 
recommended immunization schedules for persons aged 0 through 18 years - 
United States, 2014. MMWR Morb Mortal Wkly Rep, 2014. 63(5): p. 108-9. 
Doc Number: 81195327 

 
Novartis 
Document Approval Certificate / 
 
 
The individuals listed have approved this document for implementation using an electronic signature in the 
Atlas EDMS. / PPD 
/ PPD 
 
 
 
 
UserName: PPD 
Title: Cluster Physician 
Date: Monday, 15 August 2016, 05:35 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
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PPD
Doc Number: 81195327 

 
 
 
CONFIDENTIAL 
205534 (MENACWY CONJ-035 EPI VS US DB (V59_74OB)) 
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CONFIDENTIAL 
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Report Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
09-NOV-2018 
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27f3f4faf987836804192439f52f8e6112add071 
 
 
 
 
 
GlaxoSmithKline Biologicals 
Vaccines R&D 
Sponsor Signatory Approval Page 
 
 
Please note that by signing this page, you take responsibility for the content of the Study 
Report, including appendices 
 
 
 
STUDY TITLE: Post-licensure observational safety surveillance study of quadrivalent 
meningococcal ACWY conjugate vaccine MenACWY-CRM (MENVEO®) in children 2 
months through 23 months of age 
 
Study: 205534 (MENACWY CONJ-035 EPI VS US DB (V59_74OB)) 
 
Development Phase: Post-licensure observational safety surveillance study 
 
I have read this report and confirm that to the best of my knowledge it accurately 
describes the conduct and results of the study. 
 
Name of Sponsor Signatory: 
Michele Pellegrini 
Title of Sponsor Signatory: 
Clinical & Epidemiology Research and 
Development Project Lead 
 
 
Signature: 
Date: 
 
 
 
16/NOV/2018 
 
 
 
For internal use only
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