A Phase 4, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, and Immunogenicity of Vaxelis™ in Healthy Children Previously Vaccinated With a 2-Dose Primary Infant Series of Either Vaxelis™ or Hexyon™
Phase: PHASE4
Conditions: Vaccines, Combined, Hexavalent Vaccine
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT05289271 
Document Date: 
08-Jul-2022
A Phase 4, Open-label, Multicenter Study to Evaluate the Safety,
Tolerability, and Immunogenicity of Vaxelis™ in Healthy Children 
Previously Vaccinated With a 2-Dose Primary Infant Series of Either 
Vaxelis™ or Hexyon™

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 4, Open-label, Multicenter Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of Vaxelis™ in Healthy Children Previously Vaccinated 
With a 2-Dose Primary Infant Series of Either Vaxelis™ or Hexyon™
Protocol Number: 016-01
Compound Number: V419
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
Not applicable
EudraCT
2021-004053-23
Approval Date: 08 July 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
08-JUL-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity 
name change and update to the address.
Original Protocol
05-NOV-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
2
INTRODUCTION..........................................................................................................18
2.1
Study Rationale....................................................................................................18
2.2
Background ..........................................................................................................20
2.3
Benefit/Risk Assessment......................................................................................21
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................22
4
STUDY DESIGN............................................................................................................24
4.1
Overall Design......................................................................................................24
4.2
Scientific Rationale for Study Design.................................................................24
4.2.1
Rationale for Endpoints ...............................................................................25
4.2.1.1
Immunogenicity Endpoints................................................................25
4.2.1.2
Safety Endpoints................................................................................26
4.3
Justification for Dose...........................................................................................26
4.4
Beginning and End-of-Study Definition ............................................................26
4.4.1
Clinical Criteria for Early Study Termination .............................................27
5
STUDY POPULATION ................................................................................................27
5.1
Inclusion Criteria.................................................................................................27
5.2
Exclusion Criteria................................................................................................28
5.3
Lifestyle Considerations......................................................................................29
5.4
Screen Failures.....................................................................................................29
5.5
Participant Replacement Strategy......................................................................30
6
STUDY INTERVENTION............................................................................................30
6.1
Study Intervention(s) Administered...................................................................30
6.1.1
Medical Devices...........................................................................................32
6.2
Preparation/Handling/Storage/Accountability .................................................32
6.2.1
Dose Preparation..........................................................................................32
6.2.2
Handling, Storage, and Accountability........................................................32
6.3
Measures to Minimize Bias: Randomization and Blinding..............................33
6.3.1
Intervention Assignment..............................................................................33
6.3.2
Stratification.................................................................................................33
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6.3.3
Blinding........................................................................................................33
6.4
Study Intervention Compliance..........................................................................33
6.5
Concomitant Therapy..........................................................................................33
6.5.1
Rescue Medications and Supportive Care ...................................................34
6.6
Dose Modification (Escalation/Titration/Other)...............................................34
6.7
Intervention After the End of the Study............................................................34
6.8
Clinical Supplies Disclosure................................................................................34
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................34
7.1
Discontinuation of Study Intervention...............................................................34
7.2
Participant Withdrawal From the Study...........................................................34
7.3
Lost to Follow-up .................................................................................................35
8
STUDY ASSESSMENTS AND PROCEDURES........................................................35
8.1
Administrative and General Procedures ...........................................................36
8.1.1
Informed Consent.........................................................................................36
8.1.1.1
General Informed Consent.................................................................36
8.1.2
Inclusion/Exclusion Criteria ........................................................................36
8.1.3
Participant Identification Card.....................................................................37
8.1.4
Medical History ...........................................................................................37
8.1.5
Prior and Concomitant Medications Review...............................................37
8.1.5.1
Prior Medications...............................................................................37
8.1.5.2
Concomitant Medications..................................................................37
8.1.6
Assignment of Screening Number...............................................................38
8.1.7
Assignment of Treatment/Randomization Number.....................................38
8.1.8
Study Intervention Administration ..............................................................38
8.1.8.1
Timing of Dose Administration.........................................................39
8.1.9
Vaccination Report Card..............................................................................39
8.1.10
Discontinuation and Withdrawal .................................................................39
8.1.11
Participant Blinding/Unblinding..................................................................40
8.1.12
Calibration of Equipment.............................................................................40
8.2
Immunogenicity Assessments .............................................................................40
8.2.1
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen 
Serology Assay ............................................................................................40
8.2.2
Haemophilus Influenza Type b IgG ELISA.................................................40
8.2.3
Hepatitis B Enhanced Chemiluminescence (ECi) Assay.............................41
8.2.4
Poliovirus Neutralization Assay ..................................................................41
8.3
Safety Assessments...............................................................................................42
8.3.1
Physical Examinations.................................................................................42
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8.3.2
Body Temperature Measurement.................................................................42
8.3.3
Safety Assessment and Use of the VRC......................................................42
8.3.4
Clinical Safety Laboratory Assessments .....................................................43
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................43
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................44
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......45
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...45
8.4.4
Regulatory Reporting Requirements for SAE .............................................45
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................46
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................46
8.4.7
Events of Clinical Interest............................................................................46
8.4.8
Medical Device and Drug-device Combination Products -
PQCs/Malfunctions......................................................................................46
8.4.9
Adverse Events on the VRC ........................................................................46
8.4.9.1
Solicited Adverse Event.....................................................................46
8.4.9.2
Unsolicited Adverse Events...............................................................47
8.5
Treatment of Overdose........................................................................................47
8.6
Pharmacokinetics.................................................................................................48
8.7
Pharmacodynamics..............................................................................................48
8.8
Biomarkers ...........................................................................................................48
8.9
Future Biomedical Research Sample Collection...............................................48
8.10
Medical Resource Utilization and Health Economics.......................................48
8.11
Visit Requirements...............................................................................................48
8.11.1
Screening......................................................................................................48
8.11.2
Vaccination Visit .........................................................................................48
9
STATISTICAL ANALYSIS PLAN .............................................................................48
9.1
Statistical Analysis Plan Summary.....................................................................49
9.2
Responsibility for Analyses/In-house Blinding .................................................50
9.3
Hypotheses/Estimation ........................................................................................50
9.4
Analysis Endpoints...............................................................................................50
9.4.1
Immunogenicity Endpoints..........................................................................50
9.4.2
Safety Endpoints..........................................................................................51
9.5
Analysis Populations............................................................................................52
9.5.1
Immunogenicity Analysis Populations ........................................................52
9.5.2
Safety Analysis Populations ........................................................................52
9.6
Statistical Methods...............................................................................................52
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9.6.1
Statistical Methods for Immunogenicity Analyses......................................52
9.6.2
Statistical Methods for Safety Analyses ......................................................53
9.6.2.1
Overall Safety Assessment ................................................................53
9.6.2.2
Assessment of Safety Topics of Special Interest ...............................54
9.6.3
Demographic and Baseline Characteristics .................................................54
9.7
Interim Analyses ..................................................................................................54
9.8
Multiplicity ...........................................................................................................54
9.9
Sample Size and Power Calculations .................................................................54
9.9.1
Sample Size and Power for Immunogenicity Analyses...............................54
9.9.2
Sample Size and Power for Safety Analyses ...............................................55
9.10
Subgroup Analyses...............................................................................................55
9.11
Compliance (Medication Adherence).................................................................55
9.12
Extent of Exposure...............................................................................................55
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................56
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........56
10.1.1
Code of Conduct for Clinical Trials.............................................................56
10.1.2
Financial Disclosure.....................................................................................58
10.1.3
Data Protection.............................................................................................59
10.1.3.1
Confidentiality of Data ......................................................................59
10.1.3.2
Confidentiality of Participant Records...............................................59
10.1.3.3
Confidentiality of IRB/IEC Information............................................59
10.1.4
Committees Structure...................................................................................60
10.1.5
Publication Policy........................................................................................60
10.1.6
Compliance with Study Registration and Results Posting Requirements ...60
10.1.7
Compliance with Law, Audit, and Debarment ............................................60
10.1.8
Data Quality Assurance ...............................................................................61
10.1.9
Source Documents .......................................................................................62
10.1.10
Study and Site Closure.................................................................................62
10.2
Appendix 2: Clinical Laboratory Tests..............................................................63
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................64
10.3.1
Definition of AE ..........................................................................................64
10.3.2
Definition of SAE ........................................................................................65
10.3.3
Additional Events Reported.........................................................................66
10.3.4
Recording AE and SAE ...............................................................................67
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................70
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................72
10.4.1
Definitions....................................................................................................72
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....73
10.5
Appendix 5: Contraceptive Guidance................................................................75
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................76
10.7
Appendix 7: Country-specific Requirements....................................................77
10.8
Appendix 8: Abbreviations .................................................................................78
11
REFERENCES...............................................................................................................80
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LIST OF TABLES
Table 1
Vaccine Composition.......................................................................................19
Table 2
List of Primary Endpoints................................................................................25
Table 3
List of Secondary Endpoints............................................................................26
Table 4
Study Interventions..........................................................................................31
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................44
Table 6
Solicited Adverse Events .................................................................................47
Table 7
Analysis Strategy for Safety Parameters..........................................................53
Table 8
Estimates of the 95% Confidence Intervals for Different Hypothetical 
Observed Response Rates................................................................................55
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LIST OF FIGURES
Figure 1
V419-016 Study Design.............................................................................15
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 4, Open-label, Multicenter Study to Evaluate the Safety, 
Tolerability, and Immunogenicity of Vaxelis™ in Healthy Children Previously Vaccinated 
With a 2-Dose Primary Infant Series of Either Vaxelis™ or Hexyon™
Short Title: Safety, Tolerability, and Immunogenicity of Vaxelis™ after an Infant Series of 
either Vaxelis™or Hexyon™
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There is no hypothesis testing in this study.
The following objectives and endpoints will be evaluated in healthy participants who were 
previously vaccinated with a 2-dose primary infant series of either Vaxelis™ or Hexyon™ 
and who will receive a booster dose of Vaxelis™at approximately 11 to 13 months of age.
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety 
and tolerability of a booster dose 
of Vaxelis™ with respect to the 
proportion of participants with 
adverse events (AEs).
•
Solicited injection-site AEs from Day 1 
through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 through 
Day 5 postvaccination
•
Unsolicited AEs from Day 1 through Day 15 
postvaccination
•
Serious adverse events (SAEs) through 
completion of study participation
•
Objective: To describe the 
response rates to antigens 
contained in both Vaxelis™ and 
Hexyon™ 30 days after a booster 
dose of Vaxelis™.
Antibody responses to:

diphtheria toxoid

tetanus toxoid

pertussis toxoid (PT)

filamentous hemagglutinin (FHA)

Haemophilus influenzae type b 
polyribosylribitol phosphate (Hib-PRP)

hepatitis B surface antigen (HBsAg)

poliovirus serotypes 1, 2, and 3
at 30 days postvaccination with Vaxelis™
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Objectives
Endpoints
Secondary
•
Objective: To describe the 
response rates to the pertussis 
antigens contained in Vaxelis™, 
but not in Hexyon™, 30 days after 
a booster dose of Vaxelis™.
Antibody responses to:

pertactin (PRN)

fimbriae 2/3 (FIM 2/3)
at 30 days postvaccination with Vaxelis™
Overall Design:
Study Phase
Phase 4
Primary Purpose
Prevention
Indication
Vaccination against diphtheria, tetanus, pertussis, 
hepatitis B, poliomyelitis, and invasive diseases caused by 
Haemophilus influenzae type b
Population
Healthy participants approximately 11 to 13 months of 
age previously vaccinated with a 2-dose primary infant 
series of either Vaxelis™or Hexyon™at 2 and 4 months 
of age
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last laboratory result 
or at the time of final contact with the last participant, 
whichever comes last.
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Number of Participants:
Approximately 160 participants will be enrolled, with approximately 80 participants in each
group.
Intervention Groups and Duration:
Intervention 
Groups
Intervention
Group
Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Vaccination 
Regimen
Use
Group 1: 
V,V,Va
Vaxelis™
Refer to 
product 
labeling
Single dose
IM
Single dose 
on Day 1
Experimental
Group 2: 
H,H,Vb
admin.=administration; IM=intramuscular; V=Vaxelis™; H=Hexyon™
a
Participants had previously received 2 doses of Vaxelis™ at approximately 2 and 4 months of 
age.
b
Participants had previously received 2 doses of Hexyon™ at approximately 2 and 4 months of 
age.
Total 
Number of 
Intervention 
Groups/
Arms
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 30 days 
from the time the participant’s legally acceptable representative provides 
documented informed consent through the final contact.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
V419-016 Study Design
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1.3
Schedule of Activities
Study Period
Intervention
Notes
Visit Number
1
2
Scheduled Day
Day 1
Day 30
Visit Window
NA
Days 26 
to 40
Administrative Procedures
Screening Procedures
Informed Consent
X
Consent must be obtained before any study procedures.
Assignment of Screening Number
X
Inclusion/Exclusion Criteria
X
Review of prior medications/vaccinations, a physical examination, and temperature 
measurement are required at Visit 1 to determine eligibility.
Participant Identification Card
X
Medical History
X
See Section 8.1.4 for details.
Post-Enrollment Procedures
Assignment of Allocation Number
X
Prior/Concomitant Medication and 
Nonstudy Vaccination Review
X
X
See Section 8.1.5 for details. Nonstudy, non-live pediatric vaccines are permitted to be 
administered in a separate limb and after study vaccination on Day 1. Nonstudy, live and 
non-live pediatric vaccines are permitted after blood draw on Day 30.
Vaxelis™Administration (Open-label)
X
Safety Procedures
Full Physical Examination
X
To be performed by the investigator or medically qualified designee before study vaccine 
is administered.
Body Temperature Measurement
X
Each participant’s body temperature must be taken before vaccination. Participants who 
have febrile illness (defined as rectal temperature ≥38.1°C [≥100.5°F] or axillary 
temperature ≥37.8°C [≥100.0°F]) at or within 72 hours of vaccination must be rescheduled.
Provide VRC
X
A paper VRC will be provided at Visit 1 to record AEs, body temperature, concomitant
medications, and nonstudy vaccinations (see Section 8.3.3 for details). Instructions for
using the VRC will be reviewed with the participant’s legally acceptable representative.
AE/SAE Monitoring
X
X
See Section 8.4 for details.
Collection of VRC Information
X
15-Minute Postvaccination Observation 
Period
X
The observation period can be extended if clinically indicated.
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Study Period
Intervention
Notes
Visit Number
1
2
Scheduled Day
Day 1
Day 30
Visit Window
NA
Days 26 
to 40
Immunogenicity Procedures
Serum for Immunogenicity Assay
X
X
Blood samples at Visit 1 and Visit 2 must be collected before any vaccination (including 
study vaccine and nonstudy vaccines).
AE=adverse event; NA=not applicable; SAE=serious adverse event; VRC=Vaccination Report Card
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2
INTRODUCTION
2.1
Study Rationale
Vaxelis™ (DTaP-HB-IPV-Hib) is a hexavalent combination vaccine indicated for primary 
and booster vaccination in infants and toddlers for the prevention of diphtheria, tetanus, 
pertussis, hepatitis B, poliomyelitis, and invasive disease caused by Haemophilus influenzae
type b. It can be used as a 2- or 3-dose primary series beginning at 6 weeks of age, followed 
by a booster dose, given at least 6 months after the primary series.
This is an open-label study of Vaxelis™in healthy participants approximately 11 to 
13 months of age who previously received a 2-dose primary infant series of either Vaxelis™ 
(Group 1: V,V,V) or Hexyon™ (Group 2: H,H,V) at 2 and 4 months of age as part of their 
routine vaccination. A 0.5-mL intramuscular dose of Vaxelis™ (open-label) will be 
administered to all study participants at Visit 1 (Day 1).
In clinical practice, switching between childhood hexavalent vaccines is sometimes 
necessary, which results in a “mixed” vaccine schedule. This may occur due to changes in 
vaccine availability, changes in procurement, vaccine shortages, relocation, or care provider 
preference. Interchangeability studies assessing this “mixed” schedule have been conducted 
with Hexyon™where Hexyon™ was used as a booster in individuals who had previously 
been vaccinated with another hexavalent vaccine (INFANRIX™ hexa) [Aquino, A. G. B., et 
al 2012] [Lopez, P., et al 2017]. There are no clinical study data describing the safety and 
immunogenicity of Vaxelis™used as a booster dose when another hexavalent combination 
vaccine was given for the primary infant series.
The purpose of this study is to describe the safety, tolerability, and immunogenicity of a 
booster dose of Vaxelis™ administered to healthy participants approximately 11 to 
13 months of age who previously received a 2-dose primary infant series of either Vaxelis™ 
(Group 1) or Hexyon™(Group 2) as part of their routine vaccinations. The immune response 
to this booster dose of Vaxelis™ will be evaluated for each antigen contained in both
vaccines for all participants (Group 1 and Group 2) (Table 1). The immune responses to PRN 
and FIM 2/3 in children who received Hexyon™during infancy and a booster dose of 
Vaxelis™ during the study (Group 2), will also be described.
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Table 1
Vaccine Composition
One dose (0.5 mL) contains the following antigens:
Vaxelis™
Hexyon™
Antigen
Amount in Vaxelis™
Antigen
Amount in Hexyon™
Diphtheria toxoid
Not less than 20 IU
Diphtheria toxoid
Not less than 20 IU
Tetanus toxoid
Not less than 40 IU
Tetanus toxoid
Not less than 40 IU
Bordetella pertussis antigens
Pertussis toxoid (PT)
Filamentous haemagglutinin (FHA)
Pertactin (PRN)a
Fimbriae Types 2a and 3a (FIM2/3)
20 micrograms
20 micrograms
3 micrograms
5 micrograms
Bordetella pertussis antigens
Pertussis toxoid (PT)
Filamentous haemagglutinin (FHA)
25 micrograms
25 micrograms
Hepatitis B surface antigen
10 micrograms
Hepatitis B surface antigen
10 micrograms
Poliovirus (inactivated)
Type 1 (Mahoney)
Type 2 (MEF-1)
Type 3 (Saukett)
40 D antigen units
8 D antigen units
32 D antigen units
Poliovirus (inactivated)
Type 1 (Mahoney)
Type 2 (MEF-1)
Type 3 (Saukett)
40 D antigen units
8 D antigen units
32 D antigen units
Haemophilus influenzae type b polysaccharide
(Polyribosylribitol phosphate [PRP])
conjugated to meningococcal protein
3 micrograms
50 micrograms
Haemophilus influenzae type b polysaccharide
(Polyribosylribitol phosphate [PRP]) 
conjugated to tetanus protein
12 micrograms
22-36 micrograms
IU=international units; MEF=Middle East Forces
See Summary of Product Characteristics for complete details of the vaccine composition.
a
Not contained in Hexyon™.
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2.2
Background
Refer to the approved labeling for detailed background information on Vaxelis™and 
Hexyon™.
The primary measure to prevent the spread of diphtheria, tetanus, pertussis, polio, invasive 
Haemophilus influenzae type b disease, and hepatitis B is the implementation of 
comprehensive immunization programs starting in infancy and continuing throughout 
adolescence and adulthood, according to applicable official recommendations.
Three hexavalent pediatric vaccines are approved in the EU: Vaxelis™ (DTaP5-HB-IPV-
Hib), Hexyon™ (DTaP2-HB-IPV-Hib), and INFANRIX™ hexa (DTaP3-HBV-IPV/Hib).
Although the antigen composition of each vaccine is similar, there are some key differences
among the 3 vaccines with respect to the pertussis and Haemophilus influenzae type b 
components (Table 1). Vaxelis™contains 5 acellular pertussis antigens (PT, FHA, PRN, and 
FIM2/3), INFANRIX™ hexa contains 3 pertussis antigens (PT, FHA, and PRN), and 
Hexyon™contains 2 pertussis antigens (PT and FHA). The Hib PRP is conjugated to a
meningococcal outer membrane protein complex (PRP-OMPC) in Vaxelis™and conjugated 
to a tetanus protein (PRP-T) in Hexyon™ and INFANRIX™hexa. The PRP conjugation 
influences the kinetics and magnitude of the anti-PRP immune response during the primary 
series and booster dose [Decker, M.D. 1998].
Brief Summary of Diseases
Diphtheria
Diphtheria is an acute disease caused by exotoxin-producing bacterium, Corynebacterium
diphtheriae. Transmission occurs through droplets and close physical contact [American 
Academy of Pediatrics 2012]. In most industrialized countries, endemic diphtheria has 
disappeared or become extremely rare owing to immunization [World health organization 
2017]. While diphtheria is rare in infants younger than 6 months due to the presence of 
maternal antibody, it continues to produce substantial childhood morbidity and mortality in 
developing countries with low diphtheria vaccination coverage.
Tetanus
Tetanus is an infectious bacterial disease caused by Clostridium tetani, a ubiquitous spore
forming anaerobic bacillus that can produce a potent neurotoxin, tetanospasmin. Tetanus can 
never be eradicated as Clostridium tetani spores are prevalent in the environment and may be 
carried in the intestinal tracts of humans and animals, though it is not transmitted from person 
to person [American Academy of Pediatrics 2012].
Pertussis
Pertussis (whooping cough) is caused by the bacterium Bordetella pertussis, transmitted from 
infected to susceptible individuals through droplets. Most cases of clinically recognizable 
pertussis occur in children 1 to 5 years of age with most severe disease occurring in young 
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infants, where infection can lead to hospitalization and death [World health organization 
2015] [Chow, M. Y. K., et al 2016]. Despite widespread use of pertussis vaccination, young 
infants remain vulnerable until completion of the pertussis vaccination series.
Due to a resurgence of pertussis in many parts of the world [Tan, T., et al 2015],
immunization during pregnancy is recommended in some countries [Donegan, K., et al 2014] 
[Centers for Disease Control and Prevention 2013]. The maternal antibody protects the 
vulnerable infant but does lead to blunting of the immune response to pertussis antigens in 
the infant [Halperin, S. A., et al 2018]. The clinical significance of the blunted immune 
response is unclear.
Poliomyelitis
Poliomyelitis is an acute infectious and communicable disease caused by poliovirus. 
Polioviruses are single-stranded RNA enteroviruses (Picornaviridae) and consist of serotypes 
1, 2, and 3. Transmission is by person to person via fecal-to-oral and oral-to-oral routes. 
Infection is more common in infants and young children and occurs at an earlier age among 
children living in poor hygienic conditions [American Academy of Pediatrics 2012].
Hepatitis B
Hepatitis B infection is caused by HB virus, a member of the Hepadnaviridae family, which
includes a hepatotropic group of DNA viruses. Most acute cases of HB infection in children 
are asymptomatic, as evidenced by the high carriage rate of serum markers in persons who 
have no history of acute hepatitis. The rate of acquisition of chronic infection depends largely 
on the mode and age of acquisition and is up to 90% in the perinatal cases [Trepo, C., et al 
2014]. Among participants who successfully completed the 3-dose series, the clinical
efficacy is thought to approach 100% [Van Damme, P., et al 2013] [World Health 
Organization 2017].
Invasive Haemophilus influenzae type b disease
Hib, a Gram-negative coccobacillus, is transmitted primarily by airborne droplets or by direct 
contact with respiratory tract secretions. The most important manifestations of Hib infection,
namely meningitis, pneumonia, and other invasive diseases occur primarily in infants and 
toddlers aged less than 2 years [Mandell, G., et al 2010]. The disease burden is highest 
among infants aged 4 to 18 months. In unvaccinated populations, invasive Hib is the 
dominant cause of nonepidemic bacterial meningitis during the first year of life [World 
Health Organization 2013].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety, efficacy, and immunogenicity (as applicable) of an investigational medicine or 
vaccine.
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Vaccination with hexavalent vaccines (including Vaxelis™ and Hexyon™) has been shown 
to be beneficial and efficacious in preventing diphtheria, tetanus, pertussis, hepatitis B, 
poliomyelitis, and invasive disease caused by Hib. These vaccines have established safety 
profiles.
Participants enrolled will have previously received a 2-dose primary infant series with either 
Hexyon™ or Vaxelis™. All participants will receive a booster dose of Vaxelis™.
For hexavalent vaccines, a 3-dose schedule (2-dose infant primary series followed by a 
booster dose) is recommended in several EU countries. A mixed dose regimen of hexavalent 
vaccine in which Vaxelis™ is used as a booster dose after a 2-dose primary series of 
Hexyon™has not previously been evaluated. However, Vaxelis™has been evaluated as part 
of a mixed dose regimen in which a pentavalent vaccine was given as a part of a 3-dose 
series with Vaxelis™. In that study, the mixed dose regimen with Vaxelis™was well
tolerated and the immune response was acceptable for the antigens contained in the 2 
vaccines [Martinon-Torres, F., et al 2017]. Vaxelis™ administered after a primary 2-dose 
infant series of Hexyon™is expected to provide comparable immunogenicity and safety to a 
complete 3-dose regimen of Vaxelis™.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying Product Labels, and informed consent 
documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no hypothesis testing in this study.
The following objectives and endpoints will be evaluated in healthy participants who were 
previously vaccinated with a 2-dose primary infant series of either Vaxelis™ or Hexyon™ 
and who will receive a booster dose of Vaxelis™at approximately 11 to 13 months of age.
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability of a booster dose of Vaxelis™ 
with respect to the proportion of 
participants with adverse events (AEs).
•
Solicited injection-site AEs from Day 
1 through Day 5 postvaccination
•
Solicited systemic AEs from Day 1 
through Day 5 postvaccination
•
Unsolicited AEs from Day 1 through 
Day 15 postvaccination
•
Serious adverse events (SAEs) through 
completion of study participation
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Objectives
Endpoints
•
Objective: To describe the response rates 
to antigens contained in both Vaxelis™ 
and Hexyon™ 30 days after a booster 
dose of Vaxelis™.
Antibody responses to:

diphtheria toxoid

tetanus toxoid

pertussis toxoid (PT)

filamentous hemagglutinin (FHA)

Haemophilus influenzae type b 
polyribosylribitol phosphate 
(Hib-PRP)

hepatitis B surface antigen 
(HBsAg)

poliovirus serotypes 1, 2, and 3
at 30 days postvaccination with Vaxelis™
Secondary
•
Objective: To describe the response rates 
to the pertussis antigens contained in 
Vaxelis™, but not in Hexyon™, 30 days 
after a booster dose of Vaxelis™.
Antibody responses to:

pertactin (PRN)

fimbriae 2/3 (FIM 2/3)
at 30 days postvaccination with Vaxelis™
Exploratory
•
Objective: To describe the antigen-
specific geometric mean concentrations 
(GMCs) at predose and 30 days post 
booster dose with Vaxelis™, and the 
proportion of participants with a ≥4-fold 
rise from Day 1 (predose) to 30 days post 
booster dose with Vaxelis™, for each 
antigen contained in Vaxelis™.
Antibody responses to:

diphtheria toxoid

tetanus toxoid

PT

FHA

PRN

FIM 2/3

Hib-PRP

HBsAg

poliovirus serotypes 1, 2, and 3
at Day 1 (predose) and 30 days 
postvaccination with Vaxelis™
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4
STUDY DESIGN
4.1
Overall Design
This is an open-label study of Vaxelis™in healthy participants approximately 11 to 13
months of age who previously received a 2-dose primary infant series of either Vaxelis™
(Group 1: V,V,V) or Hexyon™(Group 2: H,H,V) at 2 and 4 months of age as part of their 
routine vaccination. Approximately 160 participants will be enrolled in the study (80 
participants in each group). A 0.5-mL intramuscular dose of Vaxelis™ (open-label) will be 
administered to all study participants at Visit 1 (Day 1).
Blood samples for immunogenicity will be drawn before vaccination at Visit 1 (Day 1) and at 
Visit 2 (Day 30 [30 days postvaccination with Vaxelis™]).
Immunogenicity endpoints will be described for Group 1 and Group 2. Response rates at 
30 days after a booster dose of Vaxelis™will be summarized using the serological 
thresholds that are accepted as correlates of protection against tetanus, diphtheria, hepatitis B, 
poliovirus, and Hib [Plotkin, S. A. 2010] [Andrews, Nick, et al 2003]. For pertussis, there are 
no benchmark antibody concentrations that are widely accepted as correlates of protection; 
therefore, the pertussis antigen endpoints are adapted from previously published standards 
based on assay LLOQ [Edwards, K. M. 2014].
Participants will be followed for solicited injection-site and systemic AEs from Day 1 
through Day 5 postvaccination and for unsolicited AEs from Day 1 through Day 15 
postvaccination, which will be collected using paper VRC (Section 8.3.3). Information for
SAEs, regardless of whether the events are considered vaccine-related by the investigator, 
will be collected from the time consent is given through completion of participation in the 
study.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will assess the safety, tolerability, and immunogenicity of a mixed hexavalent 
vaccine regimen in which the 2-dose primary infant series is completed with Vaxelis™ or 
Hexyon™ and is boosted with Vaxelis™(Dose 3). Data from this study will support the 
safety, tolerability, and immunogenicity of switching to Vaxelis™ after a 2-dose primary 
infant series with another hexavalent vaccine. This study will be conducted in healthy 
participants approximately 11 to 13 months of age. Although both a 2-dose and 3-dose 
primary series are approved in the EU, the 2-dose primary series (2 + 1 schedule) has been 
adopted in increasing frequency by many countries and thus chosen for the study.
It is recommended to use the same vaccine to complete a series. However, in clinical 
practice, switching between childhood hexavalent vaccines is sometimes necessary, which 
results in a “mixed” vaccine schedule. In this setting, it is recommended to complete the 
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primary series with 1 vaccine and limit the switch to the booster dose [Obando-Pacheco, P., 
et al 2018]. It is important to ensure that antibody responses are boosted (for tetanus, 
diphtheria, hepatitis B, poliovirus, and Hib) or completed (for pertussis) when the primary 
series is followed by an alternate vaccine containing similar antigens as in this study design.
Using Hexyon™for the primary series in the mixed schedule provides the opportunity to 
examine the immunogenicity of a primary series of a PRP-T containing hexavalent vaccine
followed by a booster dose of a PRP-OMPC containing vaccine.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
Primary Endpoints
Serum from study participants will be used to measure the immune responses to the antigens 
contained in both Vaxelis™and Hexyon™at 30 days postvaccination with Vaxelis™
(Table 2).
The endpoints used to evaluate the immune responses to the antigens contained in Vaxelis™ 
and Hexyon™ are consistent with established protective and acceptable antibody levels 
[Plotkin, S. A. 2010] [Andrews, Nick, et al 2003]. For pertussis, there are no benchmark 
antibody concentrations that are widely accepted as correlates of protection; therefore, the 
pertussis antigen endpoints are based on adaptations of previously published standards 
related to assay LLOQ [Edwards, K. M. 2014].
Table 2
List of Primary Endpoints
Antigen
Endpoint
Diphtheria toxoid
% ≥0.1 IU/mL
Tetanus toxoid
% ≥0.1 IU/mL
PT
% vaccine responsea
FHA
% vaccine responsea
Hib-PRP
% ≥1.0 µg/mL
HBsAg
% ≥10 mIU/mL
Poliovirus 1
% Nab ≥1:8 dilution
Poliovirus 2
% Nab ≥1:8 dilution
Poliovirus 3
% Nab ≥1:8 dilution
FHA=filamentous hemagglutinin; Hib=Haemophilus influenzae type b; HBsAg=hepatitis B surface antigen; 
IU=international unit; LLOQ=lower limit of quantitation; Nab=neutralizing antibodies; 
PRP=polyribosylribitol phosphate; PT=pertussis toxoid
a
The pertussis vaccine response is defined as follows:
1) If prevaccination <LLOQ, then postvaccination should be ≥4 × the LLOQ.
2) If prevaccination ≥LLOQ but <2 × the LLOQ, then postvaccination should achieve a 4-fold rise 
(postvaccination/prevaccination ≥4).
3) If prevaccination ≥2 × the LLOQ, then postvaccination should achieve a 2-fold response 
(postvaccination/prevaccination ≥2).
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Secondary Endpoints
Serum from study participants will be used to measure the immune responses to the pertussis 
antigens contained in Vaxelis™at 30 days postvaccination with Vaxelis™(Table 3).
Table 3
List of Secondary Endpoints
Antigen
Endpoint
PRN
% vaccine response
a
FIM 2/3b
% vaccine response
a
FIM=fimbriae; LLOQ=lower limit of quantitation; PRN=pertactin
a
The pertussis vaccine response is defined as follows:
1) If prevaccination <LLOQ, then postvaccination should be ≥4 × the LLOQ.
2) If prevaccination ≥LLOQ but <2 × the LLOQ, then postvaccination should 
achieve a 4-fold rise (postvaccination/prevaccination ≥4).
3) If prevaccination ≥2 × the LLOQ, then postvaccination should achieve a 2-fold 
response (postvaccination/prevaccination ≥2).
b
Antibodies to FIM 2 and FIM 3 are measured together.
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile shown in previous studies, and guidance from regulatory agencies during product 
development. The VRC used to record AEs during the postvaccination periods, as defined in 
Section 8.1.9, was structured as recommended in the European Medicines Agency 
Committee on Human Medicinal Products: Guideline on Clinical Evaluation of Vaccines
[European Medicines Agency 2018]. Details on the safety endpoints evaluated in this study 
can be found in Section 8.3.3 and Section 9.4.2. Details on AEs, including definitions and 
reporting requirements, can be found in Appendix 3.
4.3
Justification for Dose
The 0.5 mL dose of Vaxelis™ is approved for use in children from 6 weeks of age
administered as a 2- or 3-dose primary series and a booster dose at least 6 to 12 months 
following the last priming dose according to national recommendations. Participants in this 
study had previously received a 2-dose primary series of Vaxelis™ or Hexyon™ according 
to national recommendations.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Healthy male and female participants approximately 11 to 13 months of age, (≥327 days to
≤396 days inclusive) will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is healthy (based on a review of medical history and physical examination) based on the 
clinical judgment of the investigator.
2. Has received a 2-dose infant primary series of either Vaxelis™ or Hexyon™at 
approximately 2 and 4 months of age (based on a review of medical history), 
respectively.
Demographics
3. Is male or female, from approximately 11 months to 13 months of age (≥327 days to
≤396 days) inclusive, at the time of obtaining the informed consent.
Informed Consent
4. A legally acceptable representative has provided documented informed consent for the 
study.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a known or suspected impairment of immunological function.
2. Has known or history of functional or anatomic asplenia.
3. Has a known hypersensitivity to any component of the study vaccine.
4. Has a known or suspected blood dyscrasia, leukemia, lymphoma of any type or other 
malignant neoplasm affecting the hematopoietic and lymphatic system.
5. Has a bleeding disorder contraindicating intramuscular vaccination.
6. Has a history of Hib, hepatitis B, diphtheria, tetanus, pertussis, or poliovirus infection.
7. Was born to a mother with a known history of hepatitis B infection.
8. *Had a recent febrile illness (defined as rectal temperature ≥38.1°C [≥100.5°F] or
axillary temperature ≥37.8°C [≥100.0°F]) occurring at or within 72 hours prior to receipt 
of study vaccine.
9. Has encephalopathy of unknown etiology, occurring within 7 days following prior 
vaccination with a pertussis containing vaccine.
10. Has an uncontrolled neurologic disorder or uncontrolled epilepsy.
11. Has a health or developmental disorder that, based on the clinical judgment of the 
investigator, could affect evaluation of the vaccine.
Prior/Concomitant Therapy
12. Has received or is expected to receive immunosuppressive agents during the conduct of 
the study.
13. *Meets 1 or more of the following systemic corticosteroid exclusion criteria:
a.
Has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days and 
has not completed treatment at least 30 days before study entry.
b. Has received any systemic corticosteroids within 14 days before study vaccination.
c.
Is expected to require any systemic corticosteroids during conduct of the study.
Note: Topical, ophthalmic, and inhaled steroids are permitted.
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14. *Has received any licensed, non-live vaccine within the 14 days before receipt of study 
vaccine or is scheduled to receive any licensed, non-live vaccine prior to Visit 2 blood 
draw.
Exception: Participant may receive nonstudy pediatric licensed non-live vaccines on 
same day as study vaccine is given (Day 1).
Exception: Non-live influenza vaccine may be administered, but must be given at least 
7 days before receipt of study vaccine or at least 15 days after receipt of study vaccine.
15. *Has received any licensed live vaccine within 30 days before receipt of study vaccine or 
is scheduled to receive any live vaccine prior to Visit 2 blood draw.
16. *Has received a blood transfusion or blood products, including immunoglobulins within 
the 6 months before receipt of study vaccine or is scheduled to receive a blood 
transfusion or blood product within 30 days of receipt of study vaccine. Autologous 
blood transfusions are not considered an exclusion criterion.
Prior/Concurrent Clinical Study Experience
17. *Has participated in another clinical study of an investigational product within 2 months 
before study vaccination at Visit 1 (Day 1) or plans to participate anytime during the 
duration of the current clinical study. Participants previously or currently enrolled in a 
COVID-19 vaccine clinical study, or enrolled in observational studies may be included; 
these should be reviewed on a case-by-case basis for approval by the Sponsor.
Diagnostic Assessments
None.
Other Exclusions
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
For items with an asterisk (*), if the participant meets these exclusion criteria, Visit 1 may be 
rescheduled for a time when these criteria are not met.
5.3
Lifestyle Considerations
No lifestyle restrictions are required
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides
consent to participate in the clinical study, but are not subsequently enrolled in the study. A 
minimal set of screen-failure information is required to ensure transparent reporting of 
screen-failure participants to meet the CONSORT publishing requirements and to respond to 
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queries from regulatory authorities. Minimal information includes demography, screen-
failure details, eligibility criteria, and any AEs or SAEs meeting reporting requirements as 
outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (Vaxelis™) will be packaged to support enrollment. Clinical supplies will 
be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 4.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit 
Dose 
Strength
Dosage 
Level
Route of 
Admin.
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Group 1: 
V,V,V
Experimental
Vaxelis™
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visit 1
Experimental
IMP
Central
Group 2: 
H,H,V
Experimental
Vaxelis™
Biological/
Vaccine
Sterile 
Suspension 
(Prefilled 
Syringe)
Refer to 
product 
labeling
0.5 mL
IM
Single dose 
at Visit 1
Experimental
IMP
Central
Admin.=administration; EEA=European Economic Area; H=Hexyon™; IM=intramuscular; IMP=investigational medicinal product; mL=milliliter; 
NIMP=noninvestigational medicinal product; V=Vaxelis™
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country 
differences with respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 4 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Drug-device combination product(s), which is legally marketed and provided for use in this 
study are: Vaxelis™ prefilled syringes. Refer to Section 8.4.8 and Appendix 4 for reporting 
events associated with these devices.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the vaccine administered.
6.4
Study Intervention Compliance
Participants will receive a single dose of Vaxelis™ administered at the study site. The date 
and time of administration will be recorded in the source document and in the eCRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
Nonstudy pediatric vaccines are permitted to be administered according to local
recommended schedule, regional, and/or country guidelines, and according to the restrictions 
outlined in Section 5.2.
It is recommended that Vaxelis™be administered in the right thigh. To avoid any 
confounding results, nonstudy injectable vaccines should not be administered in the same 
limb as Vaxelis™. Documentation of which limb was used for the administration of 
Vaxelis™should be recorded on the appropriate eCRF. As the study is reporting 
injection-site AEs for Vaxelis™(and not from nonstudy pediatric vaccines), this information 
should also be recorded on the paper VRC to inform the participant’s legally acceptable 
representative of the appropriate limb to monitor for AEs related to the Vaxelis™.
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The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur before the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.10. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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Approximately 5 mL of blood will be drawn at Visit 1 and Visit 2 for immunogenicity 
assays. The maximum amount of blood collected from each participant over the duration of 
the study will not exceed 10 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant ID card also contains contact information for the emergency unblinding call
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
At the Day 1 visit, the participant’s medical history from birth through Day 1, will be 
obtained by the investigator or qualified designee. This will include a question regarding the 
receipt of a maternal pertussis vaccine during pregnancy (see Section 2.2).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record any prior medications and 
vaccinations taken by the participant within 30 days before study vaccination.
In addition, the receipt of prior Vaxelis™ and Hexyon™vaccinations, and monovalent 
hepatitis B vaccine or any other hepatitis B based combination vaccine will be recorded from 
birth through Day 1.
A participant who received any of the prior medications or vaccinations prohibited in the 
exclusion criteria (Section 5.2) should not be enrolled into the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
during the study.
If a medical condition requires the use of a prohibitive steroid regimen, immunoglobulin,
blood, or blood products during a participant’s participation in this study, one of the
individuals listed on the Sponsor Contact Information page must be notified as soon as
possible. Any concurrent medication or medical treatment must be recorded on the
appropriate eCRF.
It is important to record any analgesic or antipyretic use that occurs on the day of vaccination
on the paper VRC and appropriate eCRF. Concomitant medications taken after Visit 1 and
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nonstudy vaccines received since Visit 1 will be recorded in the paper VRC as specified in
Section 8.3.3.
The administration of nonstudy pediatric vaccines during the study should be recorded on the
appropriate eCRF. To avoid any confounding results, concomitant injectable vaccines should
not be administered in the same limb as Vaxelis™. Documentation of which limb was used 
for the administration of Vaxelis™must be recorded on the paper VRC (Section 8.1.9 and 
Section 8.3.3) and appropriate eCRF.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before allocation. Each participant will 
be assigned only 1 screening number. Screening numbers must not be reused for different 
participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation.      Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study vaccines should be prepared and administered by appropriately qualified members of 
the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Adequate treatment provision, including epinephrine and equipment for maintaining an 
airway, should be available for immediate use should an anaphylactic or anaphylactoid 
reaction occur [Centers for Disease Control and Prevention 2015].
Study intervention is given on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
Study vaccine will be administered as specified in Section 1.3. It is recommended that 
Vaxelis™be administered in the right thigh.
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Observing Participants After Vaccination
All participants will be observed by study personnel for at least 15 minutes after study 
vaccination for any untoward effects, including allergic reactions. The observation period can 
be extended if clinically indicated. This observation period will be documented in the 
participant’s study chart.
Vaccination information, such as time of vaccination and the location of the vaccine 
administered, must be recorded on the appropriate eCRF as per the data entry guidelines.
8.1.8.1
Timing of Dose Administration
Study vaccine will be administered as indicated in Section 1.3. All participants will be 
monitored for any immediate reactions as per local standard of care.
Participants must be afebrile for >72 hours prior to vaccination (Section 1.3).
Blood samples must be collected before study vaccination on Day 1.
8.1.9
Vaccination Report Card
The paper VRC used to record AEs during the postvaccination periods, was structured as 
recommended in the European Medicines Agency Committee on Human Medicinal Products: 
Guideline on Clinical Evaluation of Vaccines [European Medicines Agency 2018].
Body temperatures, injection-site reactions, vaccine-specific complaints, other complaints or 
illnesses, and concomitant medications or nonstudy vaccinations will be recorded on the 
VRC as described in Section 1.3 and Section 8.3.3. On Day 5, the study coordinator will 
remind the participant’s legally acceptable representative to complete the VRC entry. The 
investigator or delegate will review the data captured on the VRC with the participant’s 
legally acceptable representative as indicated in Section 1.3.
For the AEs outlined above, the investigator will use the information provided by the 
participant’s legally acceptable representative both on the VRC, and verbally at the time of 
VRC review, to apply the appropriate assessment of intensity as described in Appendix 3.
8.1.10
Discontinuation and Withdrawal
Participants who receive a single-dose intervention cannot discontinue study intervention 
(see Section 7.1).
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
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8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera from participants will be used to measure the immune responses to the antigens 
summarized in Table 2 and Table 3 using the assays provided below.
Blood collection, storage, and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
8.2.1
Anti-Diphtheria Toxoid, Tetanus Toxoid, and Pertussis Antigen Serology 
Assay
The Meso Scale Discovery Electrochemiluminescence is a multiplexed serological assay that 
allows for the simultaneous quantification of human antibodies to diphtheria toxoid, tetanus 
toxoid, and pertussis antigens (PT, FHA, PRN, and FIM). In this assay, each well of a 
96-well microtiter plate is precoated in precise positions with the 6 different antigens in a 
multispot fashion. Following incubation with serum samples, antigen-specific antibodies 
bind to the respective antigens. The captured antibodies are then detected using a sulfotag 
conjugated anti-human IgG conjugate. Electrical stimulation of the conjugate in the presence 
of a chemiluminescent substrate results in the generation of a light signal from each specific 
spot that is captured by a camera in relative light units. The signal generated is directly 
proportional to the amount of antibodies present in the sample, which is quantified using 
software and based on an established reference standard sample curve. The LLOQ for 
diphtheria antibody is 0.005 IU/mL, for tetanus antibody is 0.01 IU/mL, and for each 
pertussis antibody is 2.00 EU/mL.
8.2.2
Haemophilus Influenza Type b IgG ELISA
The Hib IgG ELISA for the in-vitro measurement of specific IgG antibodies against Hib 
capsular polysaccharide in human serum uses the Vacczyme™ Human Anti-Haemophilus 
influenzae Type b Enzyme Immunoassay Kit purchased from The Binding Site 
(catalog # MK016), which was further validated for use in clinical studies. The kit contains 
microtiter wells precoated with Hib polysaccharide antigen conjugated to human serum 
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albumin. Diluted serum is added to the microtiter wells and allowed to incubate. After 
incubation and washing to remove non-bound serum proteins, HRP-conjugated rabbit 
anti-human IgG is added, which binds to any captured Hib-specific IgG molecules. After 
another wash step, tetramethylbenzidine substrate is added; the ensuing color development 
reaction is then stopped at a defined time point by the addition of a dilute acid solution. The 
OD is measured at 450 nm and is directly proportional to the amount of anti-Hib IgG present 
in the serum specimen. Levels of anti-Hib IgG are quantified by interpolation from a 
standard curve that has been calibrated to the FDA lot 1983 reference serum.
8.2.3
Hepatitis B Enhanced Chemiluminescence (ECi) Assay
The purpose of the hepatitis B ECi assay is to detect total antibody to human plasma-derived 
HBsAg subtypes ad and ay before and after vaccination with HBsAg-containing vaccine(s). 
This is the primary assay used to evaluate the serological response to the vaccine(s). The 
assay is a solid phase sandwich enzyme-labeled immunoassay. Results for the assay are 
reported in mIU/mL.
This assay involves the reaction of anti-HBs in a test sample with HBsAg (ad and ay 
subtypes) coated onto the wells. A HRP-labeled HBsAg conjugate (ad and ay subtypes) then 
forms a complex with the bound anti-HBs, forming an “antigen sandwich”. Unbound 
materials are removed by washing. A reagent that contains luminogenic substrates (a luminol 
derivative and a peracid salt) and an electron transfer agent is added to the wells. The HRP in 
the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The 
electron transfer agent increases the level and duration of the light produced. The amount of 
HRP conjugate bound and subsequent light produced is indicative of the concentration of 
anti-HBs present in the sample.
Three internally prepared control serum pools, consisting of a high-positive, low-positive, 
and negative control, are used to monitor the performance of the assay. These pools are each 
prepared from 4 individual human immune sera obtained from an external vendor. 
Additionally, there are anti-HBs positive and negative manufacturer-supplied controls, which 
are prepared from freeze-dried recalcified human plasma. The hepatitis B WHO International 
reference standard at 10 mIU/mL is also run as a control in every assay. The LLOQ of the 
assay is 5 mIU/mL.
8.2.4
Poliovirus Neutralization Assay
Anti-poliovirus types 1, 2, and 3 will be measured by neutralization assay. Serial dilutions of 
sera are mixed with challenge poliovirus and incubated with cultured Vero cells that are 
sensitive to poliovirus. Specific neutralizing antibodies contained in the sera bind to and 
neutralize the challenge poliovirus. The neutralized poliovirus does not affect cellular 
viability, and these cells continue to metabolize and release CO2, reducing the pH of the 
culture medium. Cell survival correlates with the change in the pH indicator (phenol red to 
yellow at pH ≤7.0) contained in the medium. In the absence of neutralizing antibodies, the 
challenge poliovirus reduces cellular metabolism and CO2 production. Therefore, the pH 
does not decrease and a color change is not detected. The poliovirus mouse inoculation test 
measures the functional serum antibody response to poliovirus by utilizing Vero cells 
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(African green monkey kidney cells) and wild type poliovirus strains 1, 2, and 3 (Mahoney, 
MEF-1, and Saukett, respectively) as the challenge virus. The Karber method is used to 
determine the serum dilution that neutralized 50% of the challenge virus. Results are 
expressed as titers (1:dilution). The LLOQ for each of the antibodies to poliovirus types 1, 2, 
and 3 assays is 1:4.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) at Day 1 for all participants. Any clinically 
significant abnormality will be recorded on the appropriate eCRF.
The complete physical examination procedures include obtaining vital signs (heart rate, 
respiratory rate, and rectal temperature), auscultation of the heart and lung, examination of 
the abdomen, and an assessment of the head, eyes, ears, nose and throat, skin, lymph nodes, 
neurological system, and musculoskeletal system.
Findings related to the physical examinations should be documented in the participant’s 
chart/source documentation.
8.3.2
Body Temperature Measurement
Prevaccination body temperatures will be taken by study staff as indicated in Section 1.3. 
Participants who have febrile illness (rectal temperature ≥38.1°C [≥100.5°F] or axillary
temperature ≥37.8°C [≥100.0°F]) at or within 72 hours of vaccination must be rescheduled.
The participant’s legally acceptable representative will be asked to record the participant’s 
temperature reading on the VRC from Day 1 through Day 5 postvaccination.
Rectal is the preferred method of obtaining participant’s temperature. Axillary (underarm) is 
an acceptable method, but temperature needs to be confirmed by rectal measurement if the
axillary temperature is reported to be ≥37.8°C (≥100.0°F). In this case, both axillary and 
rectal temperatures must be recorded on the VRC. Temperature readings should be taken at 
approximately the same time each day. Use of temporal or tympanic thermometers to collect 
temperature for this study is prohibited.
8.3.3
Safety Assessment and Use of the VRC
All participants will be observed for at least 15 minutes postvaccination for any immediate 
reactions. If any immediate AEs are observed during this period, the time at which the event 
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occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
The limb that was used for the administration of study vaccine will be recorded in the VRC 
(Note: the study will report injection-site AEs from study vaccine only [not for nonstudy 
vaccines]; the location of study vaccine administration should be used by the participant’s 
legally acceptable representative to monitor the appropriate limb for injection-site AEs 
related to study vaccine).
Participant’s legally acceptable representative will use the VRC (Section 8.1.9) to document 
the following information:

Body temperatures measured Day 1 (day of vaccination) to Day 5 postvaccination

Solicited injection-site AEs (see Section 8.4.9.1) Day 1 to Day 5 postvaccination

Solicited systemic AEs (see Section 8.4.9.1) Day 1 to Day 5 postvaccination

Any other unsolicited injection-site or systemic AEs (see Section 8.4.9.2) Day 1 to 
Day 15 postvaccination

Use of any analgesic or antipyretic on the day of vaccination

Concomitant medications and nonstudy vaccinations Day 1 to Day 15 postvaccination
8.3.4
Clinical Safety Laboratory Assessments
There are no laboratory safety evaluations required by the protocol.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before the receipt of allocation number, must be reported 
by the investigator if they cause the participant to be excluded from the study, or are the 
result of a protocol-specified intervention, including, but not limited to washout or 
discontinuation of usual therapy, diet, placebo, or a procedure.
All AEs that occur from the time of allocation through 15 days postvaccination, must be 
reported by the investigator. All SAEs and other reportable safety events that occur from the 
time of allocation throughout the duration of the individual’s participation in the study, must 
be reported by the investigator, regardless of whether the events are considered to be 
vaccine-related by the investigator.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated Table 5.
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
- any death until 
participant 
completion of 
study
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor:
Pregnancy/Lactation 
Exposure
Not applicable since participants are infants.
Event of Clinical 
Interest
There are no events of clinical interest for this study.
Not applicable
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
NSAE=nonserious adverse event; SAE=serious adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including cancer and overdose will be followed until resolution, stabilization, until the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
allocated participants for outcome. Further information on follow-up procedures is given in 
Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This is not applicable to this study.
8.4.7
Events of Clinical Interest
There are no events of clinical interest for this study.
8.4.8
Medical Device and Drug-device Combination Products - PQCs/Malfunctions
The method of documenting and reporting of such events (complaints associated with 
medical devices, including PQCs/malfunctions) will occur as below and in Appendix 4.
To fulfill regulatory reporting obligations worldwide, medical device information associated 
with AEs will be collected and reported to the Sponsor in the same time frame as AEs per
Section 8.4.1 via CRF (paper or electronic) and as per data entry guidelines.
PQCs/malfunctions including those that involve a participant or any user/associated person 
must be reported to the Sponsor. Sponsor shall review reported events by the investigator to 
fulfill the legal responsibility of notifying appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices and drug-device combination 
products being used in clinical studies.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality between the AE and the 
medical device or device constituent of combination product.
8.4.9
Adverse Events on the VRC
Participant’s legally acceptable representative will use a paper VRC to report solicited and 
unsolicited AEs.
The definitions of solicited and unsolicited AEs can be found in Appendix 3.
8.4.9.1
Solicited Adverse Event
Solicited AEs for this study are summarized in Table 6.
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Table 6
Solicited Adverse Events
Type of Solicited 
Adverse Event
Predefined Solicited Adverse Events
(Preferred Term)
Solicited Time Period
Injection-site
Injection-site swelling
Injection-site redness (erythema)
Injection-site pain or tenderness (pain)
Day 1 through Day 5
postvaccination
Systemic
Vomiting
Drowsiness (somnolence)
Appetite lost (decreased appetite)
Irritability
Day 1 through Day 5
postvaccination
All solicited injection-site AEs will be considered related to study intervention.
In addition, the investigator will review all solicited AEs for the following:

Is the event a symptom of another diagnosis?

Is the event ongoing at the end of the solicited period?

Does the event meet serious criteria?
A solicited AE that meets any of the above criteria must also be reported on the appropriate 
eCRF as specified in the data entry guidelines.
8.4.9.2
Unsolicited Adverse Events
Unsolicited AEs for this study are events that are 1) not predefined in Table 6 or 
2) predefined in Table 6, but reported at any time outside the solicited time period.
As detailed in Section 8.4, the investigator will assess unsolicited AEs that meet the 
definition of an AE or SAE with respect to seriousness, intensity, and causality.
8.5
Treatment of Overdose
In this study, an overdose is the administration of more than 1 dose of study vaccine.
No specific information is available on the treatment of overdose.
All reports of overdose must be reported by the investigator within 5 calendar days to the 
Sponsor either by electronic media or paper. Electronic reporting procedures can be found in 
the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
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8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
FBR samples will not be collected in this study.
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening procedures/eligibility criteria will be conducted at Visit 1 as outlined in 
Section 1.3. Screening procedures may be repeated after consultation with the Sponsor.
8.11.2
Vaccination Visit
Requirements during the treatment period are outlined in Section 1.3.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in an sSAP and 
referenced in the CSR for the study. Post-hoc exploratory analyses will be clearly identified 
in the CSR.
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9.1
Statistical Analysis Plan Summary
Key elements of statistical analysis plan are summarized below; the comprehensive plan is 
provided in Section 9.2 to 9.12.
Study Design 
Overview
A Phase 4, Open-label, Multicenter, Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of Vaxelis™ in Healthy Participants Previously Vaccinated With a 2-
Dose Primary Infant Series of Either Vaxelis™ or Hexyon™
Treatment 
Assignment
Approximately 160 participants will be enrolled at ~11 to 13 months of age who have 
previously received a 2-dose primary infant series of either Vaxelis™ or Hexyon™.
Group 1: V,V,V ≈80 participants,
Group 2: H,H,V ≈80 participants.
Participants in both groups will receive Vaxelis™as their booster vaccination.
Analysis 
Populations
Immunogenicity: Per-protocol (PP)
Safety: All Participants as Treated (APaT)
Primary 
Endpoint(s)
Immunogenicity:
The following antibody responses will be measured at 30 days postvaccination with 
Vaxelis™as primary endpoints:
•
diphtheria toxoid
•
tetanus toxoid
•
pertussis toxoid (PT)
•
filamentous haemagglutinin (FHA)
•
Haemophilus influenae type b polyribosylribitol phosphate (Hib-PRP)
•
hepatitis B surface antigen (HBsAg)
•
poliovirus serotypes 1, 2, and 3
Safety:
•
solicited injection-site adverse events (AEs) from Day 1 through Day 5 
postvaccination
•
solicited systemic AEs from Day 1 through Day 5 postvaccination
•
unsolicited AEs from Day 1 through Day 15 postvaccination
•
Serious adverse events (SAEs) through completion of study participation
Key Secondary 
Endpoints
The following antibody responses will be measured at 30 days postvaccination with 
Vaxelis™as secondary endpoints:
•
pertactin (PRN)
•
fimbriae 2/3 (FIM 2/3)
Statistical 
Methods for 
Key 
Immunogenicity
Analyses
No statistical hypothesis testing will be performed for immunogenicity analyses. For the 
immunogenicity endpoints, the response rates to each antigen in Vaxelis™and the 
corresponding 95% confidence intervals (CIs) will be provided, for each group.
Statistical 
Methods for 
Key Safety 
Analyses
The overall safety endpoints and specific AEs will be summarized by providing the 
number and percentage of participants with AEs. The 95% within-group CIs for the 
percentages of participants with the event will be provided.
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Interim 
Analyses
No interim analyses are planned.
Multiplicity
No multiplicity adjustment is needed for the primary immunogenicity objective as 
there is no hypothesis testing.
Sample Size and 
Power
This study will enroll approximately 160 participants (80 in each group), which will 
allow estimation of the primary immunogenicity endpoints with a reasonable 95% CI.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a nonrandomized, open-label study, ie, participants,
investigators, and Sponsor personnel will be aware of participant vaccination assignments
after each participant is enrolled and vaccination is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study
treatment assignment.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. This is an estimation study; no hypothesis 
testing will be performed.
9.4
Analysis Endpoints
Immunogenicity and safety analysis endpoints that will be evaluated are listed below.
9.4.1
Immunogenicity Endpoints
The primary immunogenicity endpoints include the response rates, ie, proportions of 
participants with antibody-specific responses to the following antigens at 30 days 
postvaccination with Vaxelis™:

Diphtheria toxoid (% ≥0.1 IU/mL)

Tetanus toxoid (% ≥0.1 IU/mL)

PT (% vaccine response)

FHA (% vaccine response)

Hib-PRP (% ≥1.0 µg/mL)

HBsAg (% ≥10 mIU/mL)

Poliovirus 1 (% Nab ≥1:8 dilution)
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
Poliovirus 2 (% Nab ≥1:8 dilution)

Poliovirus 3 (% Nab ≥1:8 dilution)
The secondary immunogenicity endpoints include the response rates, ie, proportion of 
participants with antibody-specific responses to the following antigens at 30 days 
postvaccination with Vaxelis™:

PRN (% vaccine response)

FIM 2/3 (% vaccine response)
The response thresholds for the antigens in the primary and secondary immunogenicity 
endpoints are defined in Table 2 and Table 3 in Section 4.2.1.1.
The exploratory endpoints include the antibody-specific GMCs for all antigens contained in 
Vaxelis™ on Day 1 (predose) and 30 days postvaccination with Vaxelis™, and the 
proportion of participants with a ≥4-fold rise in antibody level from Day 1 to Day 30 for each 
antigen.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and postvaccination temperature measurements after vaccination with Vaxelis™.
The safety endpoints include:

Number of participants with solicited injection-site AEs (swelling, redness/erythema, 
tenderness/pain) from Day 1 through Day 5 postvaccination with Vaxelis™.

Number of participants with solicited systemic AEs (vomiting, 
drowsiness/somnolence, appetite lost/decreased appetite, and irritability) from Day 1 
through Day 5 postvaccination with Vaxelis™.

Number of participants with unsolicited AEs from Day 1 through Day 15
postvaccination with Vaxelis™.

Number of participants with an SAE, a vaccine-related SAE, discontinuation due to 
an AE, and death, from Day 1 through completion of study participation.

Participants body temperature measured from Day 1 through Day 5 postvaccination 
with Vaxelis™.
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9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The PP population will serve as the population for the analysis of immunogenicity data. The 
PP population consists of all enrolled participants without deviations from the protocol that 
may substantially affect the results of the immunogenicity endpoint. Potential deviations that 
may result in the exclusion of a participant from the PP population for all immunogenicity 
analyses include, but are not limited to:

Failure to receive study vaccine at Visit 1 (Day 1).

Receipt of a prohibited medication or prohibited vaccine (as defined in Section 5.2)
within the study window.

Collection of blood sample at Visit 2 outside the prespecified window (Day 26 to 
Day 40).
The final determination on important protocol deviations, and thereby the composition of the 
PP population, will be made prior to the final database lock and will be documented in a 
separate memo.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all participants 
who received study vaccination.
At least 1 temperature measurement obtained after study intervention is required for 
inclusion in the analyses of temperature.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
No statistical hypothesis testing will be performed for immunogenicity analyses.
The primary and secondary immunogenicity objectives will be evaluated by computing the 
proportion of participants with antibody responses for each antigen, detailed in 
Section 4.2.1.1, at 30 days postvaccination with Vaxelis™. Point estimates and 95% CIs will 
be provided by group (Group 1: V,V,V and Group 2: H,H,V) for both primary and secondary 
endpoints. The CIs will be calculated based on the exact binomial method proposed by 
Clopper and Pearson [CLOPPER, C. J. and PEARSON, E. S. 1934].
The analyses for the exploratory endpoints will be described in sSAP.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and postvaccination
temperatures.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary of the number and percentage of 
participants within each group with at least 1 AE, vaccine-related AE, SAE, vaccine-related 
SAE, a discontinuation from the study due to an AE, and an AE resulting in death. Point 
estimates and 95% within-group CIs for the percentages of participants with the event will be 
provided (Table 7).
The number and percentage of participants with solicited injection-site AEs from Days 1 to 5 
postvaccination, solicited systemic AEs from Days 1 to 5 postvaccination, unsolicited AEs 
from Days 1 to 15 postvaccination, maximum temperatures from Days 1 to 5 
postvaccination, and AEs by SOC will also be provided. For all AEs, point estimates and 
95% within-group CIs for the percentages of participants with the event will be provided
regardless of the number of participants with the event (Table 7).
Within-group CIs will be calculated based on the exact binomial method proposed by 
Clopper and Pearson [CLOPPER, C. J. and PEARSON, E. S. 1934]. CIs should only be 
regarded as helpful descriptive measures for the review of the safety profile and not as a 
formal method for assessing statistical significance.
Table 7
Analysis Strategy for Safety Parameters
Analysis 
Part
Safety Endpoint
Descriptive 
Statistics
95% 
Within-
group 
CI
Overall 
Safety 
Assessment
Solicited injection-site swelling (Days 1 through 5)
X
X
Solicited injection-site redness/erythema (Days 1 through 5)
X
X
Solicited injection-site tenderness/pain (Days 1 through 5)
X
X
Solicited vomiting (Days 1 through 5)
X
X
Solicited drowsiness/somnolence (Days 1 through 5)
X
X
Solicited appetite lost/decreased appetite (Days 1 through 5)
X
X
Solicited irritability (Days 1 through 5)
X
X
Unsolicited AEs (Days 1 through 15)
X
X
Any AE
X
X
Any vaccine-related AE
X
X
Any SAE
X
X
Any vaccine-related SAE
X
X
Discontinuation from study due to AE
X
X
AE that resulted in death
X
X
SOCs
X
X
Maximum temperature measurements (Days 1 through 5)
X
X
AE=adverse event; CI=confidence interval; SAE=serious adverse event; SOC=System Organ Class
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9.6.2.2
Assessment of Safety Topics of Special Interest
There are no safety topics of special interest.
9.6.3
Demographic and Baseline Characteristics
The relevant demographic and baseline characteristics will be summarized by group. No 
statistical hypothesis tests will be performed on these characteristics. The number and 
percentage of participants screened and the primary reasons for screening failure and 
discontinuation will be displayed. Demographic variables, baseline characteristics, and prior 
and concomitant vaccinations and therapies will be summarized either by descriptive 
statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned.
9.8
Multiplicity
No multiplicity adjustment is needed as there is no hypothesis testing.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Immunogenicity Analyses
This is an estimation study. This study will enroll approximately 160 participants (80 in each 
group) and will allow estimation of the primary immunogenicity endpoints with a reasonable 
95% CI. This is based on the following assumptions: 1) a 5% nonevaluability rate (76 
evaluable participants per group), and 2) underlying response rates for Vaxelis™following a 
booster dose based on the study results from V419-008 [Silfverdal, S. A., et al 2016], 
detailed in Table 8.
The CI was based on the exact binomial method proposed by Clopper and Pearson 
[CLOPPER, C. J. and PEARSON, E. S. 1934] assuming 95% evaluable participants in each 
group are included in the analysis.
Table 8 summarizes estimates of the CIs under various hypothetical observed response rates
for specific antigens.
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Table 8
Estimates of the 95% Confidence Intervals for Different Hypothetical Observed 
Response Rates
Sample Size 
(in each 
group)
Evaluable 
Sample Size (in 
each group)
Endpoint
Observed
Response (%)
95% CI
(%)
80
76
Anti-diphtheria
98
(91.8, 99.8)
Anti-Hib-PRP
90
(80.9, 95.7)
Anti-tetanus and all anti-pertussis
96
(88.8, 99.2)
CI=confidence interval; Hib=Haemophilus influenza type b; PRP=polyribosylribitol phosphate
The response rate after Vaxelis™is assumed based on historical data.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE depends on the number of participants vaccinated 
and the underlying percentage of participants with an SAE in the study population. If the 
underlying incidence of an SAE is 1.00% (1 of every 100 participants receiving the vaccine), 
there is an 80% chance of observing at least 1 SAE among 160 participants. If the underlying 
incidence of an SAE is 0.43% (1 of every 231 participants receiving the vaccine), there is a 
50% chance of observing at least 1 SAE among 160 participants. If no SAEs are observed 
among the 160 participants, this study will provide 95% confidence that the underlying 
percentage of participants with SAE is <1.85% (1 in every 53 participants).
9.10
Subgroup Analyses
Subgroup analyses based on receipt of pertussis vaccine during pregnancy by the
participant’s biological mother (ie, received vs not received; see Section 8.1.4) will be 
performed for the pertussis immunogenicity endpoints. Details of subgroup analyses will be 
documented in the sSAP.
9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of Vaxelis™during the study, 
compliance will not be calculated. However, the number and proportion of participants 
vaccinated with Vaxelis™will be summarized (Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of participants 
vaccinated with Vaxelis™.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Not applicable.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
There are no laboratory safety evaluations required by the protocol.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
Definition of Unsolicited and Solicited AE
•
An unsolicited AE is an AE that was not solicited using a VRC and that is communicated 
by a participant/participant’s legally authorized representative who has signed the 
informed consent. Unsolicited AEs include serious and nonserious AEs.
•
Solicited AEs are predefined local (at the injection/administration site) and systemic 
events for which the participant/participant’s legally authorized representative is 
specifically questioned, and which are noted by the participant/participant’s legally 
authorized representative in their VRC.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities (for pediatric studies with a 
legally acceptable representative: awareness of symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies with a legally acceptable representative: 
definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe (for 
pediatric studies with a legally acceptable representative: extremely distressed or 
unable to do usual activities).
•
Injection-site erythema/redness or swelling from the day of vaccination through Day 5
postvaccination will be evaluated by maximum size instead of intensity. After Day 5 , 
these events will be evaluated by intensity as described above.
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(diary, etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) 
Sponsor’s product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
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•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol, that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product - A product comprised of two or more regulated components (ie, a 
drug and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint - Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part - A drug, device, or biological product that is part of a combination 
product.
Customer Feedback - A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark which may suggest an improvement in the 
functionality or quality of a medical device or device-like features of a drug delivery system).
Malfunction - The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device - Any instrument, apparatus, appliance, material or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment or alleviation of disease, 
•
diagnosis, monitoring, treatment, alleviation of or compensation for an injury or 
handicap, 
•
investigation, replacement or modification of the anatomy or of a physiological process,
•
control of conception, 
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and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
function by such means.
PQC - Any communication that describes a potential defect related to the identity, strength, 
quality, purity or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury - An injury or illness that: 
1. Is life-threatening, 
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or 
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
•
When a Complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostic reports) related to the event.
•
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 
8.4.1 via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
•
The investigator will use clinical judgement to determine the relationship.
•
Alternative causes such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration should be considered and investigated.
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Follow-up
•
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
Not applicable.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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Appendix 7: Country-specific Requirements
Not applicable.
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Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event
APaT
All Participants as Treated
CI
confidence interval
CO2
carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease caused by severe acute respiratory 
syndrome coronavirus 2
CRF
Case Report Form
CSR
Clinical Study Report
DNA
deoxyribonucleic acid
DTaP-HB-IPV-Hib
diphtheria, tetanus, pertussis (acellular, component), hepatitis B 
(rDNA), poliomyelitis (inactivated), and Haemophilus influenzae
type b conjugate vaccine (adsorbed)
ECi
enhanced chemiluminescence
eCRF
electronic Case Report Form
EDC
electronic data collection
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EU
European Union
EU/mL
ELISA units per milliliter
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FHA
filamentous haemagglutinin
FIM 2/3
Fimbriae types 2 and 3
GCP
Good Clinical Practice 
HB
hepatitis B
HBsAg
hepatitis B surface antigen
Hib
Haemophilus influenza type b
HRP
horseradish peroxidase
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IRB
Institutional Review Board
IU/mL
International units per milliliter
LLOQ
lower limit of quantitation
Nab
neutralizing antibodies
OD
optical density
PP
per-protocol
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Abbreviation
Expanded Term
PQC
product quality complaint
PRN
pertactin
PRP
polyribosylribitol phosphate
PT
pertussis toxoid
RNA
ribonucleic acid
SAE
serious adverse event 
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
VRC
Vaccination Report Card
WHO
World Health Organization
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REFERENCES
[American Academy 
of Pediatrics 2012]
American Academy of Pediatrics. Red book: 
report of the committee on infectious diseases. 
29th ed. Pickering LK, Baker CJ, Kimberlin DW, 
Long SS, editors. Itasca (IL): American Academy 
of Pediatrics; c2012. Diphtheria; p. 307-11.
[06FHK8]
[American Academy 
of Pediatrics 2012]
American Academy of Pediatrics. Red Book: 
report of the committee on infectious diseases. 
29th ed. Pickering LK, Baker CJ, Kimberlin DW, 
Long SS, editors. Itasca (IL): American Academy 
of Pediatrics; c2012. Tetanus (lockjaw); p. 707-12.
[06FHMB]
[American Academy 
of Pediatrics 2012]
American Academy of Pediatrics. Red Book: 
report of the committee on infectious diseases. 
29th ed. Pickering LK, Baker CJ, Kimberlin DW, 
Long SS, editors. Itasca (IL): American Academy 
of Pediatrics; c2012. Poliovirus infections; p. 588-
92.
[06FHL8]
[Andrews, Nick, et al 
2003]
Andrews N, Borrow R, Miller E. Validation of 
serological correlate of protection for 
meningococcal C conjugate vaccine by using 
efficacy estimates from postlicensure surveillance 
in England. Clin Diagn Lab Immunol 
2003;10(5):780-6.
[03QXDF]
[Aquino, A. G. B., et 
al 2012]
Aquino AGB, Brito MG, Doniz CEA, Herrera 
JFG, Macias M, Zambrano B, et al. A fully liquid 
DTaP-IPV-Hep B-PRP-T hexavalent vaccine for 
primary and booster vaccination of healthy 
Mexican children. Vaccine. 2012;30:6492-500.
[06FFQC]
[Centers for Disease 
Control and 
Prevention 2013]
Centers for Disease Control and Prevention. 
Updated recommendations for use of tetanus 
toxoid, reduced diphtheria toxoid, and acellular 
pertussis vaccine (Tdap) in pregnant women -
Advisory Committee on Immunization Practices 
(ACIP), 2012. MMWR Morb Mortal Wkly Rep. 
2013 Feb 22;62(7):131-5.
[06FWPQ]
087XWM

PRODUCT:  V419  
81
PROTOCOL/AMENDMENT NO.:  016-01  
V419-016-01 FINAL PROTOCOL
08-JUL-2022
[Centers for Disease 
Control and 
Prevention 2015]
Centers for Disease Control and Prevention. 
Epidemiology and prevention of vaccine-
preventable diseases. 13th ed. Hamborsky J, 
Kroger A, Wolfe S, editors. Washington (DC): 
Department of Health and Human Services (HHS); 
c2015. Chapter 6, Vaccine administration; p. 79-
106.
[0508PV]
[Chow, M. Y. K., et al 
2016]
Chow MYK, Khandaker G, McIntyre P. Global 
childhood deaths from pertussis: a historical 
review. Clin Infect Dis. 2016;63(suppl 4):S134-41.
[06FWPN]
[CLOPPER, C. J. and 
PEARSON, E. S. 
1934]
Clopper CJ, Pearson ES. The use of confidence of 
fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
[03RRVC]
[Decker, M.D. 1998]
Decker MD, Edwards KM, Haemophilus 
influenzae type b vaccines: history, choice and 
comparisions. Pediatr Infect Dis J 
1998;17(9):S113-6.
[03VDCV]
[Donegan, K., et al 
2014]
Donegan K, King B, Bryan P. Safety of pertussis 
vaccination in pregnant women in UK: 
observational study. BMJ. 2014 Jul 11;349:g4219.
[03ZBMH]
[Edwards, K. M. 
2014]
Edwards KM, Berbers GAM. Immune responses 
to pertussis vaccines and disease. J Infect Dis. 
2014;209(suppl 1):S10-5.
[0533QY]
[European Medicines 
Agency 2018]
European Medicines Agency. Guideline on 
clinical evaluation of vaccines. London (England): 
European Medicines Agency (EMA); 2018. 21 p. 
EMEA/CHMP/VWP/164653/05.
[06D99T]
[Halperin, S. A., et al 
2018]
Halperin SA, Langley JM, Ye L, MacKinnon-
Cameron D, Elsherif M, Allen VM, et al. A 
randomized controlled trial of the safety and 
immunogenicity of tetanus, diphtheria, and 
acellular pertussis vaccine immunization during 
pregnancy and subsequent infant immune 
response. Clin Infect Dis. 2018 Oct 1;67(7):1063-
71.
[06FWPP]
087XWM

PRODUCT:  V419  
82
PROTOCOL/AMENDMENT NO.:  016-01  
V419-016-01 FINAL PROTOCOL
08-JUL-2022
[Lopez, P., et al 2017]
Lopez P, Arguedas Mohs A, Vasquez AA, 
Consuelo-Miranda M, Feroldi E, Noriega F, et al. 
A randomized controlled study of a fully liquid 
DTaP-IPV-HB-PRP-T hexavalent vaccine for 
primary and booster vaccinations of healthy 
infants and toddlers in Latin America. Pediatr 
Infect Dis J. 2017 Nov;36(11):e272-82.
[06FFQK]
[Mandell, G., et al 
2010]
Mandell G, Bennett J, Dolin R. Mandell, Douglas, 
and Bennett's principles and practice of infectious 
diseases, 2 Vol Set [Internet]. 7th Ed. New York 
(NY): Elsevier Health Sciences; 2010. 
Haemophilus influenzae; [cited 2021 Aug 3]; 
[about 25 screens]. Available from: 
https://www.r2library.com/Resource/detail/044306
8399/ch0225s6025.
[06FM78]
[Martinon-Torres, F., 
et al 2017]
Martinon-Torres F, Boisnard F, Thomas S, 
Sadorge C, Borrow R. Immunogenicity and safety 
of a new hexavalent vaccine (DTaP5-IPV-HB-
Hib) administered in a mixed primary series 
schedule with a pentavalent vaccine (DTaP5-IPV-
Hib). Vaccine. 2017;35:3764-72.
[0503MW]
[Obando-Pacheco, P., 
et al 2018]
Obando-Pacheco P, Rivero-Calle I, Gomez-Rial J, 
Rodriguez-Tenreiro Sanchez C, Martinon-Torres 
F. New perspectives for hexavalent vaccines. 
Vaccine. 2018;36:5485-94.
[06FWN3]
[Plotkin, S. A. 2010]
Plotkin SA. Correlates of protection induced by 
vaccination. Clin Vaccine Immunol 
2010;17(7):1055-65.
[03RV0S]
[Silfverdal, S. A., et al 
2016]
Silfverdal SA, Icardi G, Vesikari T, Flores SA, 
Pagnoni MF, Xu J. et al. A Phase III randomized, 
double-blind, clinical trial of an investigational 
hexavalent vaccine given at 2, 4, and 11-12 
months. Vaccine. 2016 Jul 19;34(33):3810-6.
[04RBHV]
[Tan, T., et al 2015]
Tan T, Dalby T, Forsyth K, Halperin SA, 
Heininger U, Hozbor D, et al. Pertussis across the 
Globe: recent epidemiologic trends from 2000 to
2013. Pediatr Infect Dis J. 2015 Sep;34(9):e222-
32.
[06FWPR]
087XWM

PRODUCT:  V419  
83
PROTOCOL/AMENDMENT NO.:  016-01  
V419-016-01 FINAL PROTOCOL
08-JUL-2022
[Trepo, C., et al 2014]
Trepo C, Chan HLY, Lok A. Hepatitis B virus 
infection. Lancet. 2014 Dec 6;384:2053-63.
[06FFR3]
[Van Damme, P., et al 
2013]
Van Damme P, Ward J, Shouval D, Wiersma S, 
Zanetti A. Hepatitis B vaccines. In: Plotkin SA, 
Orenstein WA, Offit PA, eds. 6 ed. Vaccines. 
China: Elsevier Saunders, 2013:205-34.
[03VWL9]
[World Health 
Organization 2013]
World Health Organization. Haemophilus 
influenzae type b (Hib) vaccination position paper 
- July 2013. Wkly Epidemiol Rec 
2013;88(39):413-28.
[03VWSK]
[World health 
organization 2015]
World health organization. Pertussis vaccines: 
WHO position paper – August 2015 = Note de 
synthèse: Position de l’OMS concernant les 
vaccins anticoquelucheux – août 2015. 2015 Aug 
28;90(35):433-460. English, French.
[04QSW3]
[World health 
organization 2017]
World health organization. Diphtheria vaccine: 
WHO position paper – August 2017 = Vaccin 
antidiphtérique: Note de synthèse de l’OMS – août 
2017. Wkly Epidemiol Rec. 2017 Aug 
4;92(31):417-35. English, French.
[04QSW0]
[World Health 
Organization 2017]
World Health Organization. Vaccins anti-hepatite 
B: note de synthese de l'OMS - juillet 2017 
[Hepatitis B vaccines: WHO position paper - July 
2017]. Wkly Epidemiol Rec. 2017 Jul 
7;92(27):369-92.
[04X8QL]
087XWM