A Phase 3 Randomized, Open-Label, Clinical Trial to Study the Immunogenicity and Safety of Concomitant and Non-Concomitant Administration of V260 and Inactivated Poliomyelitis Vaccine (IPV) in Chinese Healthy Infants
Phase: PHASE3
Conditions: Prevention of Rotavirus Gastroenteritis in Infants and Children Caused by Serotypes G1, G2, G3, G4, and G9
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04481191 
Document Date: 
01-Jun-2022
A Phase 3 Randomized, Open-Label, Clinical Trial to Study the
Immunogenicity and Safety of Concomitant and Non-Concomitant 
Administration of V260 and Inactivated Poliomyelitis Vaccine 
(IPV) in Chinese Healthy Infants

PRODUCT: V260  
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01-JUN-2022
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 3 Randomized, Open-Label, Clinical Trial to Study the 
Immunogenicity and Safety of Concomitant and Non-Concomitant Administration of V260 
and Inactivated Poliomyelitis Vaccine (IPV) in Chinese Healthy Infants
Protocol Number: 074-03
Compound Number: V260
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
EudraCT
2020-003329-49
Approval Date: 01 June 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
V260-074-03
01-JUN-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.
V260-074-02
11-AUG-2020
The purpose of this amendment is to add the EudraCT number to the protocol and 
to clarify baseline characteristics to be collected at enrollment and collection of 
non-study vaccination on the VRC.
V260-074-01
30-JAN-2020
The China Regulatory Agency released a new guideline on the grading scales for 
adverse events in vaccine clinical studies. The main purpose of this amendment is 
to update the protocol with the new guideline.
V260-074-00
18-NOV-2019
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [03]
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..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.3
Benefit/Risk Assessment......................................................................................22
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................23
4
STUDY DESIGN............................................................................................................24
4.1
Overall Design......................................................................................................24
4.2
Scientific Rationale for Study Design.................................................................25
4.2.1
Rationale for Endpoints ...............................................................................25
4.2.1.1
Immunogenicity Endpoints................................................................25
4.2.1.2
Safety Endpoints................................................................................26
4.2.2
Rationale for the Use of Comparator/Placebo .............................................26
4.3
Justification for Dose...........................................................................................26
4.4
Beginning and End of Study Definition .............................................................27
4.4.1
Clinical Criteria for Early Study Termination .............................................27
5
STUDY POPULATION ................................................................................................27
5.1
Inclusion Criteria.................................................................................................27
5.2
Exclusion Criteria................................................................................................27
5.3
Lifestyle Considerations......................................................................................29
5.4
Screen Failures.....................................................................................................29
5.5
Participant Replacement Strategy......................................................................29
6
STUDY INTERVENTION............................................................................................30
6.1
Study Intervention(s) Administered...................................................................30
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
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6.3.2
Stratification.................................................................................................33
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 ................................................................................................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...........................................................35
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 ........................................................................37
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.........................................................38
8.1.9
Discontinuation and Withdrawal .................................................................39
8.1.10
Participant Blinding/Unblinding..................................................................39
8.1.11
Domiciling ...................................................................................................39
8.1.12
Calibration of Equipment.............................................................................40
8.2
Immunogenicity Assessments .............................................................................40
8.2.1
Serum Samples for Antibody Testing..........................................................40
8.2.2
Immunoassays for Antibody Testing...........................................................40
8.3
Safety Assessments...............................................................................................41
8.3.1
Physical Examinations.................................................................................41
8.3.2
Axillary Temperature Measurement............................................................41
8.3.3
30-Minute Post-Vaccination Observation....................................................41
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8.3.4
Vaccination Report Card..............................................................................41
8.3.5
Clinical Safety Laboratory Assessments .....................................................42
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 ..........................................................43
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......44
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...44
8.4.4
Regulatory Reporting Requirements for SAE .............................................45
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................45
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................45
8.4.7
Events of Clinical Interest............................................................................45
8.5
Treatment of Overdose........................................................................................45
8.6
Pharmacokinetics.................................................................................................46
8.7
Pharmacodynamics..............................................................................................46
8.8
Biomarkers ...........................................................................................................46
8.9
Future Biomedical Research Sample Collection...............................................46
8.10
Medical Resource Utilization and Health Economics.......................................46
8.11
Visit Requirements...............................................................................................46
8.11.1
Screening......................................................................................................46
8.11.2
Vaccination Visit .........................................................................................46
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........47
9
STATISTICAL ANALYSIS PLAN .............................................................................47
9.1
Statistical Analysis Plan Summary.....................................................................47
9.2
Responsibility for Analyses/In-house Blinding .................................................48
9.3
Hypotheses/Estimation ........................................................................................49
9.4
Analysis Endpoints...............................................................................................49
9.4.1
Immunogenicity Endpoints..........................................................................49
9.4.2
Safety Endpoints..........................................................................................49
9.5
Analysis Populations............................................................................................50
9.5.1
Immunogenicity Analysis Populations ........................................................50
9.5.2
Safety Analysis Populations ........................................................................51
9.6
Statistical Methods...............................................................................................51
9.6.1
Statistical Methods for Immunogenicity Analyses......................................51
9.6.2
Statistical Methods for Safety Analyses ......................................................53
9.6.3
Demographic and Baseline Characteristics .................................................55
9.7
Interim Analyses ..................................................................................................55
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9.8
Multiplicity ...........................................................................................................55
9.9
Sample Size and Power Calculations .................................................................56
9.9.1
Sample Size and Power for immunogenicity Analyses ...............................56
9.9.2
Sample Size and Power for Safety Analyses ...............................................57
9.10
Subgroup Analyses...............................................................................................57
9.11
Compliance (Medication Adherence).................................................................57
9.12
Extent of Exposure...............................................................................................57
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................58
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........58
10.1.1
Code of Conduct for Clinical Trials.............................................................58
10.1.2
Financial Disclosure.....................................................................................60
10.1.3
Data Protection.............................................................................................60
10.1.3.1
Confidentiality of Data ......................................................................61
10.1.3.2
Confidentiality of Participant Records...............................................61
10.1.3.3
Confidentiality of IRB/IEC Information............................................61
10.1.4
Publication Policy........................................................................................61
10.1.5
Compliance with Study Registration and Results Posting Requirements ...62
10.1.6
Compliance with Law, Audit, and Debarment ............................................62
10.1.7
Data Quality Assurance ...............................................................................63
10.1.8
Source Documents .......................................................................................64
10.1.9
Study and Site Closure.................................................................................64
10.2
Appendix 2: Clinical Laboratory Tests..............................................................65
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................66
10.3.1
Definition of AE ..........................................................................................66
10.3.2
Definition of SAE ........................................................................................67
10.3.3
Additional Events Reported.........................................................................68
10.3.4
Recording AE and SAE ...............................................................................68
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................71
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................73
10.5
Appendix 5: Contraceptive Guidance................................................................74
10.5.1
Definitions....................................................................................................74
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................75
10.7
Appendix 7: Country-specific Requirements....................................................76
10.8
Appendix 8: Abbreviations .................................................................................90
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REFERENCES...............................................................................................................92
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................31
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................44
Table 3
Analysis Strategy for Key Immunogenicity Variables....................................52
Table 4
Each Group by Dose Period.............................................................................53
Table 5
Analysis Strategy for Safety Parameters..........................................................54
Table 6
Sample Size and Power Calculated Based on Neutralizing Antibody 
Seroconversion Percentage Difference............................................................56
Table 7
Estimate of Incidence of SAE and 95% Upper Confidence Bound Based 
on Hypothetical Number of Participants with SAE Among 200 
Participants in the Group .................................................................................57
Table 8
Grading Scales for Adverse Events at Vaccination Site (Local) .....................78
Table 9
Grading Scales for Vital Signs.........................................................................79
Table 10
Grading Scales for Adverse Events at Non-vaccination Site (Systemic) ........80
Table 11
Grading Scales for Blood Biochemistry Measurements..................................84
Table 12
Grading Scales for Blood Routine Examinations............................................86
Table 13
Grading Scales for Urine Routine Examinations.............................................87
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LIST OF FIGURES
Figure 1
Study Diagram ...........................................................................................15
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Open-Label, Clinical Trial to Study the 
Immunogenicity and Safety of Concomitant and Non-Concomitant Administration of V260 
and Inactivated Poliomyelitis Vaccine (IPV) in Chinese Healthy Infants
Short Title: Immunogenicity and safety assessment of concomitant administration of V260 
and IPV in Chinese healthy infants 
Acronym: V260-074
Hypotheses, Objectives, and Endpoints:
In healthy Chinese infants 48-63 days of age:
Note: Participants randomized to non-concomitant administration of V260 and IPV 
(staggered-use group) will receive the two study vaccines in a staggered-use schedule.
Objectives
Endpoints
Primary
•
Objective: To demonstrate that the 
immunogenicity of IPV in the 
concomitant-use group is non-inferior to 
that in the staggered-use group.
Hypothesis (H1): The seroconversion 
percentage at 1 month post dose 3 for 
each of poliovirus types 1, 2, and 3 in 
the concomitant-use group is non-
inferior to those in the staggered-use 
group. The statistical criterion for non-
inferiority requires that the lower bound 
of two-sided 95.0% confidence interval 
for the difference (concomitant-use 
group minus staggered-use group) in 
seroconversion percentages be greater 
than -10% for each poliovirus type.
•
Neutralizing antibody seroconversion to 
each of poliovirus types 1, 2, and 3
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Objectives
Endpoints
Secondary
•
Objective: To evaluate immune 
responses to IPV at 1 month post dose 3 
in the concomitant-use and staggered-
use groups as measured by geometric 
mean titers (GMTs) of neutralizing 
antibodies to poliovirus types 1, 2, and 
3.
•
Neutralizing antibody titer to each of 
poliovirus types 1, 2, and 3
•
Objective: To evaluate immune 
responses to IPV at 1 month post dose 3 
in the concomitant-use and staggered-
use groups as measured by the 
proportions of participants with 
neutralizing antibody titer ≥1:8 and 
≥1:64 for each of poliovirus types 1, 2, 
and 3.
•
Neutralizing antibody responses to each 
of poliovirus types 1, 2, and 3
•
Objective: To evaluate the safety of 
concomitant administration of V260 and 
IPV based on the proportions of 
participants experiencing solicited 
injection-site adverse events (AEs), 
solicited systemic AEs, and serious AEs 
(SAEs).
•
Solicited injection-site AEs (following 
vaccination of IPV)
•
Solicited systemic AEs
•
SAEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Prevention of rotavirus gastroenteritis in infants and children 
caused by the serotypes G1, G2, G3, G4, and G9
Population
Chinese healthy infants
Study Type
Interventional
Intervention Model
Parallel
This is a single-site study.
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Type of Control
Active control (Staggered-use group)
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of 
Study
The Sponsor estimates that the study will require approximately
7 months from the time the first participant signs the informed 
consent until the last participant’s last study-related telephone 
call or visit.
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.
Number of Participants:
Approximately 400 participants will be enrolled in the study as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Vaccine
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Use
Concomitant-
Use/Staggered-
Use Group
V260 
(ROTATEQ®)
2 mL/dose
3 doses
Oral
Experimental
IPV (Sabin 
strain based)
0.5 mL/dose
3 doses
IM
Experimental
Abbreviations: IM=Intramuscular; IPV=Inactivated poliomyelitis vaccine.
Total 
Number
Two treatment groups
Duration of 
Participation
Each participant will participate in the study for approximately 3.5 months 
from the time the participant’s legally acceptable representative signs the 
Informed Consent Form through the final contact. After enrollment, each 
participant will be receiving 3 doses of V260 and IPV in a concomitant-use 
or staggered-use schedule. After each vaccination of V260 and/or IPV, each 
participant will be followed for 30 days in the concomitant-use group and 
for 15 days in the staggered-use group. 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
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1.3
Schedule of Activities
Visit Number
1
2
3
4
5
6
7
8
Notes
Study Month
Day 1
Month 0.5
Month 1
Month 1.5
Month 2
Month 2.5
Month 3
Month 3.5
Recommended Age (Months)
~1.5
~2
~2.5
~3
~3.5
~4
~4.5
~5
Concomitant-Use 
Group
Scheduled Day
Day 1
15 days 
after V1 
15 days 
after V2
30 days 
afterV2
15 days 
after V4
30 days 
after V4
15 days 
after V6
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
(≤84 days 
of age)  
15-21d 
after
V2
30-42d
after V2
15-21d 
after V4
30-42d 
after V4
15-21d 
after V6
30-42d 
after V6
Staggered-Use 
Group
Scheduled Day
Day 1
15 days 
after V1
30 days 
after V1
30 days 
after V2
30 days 
after V3
30 days 
after V4
30 days 
after V5
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
30-42d 
after V1
& 
≥V2+15d
30-42d 
after V2
& 
≥V3+15d
30-42d 
after V3 
&
≥V4 +15d
30-42d 
after V4
& 
≥V5+15d
30-42d 
after V5
30-42d 
after V6
Administrative Procedures
Informed Consent
X
Screening procedures may not 
be performed on the same day 
of ICF, but screening or 
rescreening visit should be on 
the same day as randomization. 
Screening procedures may be 
repeated after consultation with 
the Sponsor.
Assignment of Screening Number
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
Medical History
X
Prior/Concomitant Medications 
Review
X
X
X
X
X
X
X
X
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Visit Number
1
2
3
4
5
6
7
8
Notes
Study Month
Day 1
Month 0.5
Month 1
Month 1.5
Month 2
Month 2.5
Month 3
Month 3.5
Recommended Age (Months)
~1.5
~2
~2.5
~3
~3.5
~4
~4.5
~5
Concomitant-Use 
Group
Scheduled Day
Day 1
15 days 
after V1 
15 days 
after V2
30 days 
afterV2
15 days 
after V4
30 days 
after V4
15 days 
after V6
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
(≤84 days 
of age)  
15-21d 
after
V2
30-42d
after V2
15-21d 
after V4
30-42d 
after V4
15-21d 
after V6
30-42d 
after V6
Staggered-Use 
Group
Scheduled Day
Day 1
15 days 
after V1
30 days 
after V1
30 days 
after V2
30 days 
after V3
30 days 
after V4
30 days 
after V5
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
30-42d 
after V1
& 
≥V2+15d
30-42d 
after V2
& 
≥V3+15d
30-42d 
after V3 
&
≥V4 +15d
30-42d 
after V4
& 
≥V5+15d
30-42d 
after V5
30-42d 
after V6
Assignment of 
Treatment/Randomization Number 
X
The treatment/randomization 
number will be randomly 
assigned by an interactive 
response technology (IRT) 
system.
V260 
Administration
Concomitant-
Use Group
X
X
X
1st dose of V260 should be 
given by 84 days of age 
(inclusive). 3rd dose of V260 
should be given by 224 days of 
age (inclusive).
The minimum and maximum 
interval between each dose of 
V260 should be 4 weeks (28 
days) and 10 weeks (70 days), 
respectively.
Staggered-Use 
Group
X
X
X
IPV 
Administration
Concomitant-
Use Group
X
X
X
The minimum age for the 1st
dose of IPV should be is 2 
months of age. 
The minimum interval between 
each dose of IPV should be 1
month (30 days).
In the staggered-use group, the 
minimum interval between 
V260 and subsequent IPV is 
should be 15 days.
Staggered-Use 
Group
X
X
X
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Visit Number
1
2
3
4
5
6
7
8
Notes
Study Month
Day 1
Month 0.5
Month 1
Month 1.5
Month 2
Month 2.5
Month 3
Month 3.5
Recommended Age (Months)
~1.5
~2
~2.5
~3
~3.5
~4
~4.5
~5
Concomitant-Use 
Group
Scheduled Day
Day 1
15 days 
after V1 
15 days 
after V2
30 days 
afterV2
15 days 
after V4
30 days 
after V4
15 days 
after V6
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
(≤84 days 
of age)  
15-21d 
after
V2
30-42d
after V2
15-21d 
after V4
30-42d 
after V4
15-21d 
after V6
30-42d 
after V6
Staggered-Use 
Group
Scheduled Day
Day 1
15 days 
after V1
30 days 
after V1
30 days 
after V2
30 days 
after V3
30 days 
after V4
30 days 
after V5
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
30-42d 
after V1
& 
≥V2+15d
30-42d 
after V2
& 
≥V3+15d
30-42d 
after V3 
&
≥V4 +15d
30-42d 
after V4
& 
≥V5+15d
30-42d 
after V5
30-42d 
after V6
Immunogenicity Procedures
Blood Sample 
Collection
Concomitant-
Use Group
X
X
In the concomitant-use group, 
at least 2.5 mL blood sample 
will be collected from each 
participant at Visit 1 prior to 
vaccination and Visit 8, 
respectively. 
Staggered-Use 
Group
X
X
X
In the staggered-use group, at 
least 2.5 mL blood sample will 
be collected prior to 
vaccination at Visit 1; at least 
1.5mL blood sample will be 
collected at Visit 7 and Visit 8, 
respectively.
Safety Procedures
Full Physical Examination
X
A full physical examination 
will be performed on all 
participants at Visit 1. Height 
and weight will also be 
measured at Visit 1.
Symptom/Sign-Directed Physical 
Examination
X
X
X
X
X
X
X
A symptom/sign-directed 
physical examination will be 
performed at subsequent visits 
as needed.
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Visit Number
1
2
3
4
5
6
7
8
Notes
Study Month
Day 1
Month 0.5
Month 1
Month 1.5
Month 2
Month 2.5
Month 3
Month 3.5
Recommended Age (Months)
~1.5
~2
~2.5
~3
~3.5
~4
~4.5
~5
Concomitant-Use 
Group
Scheduled Day
Day 1
15 days 
after V1 
15 days 
after V2
30 days 
afterV2
15 days 
after V4
30 days 
after V4
15 days 
after V6
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
(≤84 days 
of age)  
15-21d 
after
V2
30-42d
after V2
15-21d 
after V4
30-42d 
after V4
15-21d 
after V6
30-42d 
after V6
Staggered-Use 
Group
Scheduled Day
Day 1
15 days 
after V1
30 days 
after V1
30 days 
after V2
30 days 
after V3
30 days 
after V4
30 days 
after V5
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
30-42d 
after V1
& 
≥V2+15d
30-42d 
after V2
& 
≥V3+15d
30-42d 
after V3 
&
≥V4 +15d
30-42d 
after V4
& 
≥V5+15d
30-42d 
after V5
30-42d 
after V6
Axillary 
Temperature 
Measurement
Concomitant-
Use Group
X
X
X
X
Pre-vaccination axillary 
temperature will be collected 
for all participants at Visit 1 
and at each subsequent 
vaccination visits. Axillary is 
the only acceptable method of 
obtaining participant’s 
temperature.
If participant has a fever 
(defined as axillary 
temperature ≥37.5˚C or 
equivalent) within 24 hours 
prior to each vaccination, the 
vaccination should be 
rescheduled after fever is 
resolved.
Staggered-Use 
Group
X
X
X
X
X
X
30-Minute Post-
Vaccination 
Observation
Concomitant-
Use Group
X
X
X
Staggered-Use 
Group
X
X
X
X
X
X
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Visit Number
1
2
3
4
5
6
7
8
Notes
Study Month
Day 1
Month 0.5
Month 1
Month 1.5
Month 2
Month 2.5
Month 3
Month 3.5
Recommended Age (Months)
~1.5
~2
~2.5
~3
~3.5
~4
~4.5
~5
Concomitant-Use 
Group
Scheduled Day
Day 1
15 days 
after V1 
15 days 
after V2
30 days 
afterV2
15 days 
after V4
30 days 
after V4
15 days 
after V6
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
(≤84 days 
of age)  
15-21d 
after
V2
30-42d
after V2
15-21d 
after V4
30-42d 
after V4
15-21d 
after V6
30-42d 
after V6
Staggered-Use 
Group
Scheduled Day
Day 1
15 days 
after V1
30 days 
after V1
30 days 
after V2
30 days 
after V3
30 days 
after V4
30 days 
after V5
30 days 
after V6
Visit Window
48-63 
days of 
age
15-21d 
after V1
30-42d 
after V1
& 
≥V2+15d
30-42d 
after V2
& 
≥V3+15d
30-42d 
after V3 
&
≥V4 +15d
30-42d 
after V4
& 
≥V5+15d
30-42d 
after V5
30-42d 
after V6
Vaccination 
Report Card 
(VRC) 
Distribution
Concomitant-
Use Group
X
X
X
X
Although study vaccination is 
not scheduled at Visit 1 in the 
concomitant-use group, VRC 
will be provided to participant 
to record any reportable safety 
events from randomization
until the 1st dose of study 
vaccination (see Section 8.4.1 
for safety reporting 
requirement).
Staggered-Use 
Group
X
X
X
X
X
X
Review and Collection of VRC 
Data
X
X
X
X
X
X
X
At least one telephone contact 
will be made within 7 days 
after each visit of VRC 
distribution. The main purpose 
of phone call contact is to 
remind the participant’s legally 
acceptable representative to 
record the VRC and answer 
any questions related to VRC.
Clinical Follow-up for Safety
X
X
X
X
X
X
X
X
Review and follow AEs, SAEs 
and other reportable safety 
events.
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2
INTRODUCTION
2.1
Study Rationale
Since initial approval in the US in 2006, V260 (RotaTeq®) has been licensed in more than
100 countries including Canada, Australia, and countries in the European Union, Latin 
America, Africa, Southeast Asia and Western Pacific. V260 was approved in China as a 
prophylactic live, oral, pentavalent rotavirus vaccine in April 2018.
The administration of V260 with licensed pediatric vaccines (including INFANRIX™, 
IPOL™, INFANRIX™ hexa, etc.) has been evaluated in the global studies (Protocol 006, 
010, and 060) [Rodriguez, Z. M., et al 2007] [Ciarlet, M., et al 2009] [Okada, K., et al 2013].
Inactivated poliomyelitis vaccine (IPV) evaluated in these studies included Salk-IPV (wIPV)
(Protocol 006 and 010) and Sabin-IPV (sIPV) (Protocol 060).
Concomitant administration of V260 with trivalent oral poliomyelitis vaccine (tOPV), and 
diphtheria, tetanus toxoids and acellular pertussis (DTaP) vaccine in Chinese infants was
evaluated in the Protocol 024, an efficacy registration study conducted in China. Since 2016, 
at least one dose of sIPV was introduced into the routine polio immunization schedule in 
China. The immunization schedule in China was gradually transitioned to a 2-dose IPV 
schedule in 2019 and is expected to be changed to the all-IPV schedule in the future. 
Although concomitant administration with sIPV was evaluated in Japanese infants (Protocol 
060), the sIPV in Japan is different with the sIPV marketed in China with respect to antigen 
amounts. This study (Protocol 074) will evaluate the immunogenicity and safety of 
concomitant administration of V260 and sIPV in Chinese infants. V260 and sIPV will be 
provided by local sourcing in the study.
2.2
Background
Refer to the Investigator’s Brochure (IB)/ approved labeling for detailed background 
information on V260.
2.2.1
Pharmaceutical and Therapeutic Background
Rotavirus is the leading cause of severe diarrhea in infants and young children. Rotavirus 
infection was responsible for an estimated 128,500 deaths and 258 million episodes of 
diarrhea worldwide among children younger than 5 years of age in 2016 [Troeger, C., et al 
2018]. In China, rotavirus caused over 40% of hospitalization due to diarrhea and about 30% 
of diarrhea related outpatient visits in children under 5 years of age [Zhang, J., et al 2015].
Rotavirus gastroenteritis is characterized by the sudden onset of watery diarrhea, fever, and 
vomiting. Severity varies from asymptomatic infection to dehydrating gastroenteritis that 
may be fatal. Nearly all children are infected with rotavirus by the age of 5 years regardless 
of socioeconomic status or standards of health and sanitation [Vesikari, T., et al 2006]. This 
suggests that improvements in sanitation are unlikely to reduce the incidence rate of rotavirus 
gastroenteritis. Currently, there is no antiviral therapy available to treat rotavirus 
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gastroenteritis, and the only available therapy is treatment of associated symptoms, such as 
supportive oral or intravenous rehydration for dehydration.
V260 is a live, oral, pentavalent combination vaccine developed by Merck that contains five 
human-bovine reassortant rotavirus strains (G1, G2, G3, G4 and P1A[8]). A phase 3 study in 
healthy infants has been conducted in China (Protocol 024; May 2014 to June 2015) in 4,040 
infants aged 6-12 weeks to investigate the efficacy, immunogenicity, and safety of V260 in 
Chinese healthy infants. The study showed that the vaccine efficacy against any-severity of 
rotavirus gastroenteritis caused by vaccine serotypes was 69.3% and the efficacy against 
severe rotavirus gastroenteritis caused by vaccine serotypes was 78.9% as compared to 
placebo [Mo, Z., et al 2017]. 
In 2009, the World Health Organization recommended rotavirus vaccination to be included
in all national immunization programs for the first time to ensure access to rotavirus vaccines 
in the world’s poorest countries [World Health Organization 2009].
2.3
Benefit/Risk Assessment
V260 has been licensed in over 100 countries since 2006 and was approved in China in 2018 
for the protection against rotavirus gastroenteritis in infants and children caused by serotypes 
G1, G2, G3, G4, and G9.
Benefit/risk for concomitant administration of V260 with IPV has been established to be 
favorable in the global studies. This study aims to establish this in Chinese infants. 
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In healthy Chinese infants 48-63 days of age:
Objectives
Endpoints
Primary
•
Objective: To demonstrate that the 
immunogenicity of IPV in the 
concomitant-use group is non-inferior to 
that in the staggered-use group.
Hypothesis (H1): The seroconversion 
percentage at 1 month post dose 3 for 
each of poliovirus types 1, 2, and 3 in 
the concomitant-use group is non-
inferior to those in the staggered-use 
group. The statistical criterion for non-
inferiority requires that the lower bound 
of two-sided 95.0% confidence interval 
for the difference (concomitant-use 
group minus staggered-use group) in 
seroconversion percentages be greater 
than -10% for each poliovirus type.
•
Neutralizing antibody seroconversion to 
each of poliovirus types 1, 2, and 3
Secondary
•
Objective: To evaluate immune 
responses to IPV at 1 month post dose 3 
in the concomitant-use and staggered-
use groups as measured by geometric 
mean titers (GMTs) of neutralizing 
antibodies to poliovirus types 1, 2, and 
3.
•
Neutralizing antibody titer to each of 
poliovirus types 1, 2, and 3
•
Objective: To evaluate immune 
responses to IPV at 1 month post dose 3 
in the concomitant-use and staggered-
use groups as measured by the 
proportions of participants with 
neutralizing antibody titer ≥1:8 and 
≥1:64 for each of poliovirus types 1, 2, 
and 3.
•
Neutralizing antibody responses to each 
of poliovirus types 1, 2, and 3
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Objectives
Endpoints
•
Objective: To evaluate the safety of 
concomitant administration of V260 and 
IPV based on the proportions of 
participants experiencing solicited 
injection-site adverse events (AEs), 
solicited systemic AEs, and serious AEs
(SAEs).
•
Solicited injection-site AEs (following 
vaccination of IPV)
•
Solicited systemic AEs
•
SAEs
Exploratory
•
Objective: To evaluate immune 
responses to V260 at 1 month post dose 
3 in the concomitant-use and staggered-
use groups using anti-rotavirus type-
specific IgA based on GMTs and 
proportions of participants with ≥3-fold 
increase in titer post-vaccination from 
baseline.
•
Anti-rotavirus type-specific IgA 
antibody responses to rotavirus 
serotypes G1, G2, G3, G4, and P1A[8]
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, single-site, open-label study of concomitant administration of V260 
and IPV in Chinese healthy infants to be conducted in conformance with Good Clinical 
Practices.
Approximately 400 participants between the ages of 48 days and 63 days will be enrolled and
randomly assigned in a 1:1 ratio to receive V260 and IPV in a concomitant (concomitant-use 
group) or non-concomitant administration (staggered-use group) schedule. Each participant 
will participate in the study for approximately 3.5 months from the time the participant’s
legally acceptable representative signs the informed consent through the final contact, 
including 8 study visits for vaccination, blood sample collection, and safety follow-up. 
In the concomitant-use group, an oral dose of V260 (2 mL/dose) will be concomitantly 
administered (same day) with an intramuscular injection of IPV (0.5 mL/dose) at Visit 2, 
Visit 4, and Visit 6, respectively. In the staggered-use group, an oral dose of V260 
(2mL/dose) will be administered at Visit 1, Visit 3, and Visit 5, respectively, and an
intramuscular injection of IPV (0.5 mL/dose) will be administered at Visit 2, Visit 4, and 
Visit 6, respectively. 
In the concomitant-use group, serum samples will be obtained from each participant at Visit 
1 prior to vaccination and Visit 8 (1 month post dose 3 of V260 and IPV), respectively. In the 
staggered-use group, serum samples will be obtained from each participant at Visit 1 prior to 
vaccination, Visit 7 (1 month post dose 3 of V260), and Visit 8 (1 month post dose 3 of IPV), 
respectively.
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Paper Vaccination Report Card (VRC) will be used by each participant’s legally acceptable 
representative to record participant’s daily axillary temperature from Day 1 through Day 7 
post each study vaccination; solicited injection-site AEs (erythema, swelling, induration, and 
pain at the injection-site of IPV) from Day 1 through Day 7 post each vaccination of IPV, 
and solicited systemic AEs (diarrhea and/or vomiting) from Day 1 through Day 7 post each 
study vaccination; and any other AEs from Day 1 through Day 15 post each study 
vaccination in both the concomitant-use and staggered-use groups. In addition, any other AEs 
from Day 16 through Day 30 post each study vaccination in the concomitant-use group will
also be collected on the VRC.
Any SAEs regardless of causality, cancer, overdose, and intussusception (Event of Clinical 
Interest [ECI]) will be collected during the entire period of study.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This is a post-marketing commitment study. This study is designed to assess immunogenicity 
of IPV when concomitantly administered with V260 in Chinese infants with the staggered-
use group as a comparative control. The immunogenicity of V260 will be evaluated as 
exploratory objective. The safety of study vaccines will also be evaluated in the study.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The immunogenicity of IPV will be measured using poliovirus serum neutralizing antibody 
assay of National Institutes for Food and Drug Control (NIFDC, Beijing, China).
The primary endpoints are neutralizing antibody seroconversion percentages to each of 
poliovirus types 1, 2, and 3 at 1 month post dose 3 of IPV. The seroconversion is defined as 
antibody titer ≥1:8 post-vaccination in baseline seronegative participants or ≥4-fold increase 
in titer post-vaccination in baseline seropositive participants, which is consistent with 
WHO’s recommendation on the immunogenicity evaluation of IPV vaccines [World Health 
Organization Expert Committee on Biological Standar 2014]. The cut-off value for 
seropositivity is 1:8 for all 3 poliovirus types [Nathanson, N. 2005].
The neutralizing antibody GMTs to each of poliovirus types 1, 2, and 3 at Day 1 prior to 
vaccination and 1 month post dose 3 of IPV will be summarized as secondary endpoints. In 
addition, the proportions of participants with neutralizing antibody titer ≥1:8 and ≥1:64 at 1 
month post dose 3 of IPV will be summarized for each of poliovirus types 1, 2, and 3, as 
requested by local regulatory agency.
The immunogenicity of V260 will be measured using anti-rotavirus type-specific IgA assay 
of NIFDC as exploratory objectives. An immunological correlate of protection has not been 
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identified for rotavirus disease. The antibody responses to V260 at 1 month post dose 3 will 
be summarized using the same methods adopted in the prior efficacy study in China, i.e. 
based on GMTs and proportions of participants with ≥3-fold increase in titer post-vaccination 
from baseline.
4.2.1.2
Safety Endpoints
In the concomitant-use group, V260 and IPV will be administered on the same day with an 
interval of at least 30 days between each vaccination visit, and the safety of the two study 
vaccines will be collected for 30 days following each vaccination. In the staggered-use 
group, V260 and IPV will be administered separately with an interval of at least 15 days, 
therefore the safety of each study vaccine will be collected for 15 days following each 
vaccination.
Paper VRC will be provided to each participant’s legally acceptable representative at each 
vaccination visit to record participant’s daily axillary temperature from Day 1 through Day 7 
post each study vaccination; solicited injection-site AEs (erythema, swelling, induration, and 
pain at the injection-site of IPV) from Day 1 through Day 7 post each vaccination of IPV, 
and solicited systemic AEs (diarrhea and/or vomiting) from Day 1 through Day 7 post each 
study vaccination; and any other AEs from Day 1 through Day 15 post study each 
vaccination in both the concomitant-use and staggered-use groups. In addition, any other AEs 
from Day 16 through Day 30 post each study vaccination in the concomitant-use group will 
also be collected on the VRC.
The solicited injection-site AEs will be collected for the safety evaluation of IPV, which is a 
vaccine to be intramuscularly administered.
Although participants in the concomitant-use group will not receive any study vaccines at 
Visit 1, VRC will be provided to each participant at Visit 1 to record any reportable safety 
events from randomization through the first study vaccination (See Section 8.4.1 for safety 
reporting requirement).
In addition, any SAEs regardless of causality, cancer, overdose, and intussusception (ECI)
will be collected during the entire period of study.
4.2.2
Rationale for the Use of Comparator/Placebo
To assess the immunogenicity of IPV concomitantly administered with V260, the staggered-
use group will be used as a comparative control in the study.
4.3
Justification for Dose
The dose regimens and schedules for study vaccines are based on the approved China 
Package Circulars (CPCs). Refer to Section 6.1 – Study Intervention(s) for details regarding 
the trial vaccination.
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
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
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy Chinese infants 48-63 days of age 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 Chinese infant.
Demographics
2. Is male or female from 48 days to 63 days of age (inclusive) at Visit 1. (Date of birth is 1 
day of age).
Informed Consent
3. The participant’s legally acceptable representative provides written informed consent for 
the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has history of rotavirus disease, congenital gastrointestinal disorders, chronic diarrhea, 
failure to thrive, or abdominal surgery.
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2. Has history of intussusception.
3. Has history of poliomyelitis.
4. Has clinical evidence of active gastrointestinal illness. Note: Infants with 
gastroesophageal reflux disease [GERD] may participate in the study if the GERD is well 
controlled with or without medication.
5. Has known or suspected impairment of immunological function, including severe 
combined immunodeficiency disease (SCID).
6. Has a fever, with an axillary temperature ≥37.5°C (or equivalent) at the time of 
vaccination or within 24 hours prior to vaccination. Note: The Visit 1 may be rescheduled 
after complete resolution of febrile illness.
7. Participant who clearly has acute disease.
8. Participant who has underlying diseases such as cardiovascular, renal, liver, or blood 
disease.
9. Has history of known hypersensitivity to any components of rotavirus vaccine and/or
IPV.
10. Participant with uncontrolled epilepsy, encephalopathy, seizure, or other progressive 
neurological diseases.
11. Participant with known thrombocytopenia or any coagulation disorder that would
contraindicate intramuscular injections.
12. Is residing in a household with an immunocompromised person, including individuals 
with congenital immunodeficiency (including SCID), human immunodeficiency virus 
(HIV) infection, leukemia, lymphoma, multiple myeloma, generalized malignance, 
chronic renal failure, organ or bone marrow transplantation, or with those receiving 
immunosuppressive chemotherapy including long-term systemic corticosteroids.
13. Has any condition, which in the opinion of the investigator, may interfere with the 
evaluation of the study objectives.
Prior/Concomitant Therapy
14. Has prior administration of any rotavirus vaccines or poliovirus vaccines.
15. Received inactivated or recombinant vaccines within 14 days prior to Visit 1 or live 
vaccines within 28 days prior to Visit 1.
16. Has prior receipt of investigational or non-registered product other than study vaccines or 
is planning to use such product during the study.
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17. Has prior receipt of immunosuppressive therapies including systemic (intramuscular, 
oral, or intravenous) corticosteroids. Note: Participants using non-systemic 
corticosteroids (e.g., topical, ophthalmic, and inhaled) are considered eligible for the 
study.
18. Has prior receipt of a blood transfusion or blood products, including immunoglobulins or 
is planning to receive such product during the study.
Prior/Concurrent Clinical Study Experience
19. Participated in another interventional study prior to Visit 1 or expected anytime during 
the study.
Diagnostic Assessments
Not applicable.
Other Exclusions
20. Participant’s legally acceptable representative is unlikely to adhere to the study 
procedures, keep appointments or is planning to permanently relocate from the area prior 
to the completion of the study or to leave for an extended period when study visits would 
need to be scheduled.
21. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered 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 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 discontinues from study vaccination OR withdraws from the study will not 
be replaced.
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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.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Concomitant-
Use Group
Experimental
V260
Biological
/Vaccine
Sterile 
Solution
2 mL per 
dose
3 doses
Oral
Visit 2, 4, 6
Experi-
mental
IMP
Local 
Sourcing
Concomitant-
Use Group
Experimental
IPV (Sabin 
strain based)
Biological
/Vaccine
Vial
0.5 mL per 
dose
3 doses
Intra-
muscular
Visit 2, 4, 6
Experi-
mental
IMP
Local
Sourcing
Staggered-
use Group
Active
Comparator
V260
Biological
/Vaccine
Sterile
Solution
2 mL per 
dose
3 doses
Oral
Visit 1, 3, 5
Experi-
mental
IMP
Local
Sourcing
Staggered-
use Group
Active
Comparator
IPV (Sabin 
strain based)
Biological
/Vaccine
Vial
0.5 mL per 
dose
3 doses
Intra-
muscular
Visit 2, 4, 6
Experi-
mental
IMP
Local
Sourcing
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (e.g., 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.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided 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.
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.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
The treatment/randomization number will be randomly assigned by an interactive response 
technology (IRT) system. The enrolled participants will be randomly assigned in a 1:1 ratio 
to either concomitant-use or staggered-use group.
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 vaccines administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified vaccination schedule (i.e. administration of 3 doses 
at scheduled time points) for reasons not defined in the protocol require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Blood products (including immunoglobulin), immunosuppressive therapies, systemic 
corticosteroids, and other investigational medications/vaccines that have not been licensed 
should not be administered prior to or during the study.
If blood products, immunosuppressive therapies or systemic corticosteroids are given after 
entry into the study because of medical circumstances, this should be entered on the 
appropriate CRFs.
Any rotavirus vaccine and poliovirus vaccine other than study vaccines should not be 
administered prior to or during the study.
There is generally no need for any restriction to the administration of other routine pediatric 
vaccines (including China Expanded Program of Immunization (EPI) or non-EPI vaccines)
during the study. See Section 8.1.8 for the recommendation on administration of other 
routine vaccines during the study.
The investigator or qualified designee will review prior and concomitant
medication/vaccination use and record the information on the appropriate eCRFs as follows:

Prior/Concomitant vaccinations will be collected from birth through the final visit of 
the study.
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
Prior/Concomitant medications will be collected for 15 days before and after each 
dose of study vaccines.
6.5.1
Rescue Medications and Supportive Care
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].
6.6
Dose Modification
Not applicable.
6.7
Intervention After the End of the Study
There is no study-specified intervention following 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
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of vaccination regimen will continue 
to participate in the study as specified in Section 1.3 and Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant’s legally acceptable representative requests to discontinue study 
intervention.
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
The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk 
from continued administration of study intervention.
Participants may be allowed to begin study intervention again if deemed medically 
appropriate with consultation from the Clinical Director of Sponsor.
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 8.1.9. 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.
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 
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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 utilized 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.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written 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 
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captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The 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.
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 written informed consent. At the time of intervention allocation
assigned to the participant, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
Medical history prior to enrollment will be obtained by the investigator or qualified designee
at Visit 1. Gestational age and birth weight will be collected from each participant at Visit 1. 
The status of infant feeding will be collected.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication and non-study 
vaccination, and record any prior medications taken by the participant for 15 days before 
starting the study and all prior non-study vaccinations from birth to starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record concomitant medication taken by the 
participant during 15 days before and after each study vaccination and non-study vaccination 
from Visit 1 through the final visit of the study.
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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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used 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 provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention will be witnessed by the investigator and/or study staff.
V260 should be administered within 30 minutes of removing it from refrigerator. The 
instruction of use is showed in China Package Circulars (CPCs) of V260 and IPV.
The first dose of study vaccines should be administered after collection of baseline blood 
samples prior to vaccination (see Section 8.2.1). 
Section 8.11.2 provides additional information on the prerequisites for vaccination visits.
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.
8.1.8.1
Timing of Dose Administration
In the concomitant-use group, each participant will receive 1 dose of V260 and IPV 
concomitantly at Visit 2, 4, and 6, respectively. In the staggered-use group, each participant 
will receive 1 dose of V260 at Visit 1, 3, and 5, respectively, and 1 dose of IPV at Visit 2, 4, 
and 6, respectively. See the SoA (Section 1.3) for the protocol pre-specified time windows of 
these vaccination visits. Missed study vaccination doses within the visit window should be 
completed as soon as possible.
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The first dose of V260 should be given by 12 weeks of age (84 days of age) and the third 
dose of V260 should be given by 32 weeks of age (224 days of age). The minimum and 
maximum interval between each dose of V260 should be 4 weeks (28 days) and 10 weeks 
(70 days), respectively.
The minimum age for the first dose of IPV should be 2 months of age. The minimum interval 
between each dose of IPV should be 1 month (30 days).
In the staggered-use group, the minimum interval between V260 and subsequent IPV should 
be 15 days.
Administration of approved routine pediatric vaccine (excluding rotavirus vaccine and polio 
vaccines other than study vaccines) is allowed in the study. It is recommended other routine 
vaccines (including EPI and non-EPI vaccines) be administered on the same day as V260 or 
IPV. 
If other routine vaccines are to be administered concomitantly with V260, V260 should be 
administered before administration of other vaccines to minimize crying and the chance of 
the participant spitting up V260.
If other routine vaccines are to be administered on different day of study vaccines, the 
interval between non-study and study vaccines should meet the prerequisites of vaccination 
visit (Section 8.11.2) or may be determined in accordance with the routine practice of study 
institution.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit (blood sample collection should not be done if 
the participant has not received all 3 doses of study vaccine) 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.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Not applicable.
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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
8.2.1
Serum Samples for Antibody Testing
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. For collection of the serum samples, the study sites must follow 
instructions provided by the Sponsor-designated Central Laboratory. Samples should be 
shipped, labeled, and handled as instructed by the Sponsor/Central Laboratory. 
In the concomitant-use group, at least 2.5 mL blood sample will be collected from each 
participant at Visit 1 (baseline sample prior to vaccination) and Visit 8 (1 month post dose 3 
of V260 and IPV), respectively.
In the staggered-use group, at least 2.5 mL blood sample will be collected from each 
participant at Visit 1 (baseline sample prior to vaccination); at least 1.5 mL blood sample will 
be collected from each participant at Visit 7 (1 month post dose 3 of V260) and Visit 8 (1 
month post dose 3 of IPV), respectively.
If the blood sample is not able to be obtained, it is recommended that the study visit should 
be rescheduled as soon as possible. 
Repeat or unscheduled samples may be taken for technical issues with the samples.
8.2.2
Immunoassays for Antibody Testing
The immunogenicity of IPV will be measured using poliovirus serum neutralizing antibody 
assay of NIFDC, Beijing, China. The purpose of this assay is to detect and quantify serum 
neutralizing antibodies against each of poliovirus types 1, 2, and 3 before and after 
vaccination with polio vaccines. This was the primary assay used by NIFDC to evaluate the 
serological response to polio vaccines. Results for the assay will be reported as titer.
The immunogenicity of V260 will be measured using anti-rotavirus type-specific IgA assay 
developed by NIFDC. The purpose of this assay is to detect and quantify anti-rotavirus IgA 
antibodies against each of human rotavirus serotypes G1, G2, G3, G4, and P1A[8]. This was 
one of the primary assays used by NIFDC to evaluate the serological response to rotavirus 
vaccines. Results for the assay will be reported as Units/mL.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
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) as per institutional standard at Visit 1. Height
and weight will also be measured at Visit 1.
A symptom/sign-directed physical examination will be conducted by an investigator or 
medically qualified designee (consistent with local requirements) per institutional standard at 
subsequent visits as needed.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Axillary Temperature Measurement
Pre-vaccination axillary temperature will be measured at Visit 1 and at subsequent study 
vaccination visits. Axillary is the only acceptable method of obtaining participant’s 
temperature in the study.
If the participant has a fever within the 24-hour period prior to vaccination, the vaccination 
should be rescheduled as soon as possible after the fever has resolved. For the purpose of this 
study, a fever is defined as an axillary temperature ≥37.5°C (or equivalent), in accordance 
with the local routine medical practice and China Regulatory Agency’s Guideline for 
Grading Scales of Adverse Events in Clinical Trials of Prophylactic Vaccines (see Section 
10.7 - Appendix 7: China-specific Requirements).
See Section 8.11.2 for other prerequisites for vaccination visit.
8.3.3
30-Minute Post-Vaccination Observation
All participants will be observed for at least 30 minutes after each study vaccination for any 
immediate untoward effects with particular attention to any evidence of allergic phenomena. 
This observation period will be documented in the participant’s study chart.
8.3.4
Vaccination Report Card
VRC will be provided to each participant’s legally acceptable representative at each study 
vaccination visit. 
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Participant’s legally acceptable representative will be instructed to record the following 
information:

Daily axillary temperature from Day 1 through Day 7 following each study 
vaccination (Temperature measurement must be recorded on the VRC if a fever is 
suspected during Day 8 through Day 30 [concomitant-use group] or Day 8 through 
Day 15 [staggered-use group]);

Solicited injection-site AEs (erythema, swelling, induration, and pain at the injection-
site of IPV) from Day 1 through Day 7 following each vaccination of IPV;

Solicited systemic AEs (diarrhea and/or vomiting) from Day 1 through Day 7 
following each study vaccination;

Any AEs from Day 1 through Day 30 (concomitant-use group) or from Day 1 through 
Day 15 (staggered-use group) following each study vaccination;

Any concomitant medications from Day 1 through Day 15 following each study 
vaccination (both vaccination groups).

Any non-study vaccinations from Day 1 through Day 30 (concomitant-use group) or
from Day 1 through Day 15 (staggered-use group) following each study vaccination; 

Any medications due to AE during Day 16 through Day 30 following each study 
vaccination (concomitant-use group only).
Although Visit 1 is not a vaccination visit for participants in the concomitant-use group, 
VRC will be provided to each participant’s legally acceptable representative to record any 
reportable safety events from randomization through the first study vaccination (See Section 
8.4.1 for safety reporting requirement).
At least one telephone contact will be conducted by investigator within 7 days after each visit
of VRC distribution to remind each participant’s legally acceptable representative to record 
the VRC and answer their any questions related to VRC.
In the concomitant-use group, the purpose of Visit 3, 5, and 7 is only to review VRCs, so out 
of windows of these visits will not be reported as a protocol deviation in this vaccination 
group.
8.3.5
Clinical Safety Laboratory Assessments
1.
There are no protocol specified laboratory assessments in this study.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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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.
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 consent form is signed 
but before randomization/allocation 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.
From the time of randomization/allocation through 30 days (concomitant-use group) or 15 
days (staggered-use group) following the first vaccination(s) and from the time of any 
subsequent vaccination(s) through 30 days (concomitant-use group) or 15 days (staggered-
use group) thereafter, all AEs, SAEs, and other reportable safety events must be reported by 
the investigator.
Additionally, SAE (regardless of causality) and intussusception (ECI) at any time outside of 
the time period specified in the previous paragraph also must be reported immediately to the 
Sponsor. Other reportable safety events (cancer and overdose) at any time outside of the time 
period specified in the previous paragraph should also be reported to the Sponsor.
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 in Table 2.
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Table 2
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:
Nonserious 
Adverse Event 
(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
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report all (Follow 
ongoing to outcome)
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report all
Report all
Within 24 
hours of 
learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Report all
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Report all
Within 5 
calendar days 
of learning of 
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 pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
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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 randomized 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.
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
Not applicable to this study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
a.
Intussusception: Any cases of intussusception during the entire study should be 
immediately reported to Sponsor (see Section 8.4.1 for safety reporting requirement).
8.5
Treatment of Overdose
In this study, an overdose is defined as receiving more than one dose of V260 within a 12-
day period. Any overdose should be reported to Sponsor (see Section 8.4.1 for safety 
reporting requirement).
Sponsor does not recommend specific treatment for an overdose.
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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
Future biomedical research 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
At Visit 1, if participant has a fever (axillary temperature ≥37.5°C or equivalent) within the 
24-hour period prior to vaccination, screening visit may be rescheduled after the fever has 
resolved.
Screening procedures may not be performed on the same day of ICF, but screening or 
rescreening visit should be on the same day as randomization. Screening procedures may be 
repeated after consultation with the Sponsor.
8.11.2
Vaccination Visit
This section summarizes prerequisites for visits with study vaccinations. Deviations from 
these prerequisites require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision.
See the inclusion/exclusion criteria for specific restrictions at Visit 1 (see Section 5.1 and
Section 5.2). At the subsequent vaccination visits, study personnel should verify by 
questioning the participant and/or by examination that: 
1. The participant has not had a fever (defined as an axillary temperature of ≥37.5°C or 
equivalent) within the 24-hour period prior to each vaccination visit.
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2. The participant has not received any systemic (oral, intravenous or intramuscular) 
corticosteroids within 2 weeks (14 days) prior to each vaccination visit.
3. The participant has not received a non-study inactivated or recombinant vaccine 
within 2 weeks (14 days) prior to each vaccination visit.
4. The participant has not received a non-study live vaccine within 4 weeks (28 days)
prior to each vaccination visit.
If the participant does not meet the requirements #1 or #2 listed above during study, the 
vaccination visit should be rescheduled as soon as possible.
It is recommended other routine vaccines be administered on the same day as V260 or IPV. 
If other routine vaccines are to be administered on different day of study vaccines, the 
interval between non-study and study vaccines should meet the requirements #3 and #4 listed 
above or may be determined in accordance with institutional guidance (see Section 8.1.8.1).
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study vaccinations but continue in the study may attend study 
visits per the SoA (Section 1.3). However, post-vaccination serum samples will not be 
collected from participants who have not completed the 3-dose regimen of study vaccination.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly 
identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.  
Study Design Overview
A Phase 3 Randomized, Open-Label, Clinical Trial to Study the 
Immunogenicity and Safety of Concomitant and Non-Concomitant 
Administration of V260 and Inactivated Poliomyelitis Vaccine (IPV) in 
Chinese Healthy Infants
Treatment Assignment
Participants will be randomly assigned in a 1:1 ratio to receive V260 and 
IPV in a concomitant-use or staggered-use schedule
Analysis Populations
Immunogenicity: Per-Protocol Immunogenicity (PPI) population
Safety: All Participants as Treated (APaT) population
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Primary Endpoint(s)
Immunogenicity:

Neutralizing antibody seroconversion percentages to each of 
poliovirus types 1, 2, and 3 at 1 month post dose 3 of IPV
Secondary Endpoints
Immunogenicity:

Neutralizing antibody geometric mean titers (GMTs) to each of 
poliovirus types 1, 2, and 3 at 1 month post dose 3 of IPV

Proportions of participants with neutralizing antibody titer ≥1:8 and 
≥1:64 at 1 month post dose 3 of IPV for each of poliovirus types 1, 
2, and 3
Safety:

Proportions of participants with solicited injection-site AEs 
(erythema, swelling, induration, and pain at the injection-site of 
IPV) from Day 1 through Day 7 following any vaccination of IPV

Proportions of participants with solicited systemic AEs (diarrhea 
and/or vomiting) from Day 1 through Day 7 following any 
vaccination of V260 and/or IPV

Proportions of participants with SAEs from Day 1 through end of 
study
Statistical Methods for Key 
Immunogenicity Analyses
For the primary hypothesis, concomitant-use group will be considered 
non-inferior to staggered-use group if the lower bound of the two-sided 
95% confidence interval (CI) for the difference in seroconversion 
percentage (concomitant-use group minus staggered-use group) is greater
than -10% for each poliovirus type.
Statistical Methods for Key 
Safety Analyses
All safety data will be summarized as frequencies and percentages for 
the two vaccination groups.
Interim Analyses
No interim analysis is planned.
Multiplicity
Since success is required on all 3 poliovirus types for the primary 
hypothesis, no multiplicity adjustment will be made for the multiple tests.
Sample Size and Power 
The planned sample size is 400 participants. For the seroconversion 
percentage to each of poliovirus types 1, 2, and 3 at 1 month post dose 3, 
the study has approximately an overall 90.0% power to demonstrate that 
the concomitant-use group is non-inferior to the staggered-use group at 
an overall one-sided 2.5% alpha-level, if the underlying treatment 
difference is 0 percentage points.
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 randomized, open-label study, i.e., participants, 
investigators, and SPONSOR personnel will be aware of participant treatment assignments 
after each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using an IRT.
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Immunogenicity and safety endpoints that will be evaluated or summarized are listed below.
9.4.1
Immunogenicity Endpoints
A description of immunogenicity assessments is presented in Section 4.2.1.1.
The primary immunogenicity analysis endpoints are neutralizing antibody seroconversion 
percentages to each of poliovirus types 1, 2, and 3 at 1 month post dose 3 of IPV. The 
seroconversion is defined as antibody titer ≥1:8 post-vaccination in baseline seronegative
participants or ≥4-fold increase in titer post-vaccination in baseline seropositive participants. 
The cut-off value determining baseline seropositivity is 1:8 for all 3 poliovirus types. 
Neutralizing antibodies to poliovirus types 1, 2, and 3 will be measured by the laboratory of 
NIFDC.
The secondary immunogenicity analysis endpoints include:

Neutralizing antibody GMTs to each of poliovirus types 1, 2, and 3 at 1 month post 
dose 3 of IPV.

Proportions of participants with neutralizing antibody titer ≥1:8 and ≥1:64 at 1 month
post dose 3 of IPV for each of poliovirus types 1, 2, and 3.
The exploratory immunogenicity analysis endpoints include:

Proportions of participants with ≥3-fold increase in anti-rotavirus type-specific IgA 
titer post-vaccination from baseline to serotypes G1, G2, G3, G4, and P1A[8] at 1
month post dose 3 of V260.

Anti-rotavirus type-specific IgA GMTs to serotypes G1, G2, G3, G4, and P1A[8] at 1
month post dose 3 of V260.
9.4.2
Safety Endpoints
A description of safety measures is presented in Section 4.2.1.2 and Section 8.3. The analysis 
of safety results is described in Section 9.6.2.
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs and post-vaccination temperature measurements following V260 and/or IPV.
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The safety analysis endpoints include:

Proportions of participants with solicited injection-site AEs (erythema, swelling, 
induration, and pain at the injection-site of IPV) from Day 1 through Day 7 post-
vaccination of IPV in the two vaccination groups

Proportions of participants with solicited systemic AEs (diarrhea and/or vomiting) 
from Day 1 through Day 7 post-vaccination of V260 and IPV in the concomitant-use 
group, and from Day 1 through Day 7 post-vaccination of V260 plus from Day 1 
through Day 7 post-vaccination of IPV in the staggered-use group

Proportions of participants with any injection-site AEs from Day 1 through Day 15
post-vaccination of V260 and IPV in the concomitant-use group, and from Day 1 
through Day 15 post-vaccination of IPV in the staggered-use group

Proportions of participants with any systemic AEs from Day 1 through Day 30 post-
vaccination of V260 and IPV in the concomitant-use group, and from Day 1 through 
Day 15 post-vaccination of V260 plus from Day 1 through Day 15 post-vaccination 
of IPV in the staggered-use group

Proportions of participants with any vaccine-related injection-site AEs from Day 1 
through Day 15 post-vaccination of V260 and IPV in the concomitant-use group, and 
from Day 1 through Day 15 post-vaccination of IPV in the staggered-use group

Proportions of participants with any vaccine-related systemic AEs from Day 1 
through Day 30 post-vaccination of V260 and IPV in the concomitant-use group, and 
from Day 1 through Day 15 post-vaccination of V260 plus from Day 1 through Day 
15 post-vaccination of IPV in the staggered-use group

Proportion of participants with any SAE, any AE which is both vaccine-related and 
serious, any AE resulting in discontinuation, and proportion of participants who died,
proportion of participants with intussusception during the entire study period in the 
two vaccination groups

Proportions of participants with maximum temperature measurements from Day 1 
through Day 7 post-vaccination of V260 and IPV in the concomitant-use group, and 
Day 1 through Day 7 post-vaccination of V260 plus Day 1 through Day 7 post-
vaccination of IPV in the staggered-use group
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
The Per-Protocol Immunogenicity (PPI) population will serve as the primary population for 
the analysis of immunogenicity data in this study. The PP population is defined as 
participants who receive the 3 scheduled doses of study vaccines, adhere to guidelines for 
administration of study vaccines, provide baseline and post-vaccination blood samples within 
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acceptable day range, and do not have important deviations from the protocol that may 
substantially affect the results of the primary endpoint.
The final determination on important protocol deviations, and thereby the composition of the
PP population, will be made prior to the final database lock.
Supportive analysis for primary immunogenicity objective will be performed on the full 
analysis set (FAS) of all participants who provide baseline and post dose 3 serum samples, 
regardless of protocol deviations.
Participants will be included in the treatment group to which they are randomized for the 
analysis of immunogenicity data using both the PP and FAS populations.  
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who receive at least one dose of study 
vaccination. Participants will be included in the group corresponding to the study vaccination
they actually received for the analysis of safety data using the APaT population.
At least one temperature measurement obtained subsequent to study intervention is required 
for inclusion in the analysis of temperature.
9.6
Statistical Methods
Statistical testing and inference for immunogenicity and safety analyses are described in 
Section 9.6.1 and Section 9.6.2, respectively. Unless otherwise stated, all statistical tests will 
be conducted at the α=0.025 (1-sided) level.
9.6.1
Statistical Methods for Immunogenicity Analyses
This section describes the statistical methods that address the primary and secondary 
immunogenicity objectives. Methods related to exploratory objectives will be described in 
the supplemental SAP.
Primary Endpoint
For the primary hypothesis, seroconversion percentage at 1 month post dose 3 of IPV will be 
analyzed separately for each of 3 poliovirus types. The statistical criterion for non-inferiority 
requires that the lower bound of two-sided 95% confidence interval of the difference in 
seroconversion percentages (concomitant-use group minus staggered-use group) be greater 
than -10% for each poliovirus type. The primary hypothesis will be considered a success if 
the non-inferiority criteria for the difference in seroconversion percentages are met for all 3 
poliovirus types in the comparisons between concomitant-use group vs. staggered-use group.  
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For each poliovirus type, the hypothesis to be tested at α=0.025 level (1-sided) are 
H0: p1-p2 ≤-0.1
Ha: p1-p2 > -0.1
where p1 is the true seroconversion percentage at 1 month post dose 3 in the concomitant-use
group and p2 is the true seroconversion percentage at 1 month post dose 3 in the staggered-
use group. The confidence interval will be calculated using the method proposed by
Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
Secondary Endpoints
For the proportion-type estimates of the secondary endpoints such as seroresponse rates of 
neutralizing antibodies to poliovirus types 1, 2, and 3, the 95% CIs of within each group will 
be provided and obtained by using exact binomial method proposed by Clopper and Pearson 
(1934) [Clopper, C. J. 1934]. 
The evaluation of IPV neutralizing antibody GMTs to each of poliovirus types 1, 2, and 3
will include descriptive summaries and within-group 95% CIs. Point estimates for the GMTs
will be calculated by exponentiating the estimates of the mean of the natural log values. The 
within-group CIs will be derived by exponentiating the CIs of the mean of the natural log 
values based on the t-distribution.
Summary statistical analysis will be provided for exploratory endpoints. Details will be 
described in the supplemental SAP.
Table 3 summarizes the key immunogenicity analyses.
Table 3
Analysis Strategy for Key Immunogenicity Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Primary Objectives
Neutralizing Antibody 
Seroconversion Percentages to 
Each of Poliovirus Types 1, 2, 
and 3 at 1 Month Post Dose 3 
of IPV (each type will be tested 
separately)
P
Point and 95% CI 
estimation as well as 
statistical testing of 
binomial proportion 
based on M & N 
method§
PP
Observed data 
only
Neutralizing Antibody 
Seroconversion Percentages to 
Each of Poliovirus Types 1, 2, 
and 3 at 1 Month Post Dose 3 
of IPV
S
Point and 95% CI 
estimation as well as 
statistical testing of 
binomial proportion 
based on M & N 
method§
FAS
Observed data 
only
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Secondary Objectives
Neutralizing Antibody GMTs to 
Each of Poliovirus Types 1, 2, 
and 3 at 1 Month Post Dose 3 of 
IPV
P/S
Point and 95% CI 
estimation based on t-
distribution of natural 
log values
PP/FAS
Observed data 
only
Proportions of Participants with 
Neutralizing Antibody Titer ≥ 
1:8 at 1 Month Post Dose 3 of 
IPV for Each of Poliovirus 
Types 1, 2, and 3
P/S
Point and 95% CI 
estimation based on 
exact method
PP/FAS
Observed data 
only
Proportions of Participants with 
Neutralizing Antibody Titer ≥ 
1:64 at 1 Month Post Dose 3 of 
IPV for Each of Poliovirus 
Types 1, 2, and 3
P/S
Point and 95% CI 
estimation based on 
exact method
PP/FAS
Observed data 
only
  † P=Primary approach; S=Supportive approach.
  ‡ Statistical models are described in further detail below:
  § Miettinen and Nurminen method.
    Exact binomial method proposed by Clopper and Pearson (1934).
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and post-vaccination temperature measurements.
An overall assessment of adverse events will be summarized for each group by dose period 
(dose period is defined in Table 4) and across all dose periods.
Table 4
Each Group by Dose Period
Dose Period
Concomitant-Use Group
(Vaccine administered)
Staggered-Use Group
(Vaccine administered)
1
Visit 2 (V260 + IPV)
Visit 1 (V260)
Visit 3
Visit 2 (IPV)
2
Visit 4 (V260 + IPV)
Visit 3 (V260)
Visit 5
Visit 4 (IPV)
3
Visit 6 (V260 + IPV)
Visit 5 (V260)
Visit 7
Visit 6 (IPV)
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Summary statistics, counts and percentage without confidence interval, will be provided by 
group. Proportions of participants with solicited injection-site AEs (following vaccination of 
IPV), solicited systemic AEs within 7 days following study vaccination will be given. 
Maximum axillary temperatures recorded on the VRC from Day 1 through Day 7 post-
vaccination will be summarized. Table 5 shows the safety endpoints that will be summarized.
Table 5
Analysis Strategy for Safety Parameters
Safety Endpoints
Time Period
Descriptive 
Statistics
Solicited Injection-Site AEs
Days 1-7 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-7 post-vaccination of 
IPV in the staggered-use group, across all dose periods
and by dose period
X
Solicited Systemic AEs
Days 1-7 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-7 post-vaccination of 
V260 plus Days 1-7 post-vaccination of IPV in the 
staggered-use group, across all dose periods and by dose 
period
X
Maximum Axillary 
Temperature
Days 1-7 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-7 post-vaccination of 
V260 plus Days 1-7 post-vaccination of IPV in the 
staggered-use group, across all dose periods and by dose 
period
X
Any Injection-Site AEs
Days 1-15 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-15 post-vaccination 
of IPV in the staggered-use group, across all dose periods
and by dose period
X
Any Systemic AEs
Days 1-30 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-15 post-vaccination 
of V260 plus Days 1-15 post-vaccination of IPV in the 
staggered-use group, across all dose periods and by dose 
period
X
Any Vaccine-related Injection-
Site AEs
Days 1-15 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-15 post-vaccination 
of IPV in the staggered-use group, across all dose periods
and by dose period
X
Any Vaccine-related Systemic 
AEs
Days 1-30 post-vaccination of V260 and IPV in the 
concomitant-use group, and Days 1-15 post-vaccination 
of V260 plus Days 1-15 post-vaccination of IPV in the 
staggered-use group, across all dose periods and by dose 
period
X
Discontinuation due to any AE
Entire Study Period by Vaccination Group
X
Any Serious AEs including 
Intussusception
Entire Study Period by Vaccination Group
X
X = results will be provided.
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To assess the severity of adverse events, both Sponsor’s criteria (see “Assessment of 
Intensity/Toxicity” in Section 10.3 - Appendix 3) and China Regulatory Agency’s criteria 
(see Section 10.7 - Appendix 7: Country-specific Requirements) will be applied. The 
incidence of greatest adverse event severity reported by a participant based on both the two 
criteria will be tabulated for: all injection-site AEs and all systemic AEs across all dose 
periods.
For the across dose-period summaries and analyses, if the same AE occurs multiple times
across dose periods, the AE will be counted once. In order to evaluate any additive safety
issues for the concomitant use of V260 and IPV compared to the staggered use of these
vaccines, the following summaries will also be provided: Frequencies and percentages of the
solicited systemic AEs during Days 1 to 7 after V260 concomitant with IPV in the 
concomitant-use group, during Days 1 to 7 after V260 alone in the staggered-use group, and 
during Days 1 to 7 after IPV alone in the staggered-use group.
Any injection-site AEs and vaccine-related injection-site AEs during Days 1 to 30 post-
vaccination of V260 and IPV in the concomitant-use group will be summarized separately.
Any reportable safety events collected between Visit 1 and 2 in the concomitant-use group 
will be listed separately.
For serious adverse events observed during the study, including intussusception, a detailed
description will be included in the CSR.
9.6.3
Demographic and Baseline Characteristics
The comparability of the groups for each relevant demographic and baseline characteristic 
will be assessed by the use of summary tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables (e.g., age, race, gender, birth weight [kg]), medical history, 
prior and concomitant vaccinations and therapies will be summarized by group either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
There will be no multiplicity adjustment. The success of the study requires demonstrating 
non-inferiority for all 3 of the poliovirus types described in the primary study hypothesis.
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9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for immunogenicity Analyses
This study will randomize 200 participants into the concomitant-use group and 200 into the 
staggered-use group and has approximately an overall 90.0% power to establish that the 
concomitant-use group is non-inferior to the staggered-use group in the seroconversion
percentage to IPV at 1 month post dose 3 at an overall one-sided, 2.5% alpha-level, if the 
underlying treatment difference is 0 percentage points. The power and sample size are based 
on the following assumptions:
1. There is no difference in the true seroconversion percentages for each poliovirus type 
at 1 month post dose 3 between the concomitant-use and staggered-use groups.
2. The true seroconversion rate for poliovirus types 1, 2, and 3 at 1 month post dose 3 of 
IPV is 96%, 93% and 97% respectively based on China local IPV studies.
3. The statistical criterion for non-inferiority requires that the lower bound of two-sided 
95.0% confidence interval for the difference (concomitant-use group minus 
staggered-use group) in seroconversion percentages be greater than -10% for each 
poliovirus type.
4. An 85% evaluability rate for primary immunogenicity analysis population.
Table 6
Sample Size and Power Calculated Based on Neutralizing Antibody 
Seroconversion Percentage Difference
Antigen
Seroconversion Percentages in 
Staggered-use Group
Enrolled Participants 
in Each Group
Effective 
Sample Size
Power
Poliovirus Type 1
96%
200
170
0.9842
Poliovirus Type 2
93%
200
170
0.9188
Poliovirus Type 3
97%
200
170
0.9953
Overall Power
0.900†
†Overall power is calculated by multiplying the power for each poliovirus type.
The calculation is based on the method proposed by Miettinen and Nurminen [Miettinen, O. 
and Nurminen, M. 1985] with 170 participants in both groups expected to be included in the 
analysis and is carried out using PASS 2008. The minimum criterion for success is that the 
lower bound of two-sided 95% CI of difference >-10%. Given the assumed seroconversion 
percentage of 95% in the staggered-use group, this may occur when the observed difference 
in response rates is approximately -3% or larger.
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9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least one SAE in this study depends on the number of
participants vaccinated and the underlying percentage of participants with a SAE in the study 
population. If the underlying incidence of a SAE is 1.7% (1 of every 59 participants 
receiving the vaccine), there is a 96.8% chance of observing at least one SAE among 200 
participants both in the concomitant-use group and in the staggered-use group. If no SAEs 
are observed among the 200 participants in any group, this study will provide 97.5% 
confidence that the underlying percentage of participants with SAE is <1.8% (one in every 
67 participants) in the group.  
The estimate of and the upper bound of the 95% confidence interval for the underlying 
percentage of participants with a SAE given various hypothetical observed number of 
participants with a SAE within the group are provided in Table 7. These calculations are 
based on the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 
1934].
Table 7
Estimate of Incidence of SAE and 95% Upper Confidence Bound Based on 
Hypothetical Number of Participants with SAE Among 200 Participants in the Group
Hypothetical Number of Participants
With SAE
Estimate of Incidence
95% Upper Confidence Bound†
1
0.5%
2.75%
5
2.5%
5.74%
10
5%
9.00%
20
10%
15.02%
40
20%
26.22%
† Based on the two-tailed exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
9.10
Subgroup Analyses
No subgroup analyses will be performed.
9.11
Compliance (Medication Adherence)
Compliance is defined in this study as receipt of all scheduled study vaccinations. To 
summarize compliance, the numbers and proportion of randomized participants who receive 
each vaccination will be tabulated.
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered V260 and the number and proportion of randomized participants 
administered IPV at each vaccination schedule.
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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 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
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.
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 fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees 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.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. 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.
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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, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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.
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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 prior to 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 
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
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 
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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 International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
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 trial 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.
10.1.6
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 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.
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.
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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.
10.1.7
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.
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 signed ICF, 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 
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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.
10.1.8
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.
10.1.9
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 protocol-specified clinical laboratory assessments in the study.
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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, 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 pre-existing 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.”
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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 pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
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:

Results in death

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.

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 pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.

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, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.

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
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 (e.g., 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 
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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/toxicity
•
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, awareness of 
symptoms, but easily tolerated).
- Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, 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 used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
•
Injection site erythema/redness or swelling from the day of vaccination through Day 7
postvaccination will be evaluated by maximum size.
•
The investigator will assess toxicity for each AE based on China Regulatory Agency’s 
criteria (see Section 10.7 - Appendix 7: Country-specific Requirements).
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 
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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.
•
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 
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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.
•
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).
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-
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).
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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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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10.7
Appendix 7: Country-specific Requirements
China Regulatory Agency’s Criteria on Assessment of Toxicity of Adverse Events
Guideline for Grading Scales of Adverse Events in Clinical Trials of Prophylactic 
Vaccines (Document No.: 2019#102)
(released on 26-DEC-2019, http://www.nmpa.gov.cn/WS04/CL2182/373037.html)
I. Foreword
Prophylactic vaccines (hereinafter referred to as the “vaccines”) refer to prophylactic 
biological products used for human immunization, including immunization-program vaccines 
and non-immunization-program vaccines, in order to prevent and control the occurrence and 
prevalence of diseases.
Clinical trials of vaccines should strictly comply with the Drug Administration Law of the 
People's Republic of China, the Vaccine Administration Law of the People's Republic of 
China, the Measures for Administration of Drug Registration, the Good Clinical Practice 
(GCP), the Technical Guideline for Vaccine Clinical Trials, and the Guideline for Good
Clinical Practice of Vaccine Clinical Trials (Trial Implementation). As vaccines are usually 
used for healthy population, mostly for healthy children or infants, healthy subjects will be 
generally selected for clinical trials at each stage. Therefore, the requirements for safety and 
risk control in vaccine clinical trials shall be more stringent than those for therapeutic drugs, 
and the strictest management system shall be implemented, with the continuous efforts paid 
for risk management and control through the whole period of study.
This Guideline provided grading scales for severity assessment of adverse events in vaccine 
clinical trials, in order for scientific monitoring and evaluation of vaccine-related adverse 
reactions by reasonable assessment and determination of the relationship between adverse 
events and vaccination, thus minimizing the risks of healthy subjects in clinical trials and use 
of vaccines.
The Guidelines is developed on the basis of the available regulations, the industrial 
standards, and the current scientific knowledge. The selected grading scales are based on the 
similar guidelines issued by overseas regulatory agencies and the industrial guidelines, 
considering China's clinical practice, and will be updated in due course with the continuous 
updates of relevant regulations, standards. and the increase of scientific knowledge.
II. Scope of Application
This Guideline is applicable to evaluation of the severity (i.e. intensity) of adverse events in 
vaccine clinical trials. Since the subjects of vaccine clinical trials may be adults, teenagers, 
children or infants, the severity of clinical symptoms, signs and laboratory examination
abnormalities in the trials shall be evaluated according to the physiological characteristics of 
different age groups. The grading scales can also be used as the emergency unblinding 
standards stipulated in the design of vaccine clinical trials and as the reference to determine 
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whether to suspend/terminate the clinical trials. Additionally, the standardized grading scales
of adverse events provided by the Guidelines are also conducive to the comparison of safety 
data within clinical trials or between different clinical trials.
III. Basic Contents
The grading scales of adverse events in vaccine clinical trials provided by the Guidelines 
include two parts: (1) clinical indicators (i.e. symptoms and signs, including adverse events at 
the vaccination site, vital signs and adverse events at the non-vaccination site); and (2)
laboratory testing indicators (i.e. blood biochemistry, blood routine examination, and urine 
routine examination, etc.). In clinical trials, appropriate indicators can be selected from the 
adverse event grading table of the Guidelines for safety monitoring and evaluation according 
to characteristics of vaccine, study population, and disease.
This Guidelines does not cover all safety indicators required to be observed in vaccine 
clinical trials. For new vaccines, new indicators may be monitored based on the safety 
findings from preclinical toxicological studies of vaccines or the experience from similar 
products. The rationale for the grading scales of new indicators should be clearly described
and explained in the protocol of clinical trial.
When the grading scales adopted in a clinical trial are inconsistent with this Guidelines due 
to the difference in observation or detection methods and new grading scales are to be 
developed, the rationale should be comprehensive and explained in the protocol of clinical
trial.
The safety indicators for children and infants included in the Guidelines are limited and could
be supplemented with new indicators according to the specific requirements for safety 
assessment of candidate vaccines.
(I) Adverse Event Grading Tables
In the monitoring of adverse events in vaccine safety trials, clinical symptoms and signs 
should be considered together with the corresponding laboratory testing results, and a 
comprehensive evaluation of causality should be carried out to obtain reliable conclusions.
During clinical trials, the detailed information of adverse events concerned should be 
recorded as much as possible, in addition to the recording and reporting of adverse events 
listed in the following tables.
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1. Clinical Observations Indicators (Table 8-Table 10)
Table 8
Grading Scales for Adverse Events at Vaccination Site (Local)
Symptoms
/Signs
Grade 1
Grade 2
Grade 3
Grade 4
Pain, Tenderness (selective; tenderness is used for subjects who are unable to express pain autonomously)
Pain
Does not affect or
slightly affects limb 
activity
Affects limb activity
Affects daily life
Loss of basic self-care 
ability or 
hospitalization
Tenderness
Resistance or flinch 
of body when being 
touched or pressed
Cry when being 
touched or pressed
but can be soothed
Cry continuously 
and unable to be 
soothed
Emergency treatment 
or hospitalization
Induration *, Swelling (selective) ** #
>14 years
old
With a diameter of 
2.5 ~ 5 cm or an 
area of 6.25 ~<25 
cm2 and does not 
affect or slightly
affects daily life
With a diameter of 5
~ <10 cm or an area 
of 25 ~<100 cm2 or
affects daily life
With a diameter of 
≥10 cm or an area of 
≥100 cm2 or causing 
fester or secondary 
infection or phlebitis 
or aseptic abscess or
wound drainage or 
significantly affects
daily life
Abscess, exfoliative 
dermatitis, dermal or 
deep tissue necrosis
≤14 years
old
With a diameter of
<2.5 cm
With a diameter of 
≥2.5 cm and an area 
that is less than 50% 
of the vaccinated limb 
(i.e. the limb where 
the vaccination site is 
located anatomically, 
such as the upper arm 
or thigh)
With an area that is 
more than 50% of 
the vaccinated limb
or causing fester or
secondary infection 
or phlebitis or
wound drainage
Abscess, exfoliative 
dermatitis, dermal or 
deep tissue necrosis
Rash*, Redness (selective) ** #
>14 years
old
With a diameter of 
2.5 ~ 5 cm or an 
area of 6.25~<25 
cm2 and does not 
affect or slightly
affects daily life
With a diameter of 5
~ <10 cm or an area 
of 25 ~ <100 cm2 or
affects daily life
With a diameter of 
≥10 cm or an area of 
≥100 cm2 or causing 
fester or secondary 
infection or phlebitis 
or aseptic abscess or
wound drainage or 
significantly affects
daily life
Abscess, exfoliative 
dermatitis, dermal or 
deep tissue necrosis
≤14 years
old
With a diameter of
<2.5 cm
With a diameter of 
≥2.5 cm and an area 
that is less than 50% 
of the vaccinated limb 
(i.e. the limb where 
the vaccination site is 
located anatomically, 
such as the upper arm 
or thigh)
With an area that is 
more than 50% of 
the vaccinated limb
or causing fester or
secondary infection 
or phlebitis or
wound drainage
Abscess, exfoliative 
dermatitis, dermal or 
deep tissue necrosis
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Symptoms
/Signs
Grade 1
Grade 2
Grade 3
Grade 4
Others
Pruritus
Pruritus at the 
vaccination site that 
resolves 
spontaneously or 
resolves within 48 
hours after 
treatment
Pruritus at the 
vaccination site that 
does not resolve
within 48 hours after 
treatment
Affects daily life
NA
Cellulitis
NA
Non-injection therapy 
(e.g. treatment with 
oral antibacterial, 
antifungal and 
antiviral drugs) is 
needed
Intravenous therapy 
(e.g. treatment with 
intravenous 
antibacterial, 
antifungal and 
antiviral drugs) is 
needed
Sepsis or tissue 
necrosis, etc
Note: *The progressive changes of measurement results shall be recorded as well in addition to direct diameter 
measurement for grading evaluation.
**The maximum size of diameter or area shall be used.
#The evaluation and grading of induration and swelling or rash and redness shall be based on the functional 
grade and actual measurement results, and the indicators with higher grading level shall be selected.
Table 9
Grading Scales for Vital Signs
Signs
Grade 1
Grade 2
Grade 3
Grade 4
Fever* (axillary temperature [℃])
>14 years old
37.3 ~<38.0
38.0 ~<38.5
38.5 ~<39.5
≥39.5, persists for 
more than 3 days
≤14 years old
37.5 ~<38.0
38.0 ~<39.5
≥39.5
≥39.5, persists for 
more than 5 days
Prolonged PR interval in electrocardiogram or atrioventricular conduction block (selective)
>16 years old
With a PR interval 
of 0.21 ~ 0.25 
seconds
With a PR interval 
of ≥0.25 seconds 
or second degree 
atrioventricular 
block of type I
With second degree 
atrioventricular 
block of type II or
ventricular interval 
of ≥3 seconds
Complete 
atrioventricular block
≤16 years old
With first degree 
atrioventricular 
block (PR interval > 
normal value 
among the 
population of the 
same age and type)
With second degree 
atrioventricular 
block of type I
With second degree 
atrioventricular 
block of type II or
ventricular interval 
of ≥3 seconds
Complete 
atrioventricular block
Heart rate
Tachycardia 
(beats/minute)
101 ~ 115
116 ~ 130
>130
Arrhythmia requires 
emergency treatment 
or hospitalization.
Bradycardia 
(beats/minute)
50 ~ 54
45 ~ 49
<45
Arrhythmia requires 
emergency treatment 
or hospitalization.
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Signs
Grade 1
Grade 2
Grade 3
Grade 4
Blood 
pressure
Hypertension (mmHg)
≥18 years old
Systolic blood 
pressure: 140 ~< 
160 or diastolic 
pressure: 90 ~<100
Systolic blood 
pressure: ≥160
~<180 or diastolic 
pressure: ≥100
~<110
Systolic blood 
pressure: ≥180 or
diastolic pressure:
≥110
Occurrence of life-
threatening 
complications that 
was not diagnosed 
previously (e.g. 
malignant 
hypertension) or
hospitalization
<18 years old
Systolic blood 
pressure: >120
~<152 or diastolic 
pressure: >80 ~<95
Systolic blood 
pressure: ≥152
~<178 or diastolic 
pressure:
≥95 ~<109
Systolic blood 
pressure: ≥178 or
diastolic pressure:
≥109
Occurrence of life-
threatening 
complications that 
was not diagnosed 
previously (e.g. 
malignant 
hypertension) or
hospitalization
Hypotension
(systolic blood 
pressure)
(mmHg)
85 ~<89
80 ~<85
<80
shock or 
hospitalization
Respiration 
frequency 
(times/minute)
17 ~ 20
21 ~ 25
>25
Tracheal intubation is 
needed
Note: *Axillary temperature is usually measured in China and can be converted into oral temperature and rectal 
temperature if necessary. Generally, oral temperature = axillary temperature + 0.2℃; and rectal temperature = 
axillary temperature + (0.3~0.5℃). In the event of sustained high fever, the cause of high fever shall be 
determined as soon as possible.
Table 10
Grading Scales for Adverse Events at Non-vaccination Site (Systemic)
Symptoms/
Signs by 
Organ System
Grade 1
Grade 2
Grade 3
Grade 4
Gastrointestinal system
Diarrhea
Mild or transient, 3 
~ 4 times/day, 
abnormal fecal 
characteristics, or 
mild diarrhea 
lasting for less than 
1 week
Moderate or 
persistent, 5 ~ 7 
times/day, abnormal 
fecal characteristics, 
or diarrhea lasting 
for more than 1 
week
> 7 times/day, 
abnormal fecal
characteristics, or
bloody diarrhea, 
orthostatic 
hypotension, 
electrolyte 
imbalance, requires 
intravenous 
infusion of > 2L
Hypotensive shock, 
hospitalization is 
needed
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Symptoms/
Signs by 
Organ System
Grade 1
Grade 2
Grade 3
Grade 4
Constipation*
Requires fecal 
softener and dietary 
adjustment
Requires treatment 
with laxative drug
Intractable 
constipation that 
requires manual 
dredging or use of 
enema
Toxic megacolon or 
intestinal obstruction
Dysphagia
Mild discomfort 
when swallowing
Eating and drinking 
behavior is 
restricted
Eating and drinking 
behavior and 
conversation are 
significantly 
restricted; unable to
eat solid food
Unable to eat liquid 
food; requires 
intravenous nutrition
Anorexia
Loss of appetite but 
no reduction in food 
intake
Loss of appetite, 
reduction in food 
intake, but no 
significant 
reduction in body 
weight
Loss of appetite and 
significant weight 
loss
Requires 
intervention (such as 
gastric tube feeding 
and parenteral 
nutrition)
Vomiting
1 ~ 2 times /24 
hours, and does not 
affect daily 
activities
3 ~ 5 times /24 
hours or affects
daily activities
>6 times within 24 
hours or requires 
intravenous fluid 
infusion
Hospitalization due 
to hypotensive shock
or nutrition through 
other routes needed 
Nausea
Transient (< 24 
hours) or
intermittent with 
normal food intake
Persistent nausea 
leads to reduction in
food intake (24-48 
hours)
Persistent nausea 
leads to being 
impossible to intake 
any food (> 48 
hours), or requires 
intravenous fluid 
infusion
Life-threatening (e.g. 
hypotensive shock)
Musculoskeletal and connective tissues
Myalgia (non-
vaccination 
site)
Does not affect 
daily activities
Slightly affects 
daily activities
Severe muscle pain, 
significantly affects 
daily activities
Emergency treatment 
or hospitalization
Arthritis
Mild pain, with 
inflammation, 
erythema or joint 
swelling; but does 
not impair the 
function
Moderate pain, with 
inflammation, 
erythema or joint 
swelling; impairs 
function, but does 
not affect daily 
activities
Severe pain, with 
inflammation, 
erythema or joint 
swelling; affects
daily activities
Permanent and/or 
disabling joint 
injuries
Joint pain
Mild pain, does not 
impair function
Moderate pain; 
requires treatment 
with analgesics 
and/or the pain 
impairs function, 
but does not affect
daily activities
Severe pain; 
requires treatment 
with analgesics,
and/or the pain 
affects daily 
activities
Disabling pain
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Symptoms/
Signs by 
Organ System
Grade 1
Grade 2
Grade 3
Grade 4
Nervous system
Headache
Does not affect 
daily activities, 
does not require 
treatment
Transient, slightly 
affects daily 
activities, may need 
treatment or 
intervention
Significantly affects 
daily activities, 
requires treatment 
or intervention
Refractory, requires 
emergency treatment 
or hospitalization
Syncope
Close to syncope 
without loss of 
consciousness (e.g. 
foreboding of 
syncope)
Loss of 
consciousness but 
does not require 
treatment
Loss of 
consciousness, 
requires treatment 
or hospitalization
NA
New onset of convulsion
≥18 years old
NA
NA
1 ~ 3 times.
Long-lasting and 
multiple convulsions 
(e.g. under persistent 
state of convulsion) 
or uncontrollable 
(e.g. intractable 
epilepsy)
<18 years old
The duration of 
convulsion is less 
than 5 minutes, and 
the post-convulsion 
state lasts for less 
than 24 hours
The duration of 
convulsion is ≥5
~<20 minutes, and 
the post-convulsion 
state lasts for less 
than 24 hours
The duration of 
convulsion is ≥20 
minutes, or the 
post-convulsion 
state lasts for more
than 24 hours
Long-lasting and 
multiple convulsions 
(e.g. under persistent 
state of convulsion) 
or uncontrollable 
(e.g. intractable 
epilepsy)
Respiratory system
Cough
Transient, does not 
require treatment
Persistent, treatment 
is effective
Paroxysmal, not 
controlled by 
treatment
Requires emergency 
treatment or 
hospitalization
Acute 
bronchospasm
Transient, does not 
require treatment; 
FEV1%: 70%~80%
Requires treatment; 
returning to normal 
after treatment with 
bronchiectasis 
agent; FEV1%: 
50%~70%
Unable to return to 
normal after 
treatment with 
bronchiectasis 
agent; FEV1: 
25%~50%, or 
continuous 
depression between 
ribs 
Cyanopathy;
FEV1%<25%; or 
requires tracheal 
intubation
Dyspnea
Difficulty in 
breathing during 
exercise
Difficulty in 
breathing during 
normal activities
Difficulty in 
breathing during 
rest
Difficulty in 
breathing, requires 
oxygen-inhaling
therapy, 
hospitalization or 
assisted breathing 
treatment
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Symptoms/
Signs by 
Organ System
Grade 1
Grade 2
Grade 3
Grade 4
Skin and subcutaneous tissue
Pruritus at non-
vaccination 
sites (no skin 
damage)
Mild pruritus, does 
not affect or slightly 
affects daily life
Pruritus that affects 
daily life
Pruritus that 
prevents daily life
NA
Abnormal skin 
mucosa
Erythema/pruritus/c
olor change
Diffuse rash/
maculopapule/
dryness/desquamati
on
Blister/exudation/de
squamation/ulcer
Exfoliative 
dermatitis that 
involves mucosa, or 
erythema 
multiforme, or 
suspected Stevens-
Johnsons syndrome.
Mental system
Insomnia*
Mild difficulty in 
falling asleep, does 
not affect or slightly 
affects daily life
Moderate difficulty 
in falling asleep, 
affects daily life
Severe difficulty in 
falling asleep, 
significantly affects 
daily life, requires 
treatment or 
hospitalization
NA
Irritable or 
depressed
Mild irritable or
depressed
Irritable or lethargic
Unable to soothe or
unresponsive
NA
Mental 
disorders 
(including 
anxiety, 
depression, 
mania and 
insanity), and 
detailed 
symptoms shall 
be reported
Mild symptoms that 
does not require 
clinic visit, or the 
behavior does not 
affect or slightly 
affects daily life
With clinical 
symptoms, requires 
clinic visit, or the 
behavior affects
daily life
Requires 
hospitalization, or
unable to perform 
daily life
With the tendency to 
hurt him/herself or
others, acute mental 
disorder or loss of 
basic self-care ability
Immune system
Acute allergic 
reaction**
Local urticaria 
(blister), does not 
require treatment
Local urticaria, 
requires treatment, 
or mild 
angioedema, does 
not require 
treatment
Extensive urticaria 
or angioedema that 
requires treatment, 
or mild 
bronchospasm
Anaphylactic shock, 
life-threatening 
bronchospasm or
laryngeal edema
Others
Fatigue
Does not affect 
daily activities
Affects daily 
activities
Significantly affects 
daily activities, 
unable to work
Requires emergency 
treatment or 
hospitalization
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Symptoms/
Signs by 
Organ System
Grade 1
Grade 2
Grade 3
Grade 4
Pain at non-
vaccination site
# (The location 
of pain should 
be specified 
when 
reporting)
Mild pain, does not 
affect or slightly 
affects daily life
Pain that affects 
daily life
Pain that prevents 
daily activities
Disabling pain, 
causing loss of basic 
self-care ability
Note: FEV1% refers to forced expiratory volume (FEV1)/ forced vital capacity (FVC) for one second.
* In the event of constipation and insomnia, attention shall be paid to changes before and after vaccination.
**It refers to type-I hypersensitivity.
# It refers to pain in non-vaccinated sites in addition to muscle pain, arthralgia and headache.
2. Laboratory Indicators (Table 11~Table 13)
When laboratory indicators are used for safety evaluation, it is necessary to consider the 
update of testing technology and methods currently used in clinical practice in addition to the 
industrial scientific standards. Therefore, the rationale for selection of indicators and grading 
scales should be comprehensive and explained in the protocol of clinical trial, i.e. it should 
conform to the normal range of scandalized or recognized physiological and biochemical 
limits to prove its rationality and feasibility. The indicators listed below are provided for 
reference only.
Laboratory test results between the upper limit (ULN) or lower limit (LLN) of the reference 
range and Grade 1 will not be reported as adverse events.
Table 11
Grading Scales for Blood Biochemistry Measurements
Indicators
Grade 1
Grade 2
Grade 3
Grade 4
Liver function
(elevated ALT, 
AST)
1.25 ~ <2.5 ×ULN
2.5~ <5.0×ULN
5.0~ <10×ULN
≥10×ULN
Elevated total bilirubin (mg/dL; µmol/L)
>28 days of age
1.1~ <1.6×ULN
1.6~ <2.6×ULN
2.6 ~ 5.0×ULN
≥5.0×ULN
7 ~ <28 days of 
age 
(Breastfeeding)
5 ~ <10
85.5 ~ <171
10 ~ <20
171 ~ <342
20 ~ <25
342 ~ <427.5
≥25
≥427.5
7 ~ <28 days of 
age
(Non-
Breastfeeding)
1.1 ~ <1.6×ULN
1.6 ~ <2.6×ULN
2.6 ~ 5.0×ULN
≥5.0×ULN
72 hours ~ <7
days of age
11 ~ <16
188.1 ~ <273.6
16 ~ <18
273.6 ~ <307.8
18 ~ <24
307.8 ~ <410.4
≥24
≥410.4
48 ~ <72 hours
of age
8.5 ~ <13
145.5 ~ <222.3
13 ~ <15
222.3 ~ <256.5
15 ~ <22
256.5 ~ <376.2
≥22
≥376.2
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Indicators
Grade 1
Grade 2
Grade 3
Grade 4
24 ~ <48 hours 
of age
5 ~ <8
85.5 ~ <136.8
8 ~ <12
136.8 ~ <205.2
12 ~ <19
205.2 ~ <324.9
≥19
≥324.9
<24 hours of 
age
4 ~ <7
68.4 ~ <119.7
7 ~ <10
119.7 ~ <171
10 ~ <17
171 ~ <290.7
≥17
≥290.7
Pancreatin 
(amylase, 
lipase)
1.1 ~ <1.5×ULN
1.5 ~ <3.0×ULN
3.0 ~ <5.0×ULN
≥5.0×ULN
Creatine 
phosphokinase 
(CPK)
1.25 ~ <1.5×ULN
1.5 ~ <3.0×ULN
3.0 ~ <10×ULN
≥10×ULN
Hypernatremia 
(Na, mmol/L)
146 ~ <150
150 ~ <154
154 ~ <160
≥160
Hyponatremia 
(Na, mmol/L)
130 ~ <135
125 ~ <130
121 ~ <125
≤120 
Hyperkalemia 
(K, mmol/L)
5.6 ~ <6.0
6.0 ~ <6.5
6.5 ~ <7.0
≥7.0 
Hypokalemia 
(K, mmol/L)
3.0 ~ <3.4
2.5 ~ <3.0
2.0 ~ <2.5 
<2.0
Hypercalcemia (Ca, mmol/L)
≥7 days of age
2.65 ~ <2.88
2.88 ~ <3.13
3.13 ~ <3.38
≥3.38
<7 days of age
2.88 ~ <3.10
3.10 ~ <3.23
3.23 ~ <3.38
≥3.38
Hypocalcemia (Ca, mmol/L)
≥7 days of age
1.95 ~ <2.10
1.75 ~ <1.95
1.53 ~ <1.75
<1.53
<7 days of age
1.63 ~ <1.88
1.50 ~ <1.63
1.38 ~ <1.50
<1.38
Hyperglycemia (Glu, mmol/L)
Fasting
6.11 ~ <6.95
6.95 ~ <13.89
13.89 ~ <27.75
≥27.75
Non-fasting
6.44 ~ <8.89
8.89 ~ <13.89
13.89 ~ <27.75
≥27.75
Hypoglycemia (Glu, mmol/L)
≥1 month of 
age
3.05 ~ <3.55
2.22 ~ <3.05
1.67 ~ <2.22
<1.67
<1 month of 
age
2.78 ~ <3.00
2.22 ~ <2.78
1.67 ~ <2.22
<1.67
Note: ULN refers to the upper limit of the normal range.
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Table 12
Grading Scales for Blood Routine Examinations
Indicators 
/Grading
Grade 1
Grade 2
Grade 3
Grade 4
White blood cell 
count increased
(WBC, 109/L)
11 ~ <13
13 ~ <15
15 ~ <30
≥30
White blood cell count decreased (WBC，109/L)
>7 days of age
2.000 ~ 2.499
1.500 ~ 1.999
1.000 ~ 1.499
<1.000
≤7 days of age
5.500 ~ 6.999
4.000 ~ 5.499
2.500 ~ 3.999
<2.500
Lymphocyte 
count decreased
(LY, 109/L)
0.75 ~ 1.00
0.5 ~ 0.749
0.25 ~ 0.49
<0.25
Neutrophil count decreased (ANC，109/L)
>7 days of age
0.800 ~ 1.000
0.600 ~ 0.799
0.400 ~ 0.599
<0.400
2 ~ 7 days of age
1.250 ~ 1.500
1.000 ~ 1.249
0.750 ~ 0.999
<0.750
≤1 day of age
4.000 ~ 5.000
3.000 ~ 3.999
1.500 ~ 2.999
<1.500
Eosinophilic 
granulocyte 
(Eos, 109/L)
0.65 ~ 1.5
1.51 ~ 5.0
>5.0
Hypereosinophilic 
syndrome
Thrombocytopenia (PLT, 109/L)
>12 years old
125 ~ 140
100 ~ 124
25 ~ 99
<25
>3 months ～
≤12 years old
NA
50 ~ 75 
25 ~ 49
<25
Low hemoglobin (g/dL)
≥13 years old,
male
10.0 ~ 10.9
9.0 ~ <10.0
7.0 ~ <9.0
<7.0
≥13 years old, 
female
9.5 ~ 10.4
8.5 ~ <9.5
6.5 ~ <8.5
<6.5
57 days~ <13
years of age
(both male and 
female)
9.5 ~ 10.4
8.5 ~ <9.5
6.5 ~ <8.5
<6.5
36 days ~ 56
days of age
(both male and 
female)
8.5 ~ 9.6
7.0 ~ <8.5
6.0 ~ <7.0
<6.0
22 days ~ 35
days of age
(both male and 
female)
9.5 ~ 11.0
8.0 ~ <9.5
6.7 ~ <8.0
<6.7
8 days ~ 21 days
of age
(both male and 
female)
11.0 ~ 13.0
9.0 ~ <11.0
8.0 ~ <9.0
<8.0
≤7 days of age
(both male and 
female)
13.0 ~ 14.0
10.0 ~ <13.0
9.0 ~ <10.0
<9.0
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Table 13
Grading Scales for Urine Routine Examinations
Indicators
Grade 1
Grade 2
Grade 3
Grade 4
Urine protein (PRO)
(by urine test strip)
1+
2+
3+ or higher
NA
Urine sugar
(by urine test strip)
Trace ~ 1+
or ≤250 mg
2+
or >250 ~ ≤500
mg
>2+
or>500 mg
NA
Erythrocytes 
(microscopic 
examination)
(red blood cell count 
[rbc/hpf] in each high 
power field [excluding 
results during female 
menstruation])
6 ~ <10
≥10
Visible hematuria 
with or without 
blood clots; cylinder 
shape of urine red 
blood cell; or
treatment needed
Emergency 
treatment or
hospitalization
(II) General principles of Grading Scales for Other Adverse Events
The intensity evaluation should be made according to the following grading scales for other
adverse events that are not listed in the tables above.
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Mild: short-term 
(<48h) or mild 
discomfort, does 
not affect daily
activities, does 
not require 
treatment
Moderate: mildly or 
moderately affects 
daily activities, 
requires clinic visit, 
requires no or a little 
medical intervention
Severe: significantly 
affects daily 
activities, requires 
clinic visits and 
treatment, may 
require 
hospitalization
Critical: possibly
threatening life, 
extremely affects 
daily activities, 
requires intensive 
care
Death
Rare adverse events related to vaccination (i.e. rare adverse reactions) usually can be found 
in clinical trials with a large sample size or in large population after launch, therefore, it 
sometimes needs further evaluation in post-marketing studies. For vaccines whose primary 
target population is healthy population including infants, the safety requirements are stricter 
than those for other drugs. In pre-marketing clinical trials, the sample size shall be enlarged 
as much as possible in order to find signals of rare risk related to vaccination. When 
necessary, clinical trials with safety observation indicators as clinical evaluation endpoints 
can be conducted, and the minimum sample size should meet the statistical requirements of 
safety studies.
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(III) Causality Evaluation and Safety Report
The clinical safety monitoring should focus on the evaluation of relationship between adverse 
events and investigated vaccines, and the special attention should be paid to serious adverse 
reactions related to vaccination. During clinical trials, Suspected Unexpected Serious 
Adverse Reactions (SUSAR) and Drug Safety Update Report (DSUR) during clinical 
programs should be reported in a timely manner according to ICH.
Reference
1. The Standing Committee of the National People's Congress. Vaccine Administration Law 
of the People's Republic of China. June 29, 2019.
(http://www.npc.gov.cn/npc/c30834/201907/11447c85e05840b9b12c62b5b645fe9d.shtml)
2. ICH.E2A-E2F. (https://www.ich.org/products/guidelines/efficacy/article/efficacy-
guidelines.html)
3. NMPA (formerly CFDA). CDE. E2A - E2F Pharmacovigilance/ Pharmacovigilance 
(Chinese Version). (http://www.cde.org.cn/guide.do?method=getIchTypeList&type1=3)
4. WHO. Guidelines on clinical evaluation of vaccines: regulatory expectations; TRS 1004, 
Annex9, June 2017. 
(https://www.who.int/biologicals/expert_committee/WHO_TRS_1004_web_Annex_9.pdf
?ua=1)
5. FDA. Toxicity Grading Scale for Healthy Adult and Adolescent  Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, September 2007. 
(http://www.fda.gov/cber/gdlns/toxvac.pdf)
6. NIH. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, July 2017. (https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
event-grading-tables)
7. NMPA (formerly CFDA). CDR. Brochure for Adverse Drug Reaction Reporting and 
Monitoring, November 2012. (http://www.cdr-
adr.org.cn/xzzx/hyzl/hyzl2013nd/201304/W020130426419851149382.pdf)
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Health). Measures for Administration of Adverse Drug Reaction Reporting and 
Monitoring (Ministry of Health Order No.81), May 04, 2011.
(http://www.nhc.gov.cn/xxgk/pages/viewdocument.jsp?dispatchDate=&staticUrl=/zwgkzt
/wsbysj/201105/51770.shtml&wenhao)
9. NMPA (formerly CFDA). Notice about the Issuance of Administrative Provisions on 
Serious Adverse Events Reporting of Vaccine Clinical Trials by Food and Drug 
Administration (Trial) (CFDA Chemical Administration No.6 [2014]), January 17, 2014.
(http://samr.cfda.gov.cn/WS01/CL0844/96405.html)
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10. NMPA (formerly CFDA). Guideline for Grading of Adverse Reactions in Clinical Trials 
of Prophylactic Vaccines. October 14, 2005.
(http://samr.cfda.gov.cn/WS01/CL1616/83435.html)
11. NMPA (formerly CFDA). Technical Guideline for Vaccine Clinical Trials (to be 
updated). December 03, 2004. (http://samr.cfda.gov.cn/WS01/CL1616/83398.html)
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
All Participants as Treated
CAC
Clinical Adjudication Committee
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CPC
China Package Circular
CRF
Case Report Form 
CSR
Clinical Study Report
DMC
Data Monitoring Committee 
DTaP
diphtheria, tetanus toxoids and acellular pertussis
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FDA
The United States Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
GCP
Good Clinical Practice 
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GMT
geometric mean titer
HBV
Hepatitis B virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug 
IPV
Inactivated Poliomyelitis Vaccine
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application 
NIFDC
National Institutes for Food and Drug Control
PPI
per-protocol immunogenicity
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCID
severe combined immunodeficiency disease
sIPV
Sabin-IPV
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
tOPV
trivalent oral poliomyelitis vaccine
VRC
Vaccination Report Card
VS
vital sign
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11
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