A Phase III Open-label Safety and Immunogenicity Study of GARDASIL™9 Administered to 9- to 26-Year-Old Females and Males in Vietnam
Phase: PHASE3
Conditions: Papillomavirus Infections, Uterine Cervical Neoplasms, Vulvar Neoplasms, Vaginal Neoplasms, Adenocarcinoma in Situ, Condylomata Acuminata
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03546842 
Document Date: 
19-DEC-2017
A Phase III Open-label Safety and Immunogenicity Study of
GARDASIL™9 Administered to 9- to 26-Year-Old Females and 
Males in Vietnam

Product:  V503 
1
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: A Phase III Open-label Safety and Immunogenicity Study of 
GARDASIL™9 Administered to 9- to 26-Year-Old Females and Males in Vietnam
Protocol Number: 017-01
Compound Number: V503
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   Not Applicable
EudraCT NUMBER: 2017-001205-33
Approval Date:  19-Dec-2017
 
 
04TB5P
 
 
059WL7

Product:  V503 
2
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
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
 
 
04TB5P
 
 
059WL7

Product:  V503 
3
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 01
Overall Rationale for the Amendment:
Sections and text pertaining to Future Biomedical Research samples have been removed in response to a request by the applicable 
ethics committee.  Text regarding pregnancies has been revised in order to clarify that outcomes for pregnancies is applicable only to 
those participants who received any study vaccine.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Title
9-Valent HPV/ 9vH vaccine GARDASIL™9 
Safety, Tolerability and Immunogenicity
Brand name replaced generic designation in 
the title
The term “tolerability” has been removed as 
“safety” is a more generic term (see next row)
Throughout
The word tolerability has been removed
(eg, “safety and tolerability” now reads simply “safety”)
The term “tolerability” has been removed as 
“safety” is a more generic term to use for 
assessing adverse events (AEs) to include 
injection-site AEs, systemic AEs, and 
vaccine-related serious AEs (SAEs)
Overall Design
Multi single-site
The study is to be conducted at a single site
2. 
Schedule of Activities 
(SoA)
Removed text regarding informed consent for and collection 
of blood samples for Future Biomedical Research
Future Biomedical Research samples will no 
longer be collected in this study
4. 
Objectives/Hypotheses 
and Endpoints
“3” had been added after the word “Dose” in the endpoint 
for the primary objective, so that it now reads “Dose 3”
Correcting of inadvertent typographical 
omission in original protocol document
 
 
04TB5P
 
 
059WL7

Product:  V503 
4
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Section # and Name
Description of Change
Brief Rationale
5.1 
Overall Design
“in vaccinated subjects” added to last sentence about 
pregnancies, so that it now reads “Pregnancies and any 
associated AEs in vaccinated subjects will be followed to 
outcome”
To clarify that outcomes for pregnancies is 
applicable only to those participants who 
received any study vaccine
5.4.2 
Future Biomedical 
Research
The entire section and associated text has been removed
Sections and text pertaining to Future 
Biomedical Research samples have been 
removed in response to a request by the 
applicable ethics committee
6.1 
Inclusion Criteria
In inclusion criterion 8, the following text has been 
removed:
The participant (or, for minor participants, the parent/legal 
guardian and participant) may also provide consent/assent 
for Future Biomedical Research.  However, the participant 
may participate in the main study without participating in 
Future Biomedical Research.
To account for the removal of Future 
Biomedical Research blood sample collection 
from this study
8.3 
Lost to Follow Up
The following last/third bullet/text has been removed: 
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 pre-
specified statistical data handling and analysis guidelines
For clarification the text was removed because 
the first statement is not always the case.  The 
subject may be considered lost to follow up 
earlier than their scheduled last visit if the site 
is unsuccessful at contacting the subject after 
repeated attempts.
9. 
Study Assessments 
and Proceedures
The maximum amount of blood collected from each 
participant has been changed from 20 mL to 14 mL
To account for the removal of Future 
Biomedical Research blood sample collection 
from this study
 
 
04TB5P
 
 
059WL7

Product:  V503 
5
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Section # and Name
Description of Change
Brief Rationale
9.1.1.2 
Consent/Assent and 
Collection of 
Specimens for Future 
Biomedical Research
The entire section and associated text has been removed
Sections and text pertaining to Future 
Biomedical Research samples have been 
removed in response to a request by the 
applicable ethics committee
9.2.1. 
Serum for Anti-HPV 
Antibody Testing
Amount of blood needed for anti-HPV specimen has been 
changed from 10 mL to 7 mL
Minimum amount of serum to be aliquoted has been 
changed from 3.0 mL to 2.0 mL
The additional amount of serum (“retention serum” was 
changed from 1.5 mL to approximately 0.8 mL
The following bulleted text has been removed:
Serum may also be used during the clinical trial, for further 
HPV immunologic testing in addition to tests specified in 
the protocol.
and
After the end of study (final report of study results), 
additional testing outside that specified in the protocol may 
be conducted on leftover samples
Correction of the amounts of blood and serum 
needed, as well as removal of text regarding 
alternative uses of the samples 
9.3.1 
Time Period and 
Frequency for 
Collecting AE, SAE 
and Other Reportable 
Safety Event 
Information
The following text has been removed:
In addition, SAEs (regardless of causality), cancer, 
overdose, pregnancy, exposure during breast feeding, and 
infant SAEs are reportable for the entire study period
This text has been removed in order that the 
text is now more consistent with standard 
template text
 
 
04TB5P
 
 
059WL7

Product:  V503 
6
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Section # and Name
Description of Change
Brief Rationale
Table 2
Reporting Time 
Periods and 
Timeframes for 
Adverse Events and 
Other Reportable 
Safety Events
The following text has been added to the row pertaining to 
Pregnancy/Lactation Exposure:
“(if the participant received at least 1 vaccine dose and 
became pregnant)”
To clarify that outcomes for pregnancies is 
applicable only to those participants who 
received any study vaccine
9.3.3 
Follow-up of AE, SAE 
and Other Reportable 
Safety Event 
Information
The following text has been added:
“(if the participant received at least 1 vaccine dose)”
To clarify that outcomes for pregnancies is 
applicable only to those participants who 
received any study vaccine
9.3.5 
Disease-Related 
Events and/or Disease-
Related Outcomes not 
Qualifying as AEs or 
SAEs
Section added, with the following text:
“Not Applicable” 
This section has been included in order that 
the document structure is now more consistent 
with standard template text
9.3.6 
Pregnancy and 
Exposure During 
Breastfeeding
Section number revised from 9.3.5 to 9.3.6
The following text has been added:
“(if the participant received at least 1 vaccine dose)”
To account for the added section 
To clarify that outcomes for pregnancies is 
applicable only to those participants who 
received any study vaccine
 
 
04TB5P
 
 
059WL7

Product:  V503 
7
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Section # and Name
Description of Change
Brief Rationale
9.5.2 
Pregnancy Testing
The following text has moved from Section 9.3.6 
(Pregnancy and Exposure During Breastfeeding) to Section 
9.5.2 (Pregnancy Testing):
Management of pregnant participants will be as follows.  
All female participants undergo pregnancy testing based on 
urine or serum analyses for β-hCG at each study visit 
(Section 2: SoA).  Participants found to be pregnant at Day 
1 are not eligible to participate in the study (Section 6.2: 
exclusion criterion 14).  Female participants 16 years and 
older enrolled in the study are instructed to use effective 
contraception through Month 7 (Section 6.1: inclusion 
criterion 7).  Participants who inadvertently become 
pregnant before receiving all 3 doses of vaccine do not 
receive additional doses until ≥4 weeks after resolution of 
pregnancy and normalization of β hCG levels as described 
in Table 3 (Section 9.5.2).  Breastfeeding is not a 
contraindication to enrollment or to receiving study 
vaccinations.  Pregnancy and breastfeeding in study 
participants and infant SAEs for all infants born to 
participants who received the study vaccine or who were 
breastfed during the study must be reported must be 
reported.
To be more consistent with standard template
text organization
10.5.1 
Immunogenicity 
Analysis Population
Removal of the following text regarding determination of 
protocol deviations:
and will be documented in a separate memo
To be more consistent with recently revised 
Sponsor processes concerning protocol 
deviations
 
 
04TB5P
 
 
059WL7

Product:  V503 
8
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Section # and Name
Description of Change
Brief Rationale
Appendix 2
Collection and 
Management of 
Specimens for Future 
Biomedical Research
Entire appendix and associated text has been removed
Sections and text pertaining to Future 
Biomedical Research samples have been 
removed in response to a request by the 
applicable ethics committee
Throughout
Minor editorial and document formatting revisions
Minor, therefore have not been summarized
 
 
04TB5P
 
 
059WL7

Product:  V503 
9
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...............................................3
1.
Synopsis.......................................................................................................................16
2.
Schedule of Activities (SoA) ......................................................................................18
3.
Introduction................................................................................................................21
Study Rationale .......................................................................................................21
3.1
Background..............................................................................................................21
3.2
Pharmaceutical and Therapeutic Background .....................................................22
3.2.1
Benefit/Risk Assessment.........................................................................................22
3.3
4.
Objectives/Hypotheses and Endpoints.....................................................................23
5.
Study Design...............................................................................................................24
Overall Design .........................................................................................................24
5.1
Study Diagram .....................................................................................................25
5.1.1
Number of Participants ..........................................................................................25
5.2
Beginning and End of Study Definition ................................................................25
5.3
Clinical Criteria for Early Study Termination .....................................................25
5.3.1
Scientific Rationale for Study Design....................................................................26
5.4
Rationale for Endpoints .......................................................................................26
5.4.1
Immunogenicity Endpoints...........................................................................26
5.4.1.1
Safety Endpoints ...........................................................................................26
5.4.1.2
Justification for Dose ..............................................................................................26
5.5
6.
Study Population........................................................................................................27
Inclusion Criteria ....................................................................................................27
6.1
Exclusion Criteria ...................................................................................................28
6.2
Lifestyle Restrictions...............................................................................................30
6.3
Meals and Dietary Restrictions............................................................................30
6.3.1
Caffeine Alcohol, and Tobacco Restrictions .......................................................30
6.3.2
Activity ................................................................................................................30
6.3.3
Screen Failures ........................................................................................................30
6.4
Participant Replacement Strategy.........................................................................30
6.5
Subject Relocation...................................................................................................30
6.6
 
 
04TB5P
 
 
059WL7

Product:  V503 
10
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
7.
Treatments..................................................................................................................31
Treatments Administered.......................................................................................31
7.1
Dose Modification ...................................................................................................31
7.2
Method of Treatment Assignment.........................................................................32
7.3
Stratification.........................................................................................................32
7.3.1
Blinding....................................................................................................................32
7.4
Preparation/Handling/Storage/Accountability ....................................................32
7.5
Dose Preparation..................................................................................................32
7.5.1
Handling, Storage and Accountability.................................................................32
7.5.2
Treatment Compliance...........................................................................................33
7.6
Concomitant Therapy.............................................................................................33
7.7
Rescue Medications and Supportive Care ...........................................................34
7.7.1
Treatment After the End of the Study ..................................................................34
7.8
Clinical Supplies Disclosure ...................................................................................34
7.9
8.
Discontinuation/Withdrawal Criteria......................................................................34
Discontinuation of Study Treatment .....................................................................34
8.1
Withdrawal from the Study ...................................................................................35
8.2
Lost to Follow Up ....................................................................................................35
8.3
9.
Study Assessments and Procedures..........................................................................35
Administrative and General Procedures ..............................................................36
9.1
Informed Consent/Assent.....................................................................................36
9.1.1
General Informed Consent/Assent................................................................36
9.1.1.1
Inclusion/Exclusion Criteria ................................................................................37
9.1.2
Participant Identification Card.............................................................................37
9.1.3
Medical History ...................................................................................................37
9.1.4
Prior and Concomitant Medications Review .......................................................37
9.1.5
Prior Medications..........................................................................................37
9.1.5.1
Concomitant Medications .............................................................................38
9.1.5.2
Assignment of Screening Number .......................................................................38
9.1.6
Assignment of Treatment/Randomization Number .............................................38
9.1.7
Treatment Administration....................................................................................38
9.1.8
Preparation of Study Vaccine for Administration ........................................39
9.1.8.1
 
 
04TB5P
 
 
059WL7

Product:  V503 
11
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Study Vaccine Administration......................................................................39
9.1.8.2
Timing of Dose Administration....................................................................39
9.1.8.3
Discontinuation and Withdrawal .........................................................................40
9.1.9
Participant Blinding/Unblinding..........................................................................40
9.1.10
Calibration of Critical Equipment........................................................................40
9.1.11
Other Assessments ...............................................................................................40
9.1.12
Physical Examination and Vital Signs Prior to Study Vaccination ..............40
9.1.12.1
Optional Testing for Sexually Transmitted Infections (STIs) ......................41
9.1.12.2
Efficacy Assessments...............................................................................................41
9.2
Serum for Anti-HPV Antibody Testing...............................................................41
9.2.1
Immunogenicity Measurements...........................................................................42
9.2.2
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
9.3
Reportable Safety Events .......................................................................................43
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................43
Method of Detecting AE, SAE and Other Reportable Safety Events ..................45
9.3.2
Follow-up of AE, SAE and Other Reportable Safety Event Information............45
9.3.3
Regulatory Reporting Requirements for SAE .....................................................45
9.3.4
Disease-Related Events and/or Disease-Related Outcomes not 
9.3.5
Qualifying as AEs or SAEs..................................................................................45
Pregnancy and Exposure During Breastfeeding ..................................................45
9.3.6
Treatment of Overdose...........................................................................................46
9.4
Safety........................................................................................................................46
9.5
Patient Reported Outcome ...................................................................................46
9.5.1
Pregnancy Testing................................................................................................46
9.5.2
Post-vaccination Observation Period (30 minutes)..............................................48
9.5.3
Clinical Laboratory Assessments.........................................................................48
9.5.4
Pharmacokinetics....................................................................................................48
9.6
Pharmacodynamics.................................................................................................48
9.7
Biomarkers ..............................................................................................................49
9.8
Visit Requirements..................................................................................................49
9.9
Prerequisites for Vaccination Visits.....................................................................49
9.9.1
Discontinued Participants Continuing to be Monitored in the Study ..................49
9.9.2
 
 
04TB5P
 
 
059WL7

Product:  V503 
12
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
10.
Statistical Analysis Plan ............................................................................................49
Statistical Analysis Plan Summary........................................................................50
10.1
Responsibility for Analyses/In-House Blinding....................................................51
10.2
Hypotheses/Estimation ...........................................................................................51
10.3
Analysis Endpoints..................................................................................................51
10.4
Immunogenicity Endpoints..................................................................................51
10.4.1
Safety Endpoints ..................................................................................................51
10.4.2
Derivations of Immunogenicity Endpoints..........................................................51
10.4.3
Analysis Populations...............................................................................................52
10.5
Immunogenicity Analysis Population..................................................................52
10.5.1
Safety Analysis Populations ................................................................................53
10.5.2
Statistical Methods..................................................................................................53
10.6
Statistical Methods for Immunogenicity Analyses ..............................................53
10.6.1
Statistical Methods for Safety Analyses ..............................................................54
10.6.2
Interim Analyses .....................................................................................................54
10.7
Multiplicity ..............................................................................................................54
10.8
Sample Size and Power Calculations ....................................................................55
10.9
Sample Size and Power for Immunogenicity Analysis........................................55
10.9.1
Sample Size and Power for Safety Analyses .......................................................57
10.9.2
Subgroup Analyses..................................................................................................57
10.10
Compliance (Medication Adherence)....................................................................57
10.11
Extent of Exposure..................................................................................................57
10.12
11.
References...................................................................................................................58
12.
Appendices..................................................................................................................61
Appendix 1: Study Governance Considerations ..................................................61
12.1
Merck Code of Conduct for Clinical Trials.....................................................................61
Financial Disclosure...........................................................................................................63
Data Protection ..................................................................................................................63
Confidentiality of Data ......................................................................................................63
Confidentiality of Participant Records ............................................................................63
Confidentiality of IRB/IEC Information .........................................................................64
Publication Policy ..............................................................................................................64
 
 
04TB5P
 
 
059WL7

Product:  V503 
13
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Compliance with Study Registration and Results Posting Requirements....................64
Compliance with Law, Audit and Debarment ................................................................65
Data Quality Assurance.....................................................................................................65
Source Documents..............................................................................................................66
Study and Site Closure ......................................................................................................66
Appendix 2: Adverse Events: Definitions and Procedures for 
12.2
Recording, Evaluating, Follow-up, and Reporting ..............................................67
Definition of AE .................................................................................................................67
Definition of SAE ...............................................................................................................68
Additional Events Reported..............................................................................................69
Recording AE and SAE.....................................................................................................69
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor..............72
Appendix 3: Clinical Laboratory Tests.................................................................74
12.3
Appendix 4: Abbreviations ....................................................................................75
12.4
 
 
04TB5P
 
 
059WL7

Product:  V503 
14
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
LIST OF TABLES
    
Table 1
Study Vaccine.......................................................................................................31
Table 2
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................44
Table 3
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations .........................................................................................................47
Table 4
Acceptable Day Ranges for Vaccination Visits....................................................52
Table 5
Analysis Strategy for Key Immunogenicity Endpoints........................................54
Table 6
Power for Testing the Primary Immunogenicity Hypothesis ...............................56
Table 7
Protocol-Required Safety Laboratory Assessments .............................................74
 
 
04TB5P
 
 
059WL7

Product:  V503 
15
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
LIST OF FIGURES
          
Figure 1
Design of the V503-017 Study .............................................................................25
 
 
04TB5P
 
 
059WL7

Product:  V503 
16
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
1. Synopsis
Protocol Title:  
A Phase III Open-label Safety and Immunogenicity Study of GARDASIL™9 
Administered to 9- to 26-Year-Old Females and Males in Vietnam
Short Title: 
Immunogenicity and safety of GARDASIL™9 in Vietnam, 9-26 year-olds
Objectives/Hypotheses and Endpoints:
In 9- to 26-year-old female and male participants:
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that the 
9-valent human papillomavirus
(9vHPV) vaccine is immunogenic.

Hypothesis: 9vHPV vaccine induces 
acceptable anti-human papillomavirus 
(HPV) 6, 11, 16, 18, 31, 33, 45, 52, 
and 58 seroconversion at 4 weeks 
post Dose 3. The statistical criterion 
for acceptable anti-HPV 
seroconversion requires the lower 
limit of the 95% confidence interval 
(CI) of the percent of participants 
who seroconverted to be greater than 
90% for each HPV type.

Seroconversion, defined as a participant 
who was anti-HPV seronegative at Day 
1 and became seropositive at 4 weeks 
post Dose 3. 
Secondary

Objective: To evaluate the safety of 
9vHPV vaccine.

Proportion of participants experiencing
solicited injection-site adverse events 
(AEs).

Proportion of participants experiencing 
solicited systemic AEs.

Proportion of participants experiencing 
vaccine-related serious AEs (SAEs).

Objective: To summarize geometric 
mean titers (GMTs) at Day 1 and at 
4 weeks post Dose 3 of 9vHPV 
vaccine.

GMTs to HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 at Day 1 and 4 weeks post 
Dose 3.
 
 
04TB5P
 
 
059WL7

Product:  V503 
17
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Overall Design:
Study Phase
III
Clinical Indication
Prevention of cervical, vulvar, vaginal, and anal cancers 
and related precancers, external genital lesions, Pap test 
abnormalities, and persistent infection caused by HPV
Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.
Population
Healthy females and males between the ages of 9 and 26 
years will be enrolled in this study.
Study Type
Interventional
Type of Design
Single group, single-site
Type of Control
No control
Study Blinding
Unblinded Open-label
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 11 months from the time the first participant 
signs the informed consent/assent until the last participant’s 
last study-related phone call or visit.  For purposes of 
analysis and reporting, the overall study ends when the 
Sponsor receives the last serology assay result.
Number of Participants:
Approximately 200 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
All participants should receive 3 doses of 9vHPV vaccine 
administered at Day 1, Month 2, and Month 6.
Duration of 
Participation
Each participant will participate in the study for 
approximately 7 months, from the time the participant 
signs the informed consent form through the final 
contact. Each participant will be receiving 3 doses of 
study vaccination intramuscularly and will be followed 
up to Month 7.
A list of abbreviations used in this document can be found in Section 12.4 (Appendix 4: 
Abbreviations).
 
 
04TB5P
 
 
059WL7

Product:  V503 
18
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
2. Schedule of Activities (SoA)
Study Visit Number
1
2
3
4
Comments (Protocol Section Reference)
Study Visit Time Point
Day 1
Month 2
Month 6
Month 7
Study Visit Scheduled Day (Window)
2 Months 
After Day 1
(±3 Weeks)
6 Months 
After Day 1
(±4 Weeks)
3 to 7 Weeks 
After Month 6
Visit
To calculate visit windows, assume 1 month equals 
30 days and 1 week equals 7 days.
Informed Consent/Assent
X
Consent/assent must be obtained before any study 
procedures. (9.1.1.1)
If date of Day 1 visit is later than consent date, the 
interval between date of consent and date of Day 1 
visit should be ≤14 days. If this interval is ≥15 days, 
then participant must be re-consented.
Assign Screening Number
X
(9.1.6)
Inclusion/Exclusion Criteria
X
(6.1, 6.2, 9.1.2)
Participant Identification Card
X
(9.1.3)
Medical History/New Medical History
X
X
X
X
At Day 1, medical history for 1 year prior to Day 1 
is collected. After Day 1, new conditions not 
already recorded as medical history or adverse 
events are collected. (9.1.4)
Lifetime/New Gynecological/Genitourinary History 
X
X
X
X
Participants age 16-26 years only. At Day 1, lifetime 
gynecological/genitourinary history is collected. 
After Day 1, new conditions not already recorded as 
gynecological/genitourinary history or adverse 
events are collected. (9.1.4)
Prior/Concomitant Medication and Non-study 
Vaccination Review
X
X
X
X
(9.1.5)
Perform Physical Examination (Optional)
X
Optional, per investigator's discretion; perform if 
needed to assess inclusion/exclusion criteria
 
 
04TB5P
 
 
059WL7

Product:  V503 
19
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Study Visit Number
1
2
3
4
Comments (Protocol Section Reference)
Study Visit Time Point
Day 1
Month 2
Month 6
Month 7
Study Visit Scheduled Day (Window)
2 Months 
After Day 1
(±3 Weeks)
6 Months 
After Day 1
(±4 Weeks)
3 to 7 Weeks 
After Month 6
Visit
To calculate visit windows, assume 1 month equals 
30 days and 1 week equals 7 days.
Pregnancy Testing, Serum or Urine (all females) 
X
X
X
X
The serum pregnancy test or urine pregnancy test 
must be sensitive to 25 mIU/ML β-hCG and 
performed prior to vaccination. Results should be 
negative prior to vaccination. Pregnancy testing is 
required for all female participants. (9.5.2)
Serum for Anti-Human Papillomavirus (Anti-HPV)
Antibody Testing (Including Retention Serum)  
X
X
On Day 1, serum for anti-HPV measurements must
be collected before vaccination. (9.2)
Optional Sexually Transmitted Infections (STI)
Testing (Local Laboratory, if Clinically Indicated) 
X
X
X
X
Optional, per investigator's discretion, if needed to 
evaluate eligibility criteria or new medical 
conditions. (9.1.13.2)
Vital Signs Prior to Vaccination
X
X
X
Weight and height are to be measured at Day 1 only. 
Body temperature is to be taken prior to each 
vaccination. Participants with fever (defined as an 
oral temperature of ≥100.0°F [≥37.8°C]) will have 
the vaccination delayed until fever is resolved.
(9.1.13.1)
Assign Treatment/Randomization Number
X
At Day 1, allocation to study vaccine should not 
occur until all screening procedures have been 
completed (all items above in this table); although 
allocation is performed by non-random assignment, 
assigned numbers are referred to as
“treatment/randomization numbers”. (9.1.7)
Study Vaccine Administration
X
X
X
Day 1 visit (and all procedures) must be done within 
14 days of informed consent (screening). The first 
study vaccination may be administered only after the 
treatment/randomization number for the participant 
has been obtained. (9.1.8, 9.10.1)
 
 
04TB5P
 
 
059WL7

Product:  V503 
20
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Study Visit Number
1
2
3
4
Comments (Protocol Section Reference)
Study Visit Time Point
Day 1
Month 2
Month 6
Month 7
Study Visit Scheduled Day (Window)
2 Months 
After Day 1
(±3 Weeks)
6 Months 
After Day 1
(±4 Weeks)
3 to 7 Weeks 
After Month 6
Visit
To calculate visit windows, assume 1 month equals 
30 days and 1 week equals 7 days.
30-minute Post-Vaccination Observation Period
X
X
X
Observe participants for 30 minutes after each 
vaccination for immediate untoward effects. (9.5.3)
Provide Vaccination Report Card (VRC) to 
Participant and Review Instructions
X
X
X
(9.5.1)
Review Adverse Events/Safety Follow-Up
X
X
X
X
(9.3)
β-hCG=beta human chorionic gonadotropin; VRC=vaccination report card.
 
 
04TB5P
 
 
059WL7

Product:  V503 
21
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
3. Introduction
Study Rationale 
3.1
A local immunogenicity and safety study is generally required for vaccine registration in 
Vietnam.  For instance, an immunogenicity and safety study of the quadrivalent human 
papillomavirus HPV (qHPV) (Types 6, 11, 16, 18) vaccine previously conducted in Vietnam 
demonstrated that the vaccine was immunogenic and well tolerated [Neuzil, K. M., et al 
2011]. The study supported the licensure of the qHPV vaccine in Vietnam. Similarly, 
Protocol V503-017 is designed to evaluate the immunogenicity and safety of the 9-valent 
human papillomavirus (9vHPV) vaccine1 and support licensure of the vaccine in Vietnam.
The V503 clinical program has been conducted in males and females 9 to 26 years of age 
[Pitisuttithum, P., et al 2015] [McKeage, K. 2016].  This study is designed to assess the 
safety and immunogenicity of the 9vHPV vaccine in male and female participants 9 to 26 
years of age.
Background
3.2
Refer to the Investigator’s Brochure and approved labeling for detailed background 
information on V503 (9vHPV vaccine).
Human papillomavirus (HPV) is the causative agent of nearly all cervical cancer cases, as 
well as a substantial proportion of anal, vulvar, vaginal, penile, and oropharyngeal cancers 
[Forman, D., et al 2012]; thus, HPV is responsible for approximately 5% of the global cancer 
burden [Parkin, D. Maxwell and Bray, Freddie 2006].
The 9vHPV vaccine was developed to cover 7 cancer-causing HPV types (HPV 16, 18, 31, 
33, 45, 52, and 58) that are together responsible for approximately 90% of cervical cancers 
and HPV-related vulvar, vaginal, and anal cancers and 2 HPV types (HPV 6 and 11) that are 
responsible for 90% of genital warts worldwide [Serrano, B., et al 2015] [Alemany, L., et al 
2015] [Garland, S. M., et al 2009].  In a clinical study (Protocol V503-001), the 9vHPV 
vaccine prevented infection and disease due to the 9vHPV vaccine types in young women 16 
to 26 years of age [Joura, E. A., et al 2015].  In two separate Phase 3 clinical studies 
(Protocols V503-002 and V503-003), antibody responses to HPV 6/11/16/18/31/33/45/52/58 
in girls and boys aged 9 to 15 years and in young men 16 to 26 years of age were non-inferior 
to those among young women aged 16 to 26 years following 9vHPV vaccination, thereby 
supporting the bridging of efficacy findings with 9vHPV vaccine from young women to girls, 
boys, and young men [Van Damme, P., et al 2015] [Castellsague, X., et al 2015].  Key 
aspects of the 9vHPV vaccine development program are summarized in published literature 
[Pitisuttithum, P., et al 2015] [McKeage, K. 2016].  The 9vHPV vaccine was licensed in the 
                                                
1 The 9-valent human papillomavirus (types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine, 
also known as V503, will hereafter be referred to as 9vHPV vaccine in this protocol.
 
 
04TB5P
 
 
059WL7

Product:  V503 
22
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
United States in 2014; in Canada, the European Union, and Australia in 2015; and in other 
countries in 2015-2017 under the name GARDASIL™9 (Merck & Co., Inc., Kenilworth, 
New Jersey, USA).2 As of August 2017, the 9vHPV vaccine was approved in over 60 
countries.  
The 9vHPV vaccine formulated with amorphous aluminium hydroxyphosphate sulfate 
(AAHS) consists of highly purified virus-like particles (VLPs) of the L1 capsid proteins from 
HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58. Like for GARDASIL™,3 the L1 capsid proteins in 
the vaccine are individually expressed in Saccharomyces cerevisiae yeast. The HPV 6, 11, 
16, 18, 31, 33, 45, 52, and 58 L1 VLPs final aqueous products are comprised of recombinant 
L1 polypeptides for their respective viral types that have self-assembled into VLPs.
Following fermentation, the VLPs are isolated from lysed yeast cells by standard techniques, 
highly purified, and then adsorbed onto AAHS without the addition of preservative. After 
preparation, the monovalent bulk adsorbed products are mixed to create the 9vHPV vaccine 
with the desired concentrations of each monovalent L1 VLP. The 9vHPV vaccine is not a 
live virus vaccine. It is not capable of causing viral infection.
Pharmaceutical and Therapeutic Background
3.2.1
The 9vHPV vaccine is comprised of VLPs of the 4 HPV types (HPV 6, 11, 16, and 18) 
contained in the qHPV vaccine GARDASIL™, plus the VLPs of 5 additional oncogenic 
HPV types (HPV 31, 33, 45, 52, and 58).  The 9vHPV vaccine is intended to prevent 
cervical, vulvar, vaginal, and anal cancers and related precancers, and anogenital warts 
caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.  It is generally accepted that HPV 
VLP vaccines elicit protection by generating antibody responses to the HPV types covered 
by the vaccine [Stanley, M., et al 2012].
Benefit/Risk Assessment
3.3
As of August 2017, the 9vHPV vaccine has been licensed in over 60 countries to prevent 
cervical, vulvar, vaginal, and anal cancers and precancers and anogenital warts caused by 
HPV types covered by the 9vHPV vaccine.  The United States Food and Drug 
Administration and the European Medicines Agency have both determined that the benefits
of the 9vHPV vaccine outweigh the risks [Center for Drug Evaluation and Research 2014] 
[European Medicines Agency 2016].
                                                
2 GARDASIL™9 (human papillomavirus 9-valent vaccine recombinant) is a registered trademark of Merck & 
Co., Inc., Whitehouse Station, New Jersey, USA.
3 GARDASIL™ (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine] is a registered 
trademark of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. GARDASIL™ is also known as 
SILGARD® in some countries. SILGARD® is a trademark of Merck & Co., Inc., Whitehouse Station, New 
Jersey, USA.
 
 
04TB5P
 
 
059WL7

Product:  V503 
23
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
It cannot be guaranteed that participants in clinical studies will directly benefit from the study 
vaccine during participation in this study, as clinical studies are designed to provide 
information about the safety and effectiveness of an investigational vaccine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying Investigator’s Brochure and informed 
consent documents.
4. Objectives/Hypotheses and Endpoints
In 9- to 26-year-old female and male participants:
Objective/Hypothesis
Endpoint
Primary

Objective: To demonstrate that the 
9vHPV vaccine is immunogenic

Hypothesis: 9vHPV vaccine induces 
acceptable anti-HPV 6, 11, 16, 18, 31, 
33, 45, 52, and 58 seroconversion at 4 
weeks post Dose 3. The statistical 
criterion for acceptable anti-HPV 
seroconversion requires the lower limit of 
the 95% confidence interval (CI) of the 
percent of participants who seroconverted 
to be greater than 90% for each HPV 
type.

Seroconversion, defined as a 
participant who was anti-HPV 
seronegative at Day 1 and became 
seropositive at 4 weeks post Dose 3.
Secondary

Objective: To evaluate the safety of 
9vHPV vaccine.

Proportion of participants experiencing 
solicited injection-site adverse events 
(AEs).

Proportion of participants experiencing 
solicited systemic AEs.

Proportion of participants experiencing 
vaccine-related serious AEs (SAEs).

Objective: To summarize geometric 
mean titers (GMTs) at Day 1 and at 4 
weeks post Dose 3 of 9vHPV vaccine.

GMTs to HPV 6, 11, 16, 18, 31, 33, 45, 
52, and 58 at Day1 and 4 weeks post 
Dose 3.
 
 
04TB5P
 
 
059WL7

Product:  V503 
24
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
5. Study Design 
Overall Design 
5.1
This is a non-randomized, single-site, open-label study of the 9vHPV vaccine in 9- to 26-
year-old females and males to be conducted in conformance with Good Clinical Practice 
(GCP).
A total of approximately 200 participants will be enrolled (see Section 5.2).  Participants will 
receive a centrally generated “treatment/randomization number”; however, as all participants
will receive the same open-label study vaccine regimen, and no actual randomization will 
occur.  At the time of enrollment, participants must meet all inclusion criteria and must not 
meet any exclusion criteria.
Collection of medical history and vital signs will be conducted at Day 1 for all participants.  
Physical examination at Day 1 is optional and will be conducted, per investigator's discretion, 
if needed to assess inclusion/exclusion criteria.
Study vaccine will be administered under open-label conditions at the following time points: 
Day 1, Month 2, and Month 6.  
Serum samples will be obtained at Day 1 and Month 7 for measurement of anti-HPV 
antibodies for HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58.  
Safety will be monitored from Day 1 until Month 7; a vaccination report card (VRC) will be 
provided to each participant for recording AE information.  
A pregnancy test will be performed on all female participants at Day 1, Month 2, Month 6, 
and Month 7 visits.  Any female participant with a positive pregnancy test at Day 1 will not
be vaccinated and will not be allowed to participate in the study.  Female participants with a
positive pregnancy test after Day 1 will not be vaccinated until after pregnancy outcome.  
Pregnant participants who receive less than 3 vaccinations during the study will be offered
the possibility to complete the vaccination course.  Pregnancies and any associated AEs in 
vaccinated subjects will be followed to outcome.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
 
 
04TB5P
 
 
059WL7

Product:  V503 
25
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Study Diagram
5.1.1
The study design is depicted in Figure 1.
Figure 1
Design of the V503-017 Study
Number of Participants
5.2
Approximately 200 participants will be enrolled.  Enrollment will be stratified by age and 
gender (see Sections 7.3 and 7.3.1).  Age stratification will include the following age strata, 
in a 1:1 ratio: 9 to 15 years and 16 to 26 years.  Gender stratification will include a 
female:male ratio of 2:1.  
Additionally, enrollment limits will be applied in the 9 to 15 years age group to ensure ≥30% 
enrollment into each of the following 2 age subgroups (with a minimum number of female 
and male participants in each age subgroup): 9 to 12 years and 13 to 15 years (at least 20 
female and 10 male participants in each age subgroup).  Enrollment will be managed by use 
of an interactive response technology (IRT) system.  
Beginning and End of Study Definition
5.3
The overall study begins when the first participant signs the informed consent/assent form.  
The overall study ends when the last participant completes the last study-related phone-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 serology assay result.
Clinical Criteria for Early Study Termination
5.3.1
There are no pre-specified criteria for terminating the study early.
 
 
04TB5P
 
 
059WL7

Product:  V503 
26
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Scientific Rationale for Study Design 
5.4
The purpose of this trial is to fulfill the requirement for licensure in Vietnam to conduct an
immunogenicity and safety study of the 9vHPV vaccine within Vietnam.  All participants 
will receive 3 doses of 9vHPV vaccine at Day 1, Month 2, and Month 6.  Each participant is 
expected to participate in the trial for approximately 7 months.  
Rationale for Endpoints
5.4.1
Immunogenicity Endpoints
5.4.1.1
Serum will be collected at Day 1 (before the first study vaccination) and at Month 7
(approximately 4 weeks post Dose 3) for analysis of HPV 6, 11, 16, 18, 31, 33, 45, 52, and 
58 antibody responses, by competitive Luminex immunoassay (cLIA), to support the primary 
and secondary objectives of the study.
Seroconversion as defined in Section 10.4.1 is the primary study immunogenicity endpoint.  
Seroconversion at 4 weeks post Dose 3 is a standard immunogenicity endpoint in the qHPV 
and 9vHPV vaccine clinical programs and is an appropriate measure of immune response to 
HPV vaccination in a single arm study with no control arm.  
GMTs at 4 weeks post Dose 3 will be calculated for each HPV type as part of assessments of 
the secondary immunogenicity objective.  Summarization of GMTs is also the standard 
immune response assessment in qHPV and 9vHPV vaccine clinical programs.
Safety Endpoints
5.4.1.2
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in previous studies and feedback received from regulatory agencies 
during product development. A list of the safety endpoints to evaluate safety in the study 
population is provided in Section 10.4.2. 
Justification for Dose 
5.5
The efficacy of the 9vHPV vaccine was established in young women 16-26 years of age 
based on a dosing regimen of 0, 2, 6 months [Joura, E. A., et al 2015].  Efficacy results were 
extended to girls and boys 9-15 years of age and young men 16-26 years of age who received 
3 doses at 0, 2, 6 months based on the demonstration of noninferior HPV antibody responses 
compared with young women who received 3 doses at 0, 2, 6 months [Van Damme, P., et al 
2015] [Castellsague, X., et al 2015].  This dosing regimen is similar to that previously 
developed for the qHPV vaccine [Schiller, J. T., et al 2012].
The dose formulation of 9vHPV vaccine (including dose of antigen and amount of adjuvant) 
was determined based on immunogenicity and safety results of Phase II studies 
[Pitisuttithum, P., et al 2015] [Luxembourg, A., et al 2015].
 
 
04TB5P
 
 
059WL7

Product:  V503 
27
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
6. Study Population
Healthy female and male participants between the ages of 9 and 26 years (inclusive) will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
6.1
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Is a healthy individual who meets all enrollment criteria defined in this section.
Demographics and General Medical History
2. Is female or male between the ages of 9 years and 0 days and 26 years and 364 days 
on the day of enrollment.
3. Is judged to be in good physical health on the basis of medical history, physical 
examination, and laboratory results.
4. (Participants 9 to 15 years of age only) Has not yet had coitarche and does not plan 
on becoming sexually active during the vaccination period (Day 1 through Month 7).
5. (Participants 16 to 26 years of age only) Has never had Pap testing (cervical or anal) 
or has had only normal Pap test results.
6. (Participants 16 to 26 years of age only) Has a lifetime history of 0 to 4 male and/or 
female sexual partners at the time of enrollment.  Male or female partner is defined as 
someone with whom the participant has had penile penetrative sexual intercourse or 
someone who has contacted, either by penetrative (with fingers or other objects) or 
non-penetrative means, the participant's genitalia during sexual activity.
Female participants:
7. (Female participants 16 to 26 years of age only) Has not had sex with males or has
had sex with males and used effective contraception with no failures (an example of a 
failure is a male condom that ruptures during sexual intercourse) since the first day of 
the participant’s last menstrual period through Day 1.  Effective contraception is 
defined as a marketed, approved contraceptive product that the participant has used 
per the manufacturer’s instructions with every act of sexual intercourse.  The 
participant understands and agrees that during the Day 1 through Month 7 period, she 
should not have sexual intercourse with males without effective contraception, and 
that the use of the rhythm method, withdrawal, and emergency contraception are not 
acceptable methods per the protocol.  
 
 
04TB5P
 
 
059WL7

Product:  V503 
28
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Informed Consent/Assent
8. Participant (or, for minor participants, the parent/legal guardian and participant) 
fully understands study procedures, alternative treatments available, and the risks 
involved with the study, and voluntarily agrees to participate by giving written 
informed consent/assent.    
General
9. Agrees to provide study personnel with a primary telephone number as well as an 
alternate form of contact, if available, for follow-up purposes. 
Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a known allergy to any vaccine component, including aluminum, yeast, or 
BENZONASE™ (nuclease, Nycomed [used to remove residual nucleic acids from 
this and other vaccines]).  For the purpose of this exclusion criterion, an allergy to 
vaccine components is defined as an allergic reaction that met the criteria for SAEs as 
defined in Section 9.3.
2. Has a history of severe allergic reaction (eg, swelling of the mouth and throat, 
difficulty breathing, hypotension, or shock) that required medical intervention.
3. Has thrombocytopenia or any coagulation disorder that would contraindicate 
intramuscular injections.
4. Is concurrently enrolled in clinical studies of investigational agents.
5. Is currently immunocompromised or has been diagnosed as having a congenital or 
acquired immunodeficiency, human immunodeficiency virus (HIV) infection, 
lymphoma, leukemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile 
rheumatoid arthritis, inflammatory bowel disease, or other autoimmune condition.
6. Has had a splenectomy.
7. Has had a fever (defined as an oral temperature of ≥100.0°F or ≥37.8°C) within the 
24-hour period prior to the Day 1 vaccination (if the participant meets this exclusion 
criterion, the Day 1 visit may be rescheduled for a time when this criterion is not 
met).
8. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might confound the results of the study, or interfere with the 
participant's participation for the full duration of the study, such that it is not in the 
best interest of the participant to participate.
9. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within the last year) of drug abuse or dependence.  Alcohol 
abusers are defined as those who drink despite recurrent social, interpersonal, and/or 
legal problems as a result of alcohol use.  
 
 
04TB5P
 
 
059WL7

Product:  V503 
29
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
10. Has a history of a positive test for HPV.
11. (Male participants 16 to 26 years of age only) Has a history of HPV-related external 
genital lesions (eg, condyloma acuminata) or HPV-related anal lesions (eg, 
condyloma acuminata, or anal intraepithelial neoplasia) or anal cancer.
12. (Female participants 16 to 26 years of age only) Has a history of an abnormal 
cervical biopsy result (showing cervical intraepithelial neoplasia or worse).  
13. (Female participants 16 to 26 years of age only) Has a history of HPV-related 
external genital lesions (eg, condyloma acuminata, or vulvar intraepithelial neoplasia) 
or external genital cancer, HPV-related vaginal lesions (eg, condyloma acuminata, or 
vaginal intraepithelial neoplasia) or vaginal cancer, or HPV-related anal lesions (eg, 
condyloma acuminata, or anal intraepithelial neoplasia) or anal cancer.  
14. (Female participants only) Is pregnant as determined by a serum pregnancy test or 
urine pregnancy test that is sensitive to 25 mIU/mL beta human chorionic 
gonadotropin (β-hCG).  
15. (Female participants only) Is expecting to donate eggs during Day 1 through Month 7 
of the study.  
Prior/Concomitant Therapy
16. Is receiving or has received in the year prior to enrollment the following 
immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine, 
methotrexate, any chemotherapy, cyclosporin, leflunomide (Arava™), tumor necrosis 
factor (TNF)-α antagonists, monoclonal antibody therapies (including rituximab 
[Rituxan™]), intravenous gamma globulin (IVIG), antilymphocyte sera, or other 
therapy known to interfere with the immune response.  With regard to systemic 
corticosteroids, a participant will be excluded if he/she is currently receiving steroid 
therapy, has recently (defined as within 2 weeks of enrollment) received such therapy, 
or has received 2 or more courses of high-dose corticosteroids (orally or parenterally) 
lasting at least 1 week in duration in the year prior to enrollment.  Participants using 
inhaled, ophthalmic, topical steroids, or intra-articular / soft tissue injection are 
considered eligible for the study.  
17. Has received any immune globulin product (including RhoGAM™ [Ortho-Clinical 
Diagnostics]) or blood-derived product within the 3 months prior to the Day 1 
vaccination, or plans to receive any such product during Day 1 through Month 7 of 
the study.
18. Has received inactivated or recombinant vaccines within 14 days prior to the Day 1 
vaccination or has received live vaccines within 21 days prior to the Day 1 
vaccination.  
19. Has received a marketed HPV vaccine, or has participated in an HPV vaccine clinical 
study and has received either active agent or placebo.  
 
 
04TB5P
 
 
059WL7

Product:  V503 
30
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
General
20. Is unlikely to adhere to the study procedures, keep appointments, or is planning to 
relocate during the study.  
21. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
Lifestyle Restrictions
6.3
Meals and Dietary Restrictions
6.3.1
There are no dietary restrictions for participants participating in the study.
Caffeine Alcohol, and Tobacco Restrictions
6.3.2
There are no caffeine, alcohol, or tobacco restrictions for participants participating in the 
study. 
Activity
6.3.3
There are no activity restrictions for participants participating in the study.
Screen Failures
6.4
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently randomized.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
6.5
A participant who discontinues study vaccination or withdraws from the study will not be 
replaced.
Subject Relocation
6.6
Given the duration of the study and the age of the study population, it can be expected that 
subjects may relocate during the study.  The Sponsor must be contacted for each temporary 
and permanent relocation as soon as the situation is known.  Every effort should be made to 
adjust study visits around a subject’s temporary absence (eg, college breaks, summer 
vacation) so that the visits will be within the visit windows.  Every effort should be made to 
have a relocated subject seen at another site participating in this study in order to keep the 
visits within the visit windows and to allow the subject to complete the study.
 
 
04TB5P
 
 
059WL7

Product:  V503 
31
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment.  Participants will receive open-label single-dose vials, each vial containing 1 
dose of study vaccine; no kitting will be required.  Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
Treatments Administered
7.1
The vaccine to be used in this study is outlined below in Table 1.
Table 1
Study Vaccine
Study Vaccine Name:
9vHPV vaccine (9-valent human papillomavirus vaccine)
Also known as V503
Dosage Formulation:
Sterile suspension for intramuscular injection
Unit Dose Strength:
0.5 mL
Dosage Level:
1 dose on each of 3 occasions: Day 1, Month 2, Month 6
Amount per unit dose:
    HPV Type:
  6
11
16
18
31
33
45
52
58
    Amount (μg):
30
40
60
40
20
20
20
20
20
Amorphous aluminum hydroxyphosphate sulfate (500 μg)
Excipients: sodium chloride (9.56 mg), L-histidine (0.78 mg), 
polysorbate 80 (50 μg), sodium borate (35 μg), water for 
injection (quantum satis)
Route of Administration:
Intramuscular injection
Sourcing:
Provided by the Sponsor (manufactured by the Sponsor)
All supplies indicated in Table 2 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
Dose Modification
7.2
Not Applicable
 
 
04TB5P
 
 
059WL7

Product:  V503 
32
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Method of Treatment Assignment 
7.3
Participants participating in this study will be allocated by non-random assignment.
Stratification
7.3.1
Treatment allocation will be stratified according to the following factors:
1. Age: 1:1 allocation between 9 to 15 and 16 to 26 year-old age strata. 
Within 9 to 15 year-old stratum: enrollment will be monitored to ensure ≥30% 
enrollment in the 9 to 12 year-old range and ≥30% enrollment in the 13 to 15 year-old 
age range.
2. Gender: 2:1 allocation between females and males within each of the 9 to 15 and 16 
to 26 year-old age strata.
Therefore, it is expected that the study will enroll 200 participants in the following strata:

Approximately 33 male participants, 9 to 15 years of age (at least 10 participants 9 to 
12 years of age and at least 10 participants 13 to 15 years of age)

Approximately 67 female participants 9 to 15 years of age (at least 20 participants, 9 
to 12 years of age and at least 20 participants, 13 to 15 years of age

Approximately 33 male participants 16 to 26 years of age

Approximately 67 female participants 16 to 26 years of age
Blinding 
7.4
This is an open-label study; therefore, the Sponsor, investigator and participant will know the 
identity of the study vaccine administered.
Preparation/Handling/Storage/Accountability
7.5
Dose Preparation
7.5.1
Processes for preparation and administration of the study vaccine are described in Section
9.1.8 (ie, Sections 9.1.8.1 and 9.1.8.2).
The rationale for selection of doses to be used in this study is provided in Section 5.5 
(Justification for Dose).  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each participant.
Handling, Storage and Accountability
7.5.2
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
 
 
04TB5P
 
 
059WL7

Product:  V503 
33
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
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 treatment 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 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 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
7.6
Interruptions from the protocol specified vaccination schedule (ie, administration of 3 doses 
at scheduled time points; Section 9.1.8) for reasons not defined per protocol require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
Concomitant Therapy
7.7
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination.  If there is a 
clinical indication for any medication or vaccination specifically prohibited, discontinuation 
from study therapy or vaccination may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician. However, the decision to continue the participant on study treatment requires the 
mutual agreement of the investigator, the Sponsor and the participant.
See the exclusion criteria for specific restrictions for prior and concomitant medications at 
Day 1 (Section 6.2) and prerequisites for other vaccination visits (Section 9.10.1). 
If possible, participants should not receive “special medications” (corticosteroids, 
immunosuppressives, immune globulins, and blood products) from 3 days prior to Day 1 
through Month 7, nonstudy inactive or recombinant vaccines for 14 days prior to each study 
vaccination through 14 days after each study vaccination, or nonstudy live vaccines for 21 
days prior to each study vaccination through 14 days after each study vaccination.
Participants may receive allergen desensitization therapy and tuberculin skin testing while 
participating in the study.
 
 
04TB5P
 
 
059WL7

Product:  V503 
34
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Use of prior and concomitant medications/vaccination should be recorded as described in 
Section 9.1.5.
Rescue Medications and Supportive Care
7.7.1
No rescue or supportive medications are specified to be used in this study.
Treatment After the End of the Study 
7.8
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
7.9
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
8.1
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the third vaccination will still continue to 
participate in the study as specified in Section 2 (SoA) and Section 9.10.2 (Discontinued 
Participants Continuing to be Monitored in the Study).  Whenever possible, when a 
participant discontinues/withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation except 
for serum collection for HPV testing. The final visit assessments can be done via a phone 
call and the VRC.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 (Discontinuation and Withdrawal).
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Participants may be allowed to begin study treatment again if deemed medically appropriate, 
with consultation from the Clinical Director.  
 
 
04TB5P
 
 
059WL7

Product:  V503 
35
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Withdrawal from the Study
8.2
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 treatment 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 9.1.9 (Discontinuation and Withdrawal). 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 8.3 (Lost to Follow Up).
Lost to Follow Up
8.3
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, phone 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.
9. 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 assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

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.
 
 
04TB5P
 
 
059WL7

Product:  V503 
36
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential

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, etc.), 
and thus local regulations may require that additional informed consent, and assent if 
applicable, be obtained from the participant.  In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant to assess the primary study 
objective over the duration of the study, including any extra assessments that may be 
required, will not exceed 14 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
9.1
Informed Consent/Assent
9.1.1
The investigator or qualified designee must obtain documented consent, and assent if 
applicable, 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 qualified designee must ensure the appropriate consent/assent is in place. 
General Informed Consent/Assent
9.1.1.1
Consent/assent must be documented by the participant’s dated signature or by the 
participant’s legally acceptable representative’s dated signature on a consent/assent form 
along with the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the participant before 
participation in the study.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form 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/assent form or addendum to the original consent/assent form that 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/assent form 
template at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
 
 
04TB5P
 
 
059WL7

Product:  V503 
37
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Inclusion/Exclusion Criteria
9.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or medically 
qualified designee to ensure that the participant qualifies for the study.
Participant Identification Card
9.1.3
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 utilized 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/assent. At the time 
of treatment allocation/randomization, 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 health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
9.1.4
At the Day 1 visit, the participant’s medical history for the year prior to Day 1 will be 
collected. For participants in the 16- to 26-year-old women's group, lifetime gynecological 
history will also be collected at the Day 1 visit.  For participants in the 16- to 26-year-old 
men's group, lifetime genitourinary history will also be collected at the Day 1 visit.
After the Day 1 visit, any new medical history that has not been previously documented 
(either as adverse experiences or as medical history conditions) will be collected.  For 
participants in the 16- to 26-year-old women's group, new gynecologic history will be 
collected.  For participants in the 16- to 26-year-old men's group, new genitourinary history 
will be collected.  
Other documentation, such as demographics, sexual history, pregnancy history, and 
contraceptive use, will be collected in the data collection system, as discussed in the 
electronic case report form (eCRF) entry guidelines.  
Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
Prior and concomitant use of medicines and nonstudy vaccines should be documented in the 
data collection system in the following manner:
1. “Special medications” (corticosteroids, immunosuppressives, immune globulins, and 
blood products) from 3 days prior to Day 1 through Month 7.
2. “Other medications” from 3 days prior to each study vaccination through 14 days 
after each study vaccination
3. “Nonstudy inactive or recombinant vaccines” for 14 days prior to each study 
vaccination through 14 days after each study vaccination
 
 
04TB5P
 
 
059WL7

Product:  V503 
38
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
4. “Non-study live vaccines” for 21 days prior to each study vaccination through 14 
days after each study vaccination.  
Concomitant Medications
9.1.5.2
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study as outlined above.  
Assignment of Screening Number
9.1.6
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 treatment allocation.  Each 
participant will be assigned only one 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.
Assignment of Treatment/Randomization Number
9.1.7
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Treatment 
allocation will occur centrally using an IRT system.  All prevaccination (screening) data must 
be collected and all study procedures must be completed before the participant is assigned a 
treatment/ randomization number and vaccine administration.  
Day 1 (and all Day 1 procedures) must occur within 14 days after informed consent 
(screening).  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.
Treatment Administration
9.1.8
Vaccine will be administered at the study sites by the investigator and/or study staff.
The first dose of study vaccine will be administered on Day 1, which should be the day of 
allocation.  The second and third (final) doses of study vaccine will be administered 
subsequently, at time points 2 and 6 months, respectively, after the first dose.  
Participants should not be enrolled or vaccinated if protocol requirements are not met.  At 
Day 1, vaccine should be administered after the blood draw for HPV testing (see Section 
9.2.1 for procedures related to blood draw).  Pregnant participants should not be vaccinated 
(see Section 9.5.2 for management of study visits and study vaccinations for pregnant 
participants).  Section 9.10.1 provides additional information on other prerequisites for 
vaccination visits.
 
 
04TB5P
 
 
059WL7

Product:  V503 
39
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Preparation of Study Vaccine for Administration
9.1.8.1
This study vaccine must be used as supplied (no dilution before administration).  Prior to 
administration, mix the contents of the vial thoroughly by rolling the vial between the palms 
of both hands for 30 seconds.  Withdraw a 0.5-mL dose from the vial, which contains 
approximately 0.75 mL of study vaccine.  The study vaccine should be a whitish, semi-
translucent suspension when thoroughly mixed.  If the appearance is otherwise, do not 
administer and contact the Sponsor immediately.
Study Vaccine Administration
9.1.8.2
Study vaccine will be administered at Day 1, Month 2, and Month 6.  At each vaccination 
visit, participants will receive 9vHPV vaccine as a 0.5-mL intramuscular injection.  The 
deltoid muscle of the nondominant arm is the preferred site of vaccination.  
Study vaccinations should not be administered in the buttocks area.  If the female participant
has an implanted contraceptive (eg, NORPLANT™) at the time of the study vaccination, 
avoid administering the study vaccination in the arm with the implanted contraceptive.  If 
female participants have received injectable contraceptives (eg, DEPO PROVERA™) or 
implanted contraceptives (eg, NORPLANT™) in both arms in the past 9 months, the 
injection may be given in the thigh rather than in an arm.  Injections should not be given 
within 2 cm of a tattoo, scar, or skin deformation.
Injections should be administered at a 90° angle into the muscle tissue using a needle long 
enough to ensure intramuscular deposition of study vaccine.  The study vaccine should be 
administered in the deltoid muscle using preferably a 1.0-mL syringe (the largest allowable 
size is a 3.0-mL syringe) with the following needle length and gauge specifications:

1-inch needle, 22 to 23 gauge for participants weighing <200 pounds (<90.9 kg)

1½-inch needle, 22 to 23 gauge for participants weighing ≥200 pounds (≥90.9 kg)

1½ -inch needle, 22 to 23 gauge for thigh injections
All participants will be observed for at least 30 minutes after each study vaccination for any 
untoward effects, including allergic reactions.  This observation period will be documented in 
the participant’s study chart.
Timing of Dose Administration
9.1.8.3
Vaccination will be administered at the following time points: Day 1, Month 2, and Month 6.
Acceptable day ranges for vaccination visits are as follows: 

Dose 1: Day 1 (±0 days)

Dose 2: Month 2 (±3 weeks)

Dose 3: Month 6 (±4 weeks)
The Day 1 visit is defined as the day that the first study vaccination is given (ie, date when 
Dose 1 of 9vHPV vaccine is injected).  
 
 
04TB5P
 
 
059WL7

Product:  V503 
40
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
The visit windows described here are for site scheduling purposes.  The visit windows used 
for exclusion from the statistical analyses are provided in Section 10.5.1.  
For post-Day 1 vaccinations, the day ranges for inclusion in the statistical analysis are wider 
than the protocol specified visit windows primarily to account for differences at the sites in 
counting months (eg, 1 calendar month versus 30 days versus 4 weeks).
To calculate visit windows, assume 1 month equals 30 days and 1 week equals 7 days.
Discontinuation and Withdrawal
9.1.9
Participants who discontinue study treatment prior to completion of the vaccination regimen
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (exception: serum collection should not be done if the 
participant has not received all 3 scheduled doses of study vaccine) should be performed (at 
the time of withdrawal).  Any adverse events which are present at the time of withdrawal 
should be followed in accordance with the safety requirements outlined in Section 9.3.
Participant Blinding/Unblinding
9.1.10
This is an open label study; there is no blinding for this study.
Calibration of Critical Equipment
9.1.11
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical study that provides 
important information about inclusion/exclusion criteria and/or safety or efficacy parameters 
shall be suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the study site.
Critical Equipment for this study includes:

Refrigerator equipped with an appropriate temperature monitoring device to ensure 
the temperature is maintained at 2°C to 8°C for storage of study vaccine supplies

Non frost-free freezer with an appropriate temperature monitoring device to ensure 
serum samples are stored at -20°C or colder until shipped to the Central Laboratory

Centrifuge for processing of blood samples
Other Assessments
9.1.12
Physical Examination and Vital Signs Prior to Study Vaccination
9.1.12.1
A physical examination at Day 1 is optional.  It will be conducted, per investigator’s
discretion, if needed to determine whether the subject meets enrollment criteria for the study.  
Physical examination details will be documented in the subject’s chart and any medical 
condition will be documented in the data collection system.  
Oral temperature, height, weight will be taken before study vaccine is administered at Day 1.
 
 
04TB5P
 
 
059WL7

Product:  V503 
41
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Oral temperature will also be taken before study vaccine is administered at Month 2, and 
Month 6 visits).  If the participant has a fever (defined as an oral temperature of ≥100.0°F or 
≥37.8°C) within the 24-hour period prior to receiving a study vaccination, the participant 
should not receive the study vaccine, and the vaccination visit should be rescheduled until 
after the fever has resolved.
Optional Testing for Sexually Transmitted Infections (STIs)
9.1.12.2
Local laboratory testing to screen for sexually transmitted infections (STIs), including HPV
testing (cervical and/or anal); Pap test and/or HPV polymerase chain reaction, chlamydia, 
gonorrhea, herpes simplex virus, syphilis, hepatitis B, and HIV may be performed on any 
participant at any visit if deemed necessary by the investigator.  Any participant who tests 
positive for an STI will not be discontinued from the trial and may participate in all study 
procedures.  These participants will be referred for appropriate counseling and treatment 
outside of the context of the protocol.
Efficacy Assessments 
9.2
Serum for Anti-HPV Antibody Testing
9.2.1
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. 
Each participant will have serum collected for anti-HPV measurements at scheduled time 
points (Section 2: SoA).  For collection of the serum samples, the study sites must adhere to 
the procedures described in the protocol, must follow instructions provided by the Sponsor-
designated Central Laboratory, and must use the materials provided by the Sponsor-
designated Central Laboratory.  Samples should be shipped, labeled, and handled as 
instructed by the Sponsor/Central Laboratory.  Specimen collection supplies provided by the 
Sponsor/Central Laboratory must be used by the site without substitution.  
The following are the step-by-step procedures for collection of study specimens, a 
description of supplies needed, and the guidelines for handling specimens:  

For each visit that requires a serum specimen for anti-HPV measurements, a 7-mL 
(non-heparinized, non-serum separator, red-top tube provided by the Sponsor-
designated Central Laboratory) blood specimen will be collected and should be 
separated to avoid hemolysis.

A minimum of 2.0 mL of serum should be aliquoted to a vial provided by the 
Sponsor-designated Central Laboratory.

An additional approximately 0.8 mL of serum (“Retention Serum”) should be 
aliquoted to a vial provided by the Sponsor-designated Central Laboratory and 
labeled with the “Retention Serum” label provided by the Sponsor-designated Central
Laboratory.

After the serum has been processed, transfer the vials to the freezer (-20 °C or lower) 
without delay.
 
 
04TB5P
 
 
059WL7

Product:  V503 
42
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential

All serum samples are kept in the freezer until they shipped on dry ice as instructed 
by the Sponsor (see Administrative Binder).
o
If the samples thaw, contact the Sponsor.
o
Thawed serum samples require written documentation, including details such 
as treatment/randomization number, visit interval, date of collection, and 
sample accession numbers (see the Administrative Binder for a summary of 
deviations that require documentation in this study).  

“Serum” vials will be stored at the site at -20 °C (or lower) until shipped on dry ice to 
the address noted on Sponsor-designated Central Laboratory contact information 
page.
o
The freezer used to store the vials must be a non-frost-free freezer.

All available serum should be used for conducting assays specified in the clinical 
protocol.

“Retention Serum” vials will remain stored at the site at -20 °C (or lower).
o
The freezer used to store the vials must be a non-frost-free freezer.

The site should ship "Retention Serum" separately from the "Serum" sample.
o
If "Retention Serum" is sent to the Sponsor-designated Central Laboratory, it 
may also be used for further HPV immunologic testing, in addition to tests 
specified in the protocol.
Immunogenicity Measurements
9.2.2
The 9-valent HPV competitive Luminex immunoassay (HPV-9 cLIA) is used for the primary 
and secondary objectives of the study.  
The purpose of the HPV-9 cLIA assay is to quantify the antibodies specific to the 
neutralizing epitopes of HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. This assay is used 
by the Testing Laboratory to evaluate the serological response before and after vaccination 
with the 9vHPV vaccine and to measure HPV infection-induced antibodies for sero-
epidemiology studies.
HPV virus-like particles (VLPs) derived from yeast for each of the 9HPV types are coupled 
to one of 9 distinct fluorescent Luminex MagPlex® magnetic microspheres.  Each 
microsphere has its own distinct fluorescent dye that can be recognized by excitation with an 
infrared laser, allowing for the measurement of antibodies against multiple HPV types from a 
single test of a human serum sample.  HPV type-specific neutralizing monoclonal antibodies 
conjugated with phycoerythrin (PE-mAb conjugate) compete with the antibodies in the 
serum sample for binding to the neutralizing epitopes of the VLPs coupled to the 
microspheres. After incubation with PE-mAb conjugate and sample serum, the microspheres 
are washed and the fluorescent signal from the PE-mAb conjugate is read. The fluorescence 
signal is inversely proportional to the HPV antibody concentration of the serum sample 
tested. Antibody concentrations are derived from a standard curve, which is generated using 
a Reference Standard made from a pool of serum from individuals immunized against the 
nine HPV types. A standard curve for each HPV type is calculated using a weighted 4-
 
 
04TB5P
 
 
059WL7

Product:  V503 
43
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
parameter logistic curve fit. Antibody concentration results are expressed as milliMerck 
Units/mL (mMU/mL).
The high, medium, low, and negative controls used for this assay were collected from 
humans who were either HPV-seronegative, had low antibody titers from natural infection, or 
had medium-to-high antibody titers to the 9 HPV types following vaccination.  
Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
9.3
Events 
The definitions of an adverse event (AE) or serious adverse event (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 Section 12.2 (Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.
AE, 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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, 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 AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before allocation/randomization 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 treatment or a procedure.  
From the time of allocation/randomization through 14 days following the first vaccination(s) 
and from the time of any subsequent vaccination(s) through 14 days thereafter, all AEs, 
SAEs and other reportable safety events must be reported by the investigator.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the 
Sponsor if the event is either:
1.
A death that occurs prior to the participant completing the study, but outside the time 
period specified in the previous paragraph.
2.
An SAE is an AE that is considered by an investigator who is a qualified physician to 
be vaccine related.
Investigators are not obligated to actively seek AE or SAE 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 treatment or study participation, the 
investigator must promptly notify the sponsor.
 
 
04TB5P
 
 
059WL7

Product:  V503 
44
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 2.
Table 2
Reporting Time Periods and Timeframes 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
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
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
Report all
Report if:
- drug/vaccine related.
- any death until 
participant completion 
of study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome (if the 
participant received at 
least 1 vaccine dose and 
became pregnant)
Within 24 
hours of 
learning of 
event
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Overdose
-
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
04TB5P
 
 
059WL7

Product:  V503 
45
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
A VRC will be used by the participant to document any AEs.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy (if the participant received at least 1 vaccine dose) and exposure during 
breastfeeding, Cancer and Overdose will be followed until resolution, stabilization, until the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 
8.3). In addition, the investigator will make every attempt to follow all non-serious AEs that 
occur in randomized participants for outcome.  Further information on follow-up procedures 
is given in Section 12.2 (Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting).
Regulatory Reporting Requirements for SAE
9.3.4

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 treatment 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 treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes not Qualifying as AEs 
9.3.5
or SAEs
Not Applicable
Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the trial are reportable to the 
Sponsor. All reported pregnancies (in participants who received at least 1 vaccine dose) must 
be followed to the completion/termination of the pregnancy.  
 
 
04TB5P
 
 
059WL7

Product:  V503 
46
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Treatment of Overdose
9.4
In this study, an overdose is defined as a participant receiving >3 doses (0.5 mL each dose), 
or receiving ≥0.75 mL of 9vHPV vaccine in any one dose.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
Safety 
9.5
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. 
Planned time points for all safety assessments are provided in the SoA.
Patient Reported Outcome
9.5.1
Adverse events will be documented using a validated VRC.  
All participants will receive a VRC at the Day 1, Month 2, and Month 6 study vaccination 
visits.  Using the VRC, the participant or the parent/guardian of the participant will be asked 
to record the participant’s oral temperature in the evening after each study vaccination and 
daily for 4 days after each study vaccination for the purpose of identifying febrile events.  
Also, beginning after each study vaccination and for a total of 15 days including the day of 
vaccination, the participant will be asked to record injection-site and systemic AEs, 
concomitant medications, and concomitant vaccinations by means of the VRC.
Serious AEs, cancers and overdoses, pregnancy information, lactation information, and infant 
SAEs will also be collected for the entire duration of the study as described in Section 9.3.  In 
addition, new medical conditions not present at baseline and not reported as an adverse 
experience will be collected throughout the study.
Pregnancy Testing
9.5.2
All female participants will have a serum or urine pregnancy test (sensitive to 25 mIU/mL 
β-hCG performed at each vaccination visit (ie, Day 1, Month 2, or Month 6) and at Month 7 
per the manufacturer’s instructions.  All materials used for serum and/or urine pregnancy 
testing will be provided by the study sites.  
The pregnancy test results must be obtained prior to each study vaccination (on the day the 
participant is vaccinated).  Any participant found to be pregnant at Day 1 will not be 
allocated and will not participate in the study.  For randomized participants who become 
pregnant after receiving one or two study vaccinations, study visits and vaccinations will be 
paused until resolution of the pregnancy (eg, term, elective termination, spontaneous 
abortion).  Study visits and study vaccination in pregnancy participants will be handled as 
described in Table 3.
 
 
04TB5P
 
 
059WL7

Product:  V503 
47
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Table 3
Guidelines for Pregnant Participants: Managing Study Visits and Study 
Vaccinations
Time When Pregnancy 
is Detected
Action
Day 1 (before first 
vaccination)
Do not enroll.
Between Day 1 and 
Month 2
(After study vaccine dose 
1 and before study 
vaccine Dose 2 was 
administered)

No scheduled visits until resolution of the 
pregnancy (eg, term, elective termination, 
spontaneous abortion).  

The Month 2 study vaccination should be 
administered at least 4 weeks following resolution 
of pregnancy and after normalization of β-hCG 
levels.  

The Month 6 study vaccination should be 
administered 4 months after the Month 2 study 
vaccination.  

The Month 7 visit should be conducted 1 month 
after the Month 6 study vaccination.
Between Month 2 and 
Month 6
(After study vaccine dose 
2 and before study 
vaccine Dose 3 was 
administered)

No scheduled visits until resolution of the 
pregnancy (eg, term, elective termination, 
spontaneous abortion).  

The Month 6 study vaccination should be 
administered at least 4 weeks following resolution 
of pregnancy and after normalization of β-hCG 
levels.  

The Month 7 visit should be conducted 1 month 
after the Month 6 study vaccination.
After Month 6
(After study vaccine Dose 
3 was administered)

Continue with scheduled study visits during the 
pregnancy.  

Safety follow-up will be conducted after resolution 
of the pregnancy (eg, term, elective termination, 
spontaneous abortion).
β-hCG=beta human chorionic gonadotropin.
 
 
04TB5P
 
 
059WL7

Product:  V503 
48
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Management of pregnant participants will be as follows.  All female participants undergo 
pregnancy testing based on urine or serum analyses for β-hCG at each study visit (Section 2: 
SoA).  Participants found to be pregnant at Day 1 are not eligible to participate in the study 
(Section 6.2: exclusion criterion 14).  Female participants 16 years and older enrolled in the 
study are instructed to use effective contraception through Month 7 (Section 6.1: inclusion 
criterion 7).  Participants who inadvertently become pregnant before receiving all 3 doses of 
vaccine do not receive additional doses until ≥4 weeks after resolution of pregnancy and 
normalization of β-hCG levels as described in Table 3.  Breastfeeding is not a 
contraindication to enrollment or to receiving study vaccinations.  
Pregnancy and breastfeeding in study participants and infant SAEs for all infants born to 
participants who received the study vaccine or who were breastfed during the study must be 
reported.
Post-vaccination Observation Period (30 minutes)
9.5.3
All participants will be observed for at least 30 minutes after each study vaccination for any 
untoward effects, including allergic reactions.  This observation period will be documented in 
the participant’s study chart.
Clinical Laboratory Assessments
9.5.4
Refer to Section 12.3 (Appendix 3: Clinical Laboratory Tests) for the list of clinical 
laboratory tests to be performed and to the SoA for the timing and frequency. 

All protocol-required laboratory assessments, as defined in Section 2 (SoA), must be 
conducted in accordance with the manufacturer’s specifications.

If laboratory values from non-protocol 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).

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study. The laboratory reports 
must be filed with the source documents. 

For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 15 days after the last dose of study 
treatment, repeat assessments may be performed as determined by the investigator. 
Pharmacokinetics
9.6
Pharmacokinetic parameters will not be evaluated in this study. 
Pharmacodynamics
9.7
Pharmacodynamic parameters will not be evaluated in this study.
 
 
04TB5P
 
 
059WL7

Product:  V503 
49
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Biomarkers
9.8
Biomarkers are not evaluated in this study.
Visit Requirements
9.9
Visit requirements are outlined in Section 2 (SoA).  Specific procedure-related details are 
provided above in Section 9 (Study Assessments and Procedures).
Prerequisites for Vaccination Visits 
9.9.1
This section summarizes prerequisites for visits with study vaccinations and specimen 
collection. Deviations from these prerequisites require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision.  See the 
Administrative Binder for a summary of deviations that require documentation in this study.
See the inclusion/exclusion criteria for specific restrictions at Day 1.  For visits with study 
vaccinations, study personnel should verify by questioning the participant and/or by 
examination that: 
1. The participant has not had a fever (defined as an oral temperature of ≥100.0°F or 
≥37.8°C) within the 24-hour period prior to any study vaccination visit.
2. The participant has not received any systemic (oral or parenteral) corticosteroids in 
the 2 weeks prior to the Month 2 and Month 6 study vaccination visits.  
3. The participant has not received a nonstudy inactive or recombinant vaccine within 
14 days prior to any study vaccination visit or a nonstudy live vaccine within 21 days 
prior to any study vaccination visit.
4. The participant is not pregnant as confirmed by a serum or urine pregnancy test.
If the participant does not meet the requirements listed above, the study visit (including 
specimen collection and study vaccination) should be rescheduled.
Discontinued Participants Continuing to be Monitored in the Study
9.9.2
Participants who discontinue study vaccinations but continue in the study may attend study 
visits per the study flow chart (SoA table). However, serum will not be collected at the 
Month 7 study visit from participants who did not complete the 3-dose vaccination regimen.
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to the final database lock, changes are made to the primary 
hypothesis, or the statistical methods related to those hypothesis, 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 Statistical Analysis Plan and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.
 
 
04TB5P
 
 
059WL7

Product:  V503 
50
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Statistical Analysis Plan Summary
10.1
This section contains a brief summary of the statistical analyses for this study.  Full details 
are provided in the following sections.
Study Design Overview
A Phase III open-label, safety, and immunogenicity study of a 
9vHPV vaccine administered to 9- to 26-Year-Old Females 
and Males in Vietnam
Treatment Assignment
Single-arm, open-label, 9vHPV vaccine administration with 
1:1 allocation ratio among 9- to 15- and 16- to 26-year-old 
participants.  The study will recruit females and males, with 
2:1 enrollment ratio within each age group.
Analysis Populations
Immunogenicity: Per-Protocol Immunogenicity (PPI)
Safety: All Participants as Treated (APaT)
Primary Endpoint
Percent of participants who seroconverted to HPV Types 6, 
11, 16, 18, 31, 33, 45, 52, and 58 at 4 weeks post Dose 3.
Key Secondary Endpoints
Immunogenicity: GMTs of HPV Types 6, 11, 16, 18, 31, 33, 
45, 52, and 58 at 4 weeks post Dose 3.
Safety: Number (and proportion) of participants with the 
following: vaccine-related SAEs and any SAE (occurring at 
any time during the study); injection-site AEs, systemic AEs, 
and discontinuations due to an AE within Day 1 to Day 15 
following receipt of 9vHPV vaccination; and, oral 
temperatures within Day 1 to Day 5 following receipt of 
9vHPV vaccination.
Statistical Methods for Key 
Immunogenicity Analysis
The primary immunogenicity hypothesis will be addressed by 
calculating point and 95% CI estimates of percent 
seroconversion based on the exact binomial method of 
Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934].
The secondary immunogenicity objective will be addressed by 
calculating point and 95% CI estimates of GMTs based on the 
t-distribution.
Statistical Methods for Key 
Safety Analyses
Safety assessments will be descriptive in nature and will 
include calculation of proportions of participants with adverse 
events.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
No multiplicity adjustment is planned as successful 
demonstration of the primary immunogenicity hypothesis 
requires the lower limit of the 95% CI of percent 
seroconversion be >90% of all 9 HPV Types 6, 11, 16, 18, 31, 
33, 45, 52, and 58.
 
 
04TB5P
 
 
059WL7

Product:  V503 
51
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Sample Size and Power 
The planned sample size of 200 participants to be vaccinated 
with 9vHPV vaccine provides ~97% power at an overall 
1-sided Type I error equal to 0.025 to establish that the 
9vHPV vaccine induces among participants >90% 
seroconversion to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, 
and 58 at 4 weeks post Dose 3.
Responsibility for Analyses/In-House Blinding
10.2
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 non-randomized, open-label study (ie, 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 allocation schedules for study 
treatment assignment.  Treatment allocation will be implemented via an IRT.
Hypotheses/Estimation
10.3
Objectives and hypothesis of the study are stated in Section 4.
Analysis Endpoints
10.4
Immunogenicity Endpoints
10.4.1
The primary immunogenicity endpoints are the seroconversion percentages to each of HPV 
6, 11, 16, 18, 31, 33, 45, 52, and 58 by 4 weeks post Dose 3.  Seroconversion is defined as 
changing a participant’s serostatus from seronegative at Day 1 to seropositive by 4 weeks
post Dose 3.  A participant with anti-HPV cLIA titer at or above the serostatus cutoff for a 
given HPV type is considered seropositive for that HPV type.
The secondary immunogenicity endpoints are GMTs to HPV 6, 11, 16, 18, 31, 33, 45, 52, 
and 58 at 4 weeks post Dose 3.  
Safety Endpoints
10.4.2
The safety endpoints are the number (and proportions) of participants who reported injection-
site AEs, systemic AEs, and discontinuations due to an AE within Day 1 to Day 15 following 
receipt of 9vHPV vaccination.  In addition, SAEs occurring at any time during the study and 
oral temperatures (reported Day 1 to Day 5 following any vaccination) will be summarized.  
Derivations of Immunogenicity Endpoints
10.4.3
In numerical calculation of HPV type-specific GMTs, anti-HPV titer results reported as “less 
than [lower limit of quantification (LLOQ)]” or “<[LLOQ]”, where [LLOQ] corresponds to 
the lower limit of quantitation of the cLIA assay for the relevant HPV type, will be replaced 
by a numerical number equal to half of LLOQ of the relevant HPV type.
 
 
04TB5P
 
 
059WL7

Product:  V503 
52
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Analysis Populations
10.5
Immunogenicity Analysis Population
10.5.1
The PPI population will serve as the primary population for the analysis of immune response 
to each of the HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in this study.  The PPI 
population is HPV type-specific and consists of all allocated participants who:
1. Were seronegative to the appropriate HPV type at Day 1;
2. Have received all 3 vaccinations with the correct dose of 9vHPV vaccine within 
acceptable day ranges around the planned vaccination visits as shown in Table 4;
3. Have provided serum sample within 21 to 49 days post Dose 3;
4. Have no protocol deviations that could interfere with the evaluation of participant’s 
immune response to 9vHPV vaccination.  At Day 1, participants 9 to 15 years of age 
must satisfy inclusion criterion 4 (ie, "Has not yet had coitarche and does not plan on 
becoming sexually active during the vaccination period (Day 1 through Month 7)” as 
specified in Section 6.1.
To be included in the PPI population for HPV 6 and 11, participants must be seronegative to 
both HPV 6 and 11 at Day 1.  To be included in the PPI population for any other vaccine 
HPV type, participants need to be seronegative at Day 1 only for the HPV type being 
analyzed.
The final determination of protocol deviations that could interfere with the evaluation of 
participant’s immune response to 9vHPV vaccination, and thereby the composition of the 
PPI population, will be made prior to the final database lock.  
Details on the approach to handling missing data are provided in Section 10.6 (Statistical 
Methods).
Table 4
Acceptable Day Ranges for Vaccination Visits
Dose of 9vHPV vaccine
Scheduled for Injection
Protocol Specified
Visit Window
Day Range for Inclusion in 
Statistical Analysis 
(Relative to Day  1a)
Dose 1
Day 1a
0
Dose 2
Month 2 ±3 weeks
36 to 84
Dose 3
Month 6 ±4 weeks
148 to 218
a Day 1 refers to the date when Dose 1 of 9vHPV vaccine is injected.  For post Day 1 vaccinations, the day 
ranges for inclusion in the statistical analysis are wider than the protocol specified visit windows primarily to 
account for differences at the sites in counting months (eg, 1 calendar month versus 30 days versus 4 weeks).
 
 
04TB5P
 
 
059WL7

Product:  V503 
53
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Safety Analysis Populations
10.5.2
The APaT population will be used for the analysis of safety in this study.  The APaT 
population consists of all allocated participants who received at least one dose of 9vHPV 
vaccine and have provided safety data at any time during the study.
Statistical Methods
10.6
Statistical analyses of safety described in Section 10.6.2.  Immunogenicity results that will be 
deemed to be statistically significant after consideration of the Type I error control strategy 
are described in Section 10.8 (Multiplicity).
Statistical Methods for Immunogenicity Analyses
10.6.1
A summary of the analysis strategy for key primary and secondary immunogenicity 
endpoints is shown in Table 5.
The primary immunogenicity hypothesis will be addressed by calculating point and 95% CI 
estimates of percent seroconversion, to be derived from the point and 95% CI estimates of 
the proportion of participants who seroconverted (ie, point estimate and 95% CI of 
proportion × 100%).  Specifically, for each HPV type:

The point estimate of proportion of participants who seroconverted to a particular 
HPV type is the ratio of the number of PPI-eligible participants for that particular 
HPV type who seroconverted to the relevant HPV type over the total number PPI-
eligible participants for that particular HPV type who had evaluable Month 7 serology 
result based on serum sample collected within 21 to 49 days post Dose 3.

The corresponding 95% CI estimate of proportion will be derived based on exact 
binomial calculations.  

The statistical criterion for acceptable anti-HPV seroconversion requires the lower 
limit of the 95% CI of the percent of participants who seroconverted to be greater 
than 90% for each HPV type.
The secondary immunogenicity objective will be addressed by calculating point and 95% CI 
estimates of GMTs.  For each HPV type:

The point estimate of GMT will be calculated by taking the anti-natural-logarithm of 
the arithmetic mean of the natural-logarithm-transformed anti-HPV titers.

The two-sided 95% CI estimate of GMT will be calculated by taking the anti-natural-
logarithm of the two-sided 95% CI estimate of the mean of the natural-logarithm-
transformed anti-HPV titers based on the t-distribution.
 
 
04TB5P
 
 
059WL7

Product:  V503 
54
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Table 5
Analysis Strategy for Key Immunogenicity Endpoints
Endpoint
Primary 
vs. 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis
Percent 
seroconversion
Primary
Point and  95% CI 
estimation of binomial 
proportion based on 
Clopper-Pearson (exact)
method
PPI
Observed data 
only
Secondary Objective
GMTs
Primary
Point and 95% CI 
estimation of means 
based on t-distribution
PPI
Observed data 
only
CI=confidence interval; GMT=geometric mean titer; PPI=Per-Protocol Immunogenicity.
Statistical Methods for Safety Analyses
10.6.2
Safety will be assessed by clinical review of all safety data collected after each vaccination.
Since this study is a single-arm study with no comparator arm, safety assessments will be 
descriptive in nature and will include calculation of proportions of participants with any AEs, 
injection-site AEs, systemic AEs, SAEs, vaccine-related SAEs, and discontinuations due to 
an AE within Day 1 to Day 15 following receipt of 9vHPV vaccination; in addition, 95% CI
values for AEs will be provided for SAEs, injection site AEs, systemic AEs, and vaccine-
related systemic AEs. Oral temperatures recorded on the VRC will be summarized.
Interim Analyses
10.7
No interim analyses are planned for this study.
Multiplicity
10.8
The criterion for successful demonstration of the primary immunogenicity hypothesis 
requires demonstration of the lower limit of the 95% CI of the percent of participants who 
seroconverted to be greater than 90% for each (ie, all) HPV Types 6, 11, 16, 18, 31, 33, 45, 
52, and 58.  The corresponding tests of hypothesis for each of these HPV types will be 
conducted at 1-sided Type I error level of 0.025 (see Section 10.9; Sample size and Power 
Calculations).  No multiplicity adjustment is required on the 0.025 1-sided Type I error level 
since success is required for all of the 9 HPV types being tested.
 
 
04TB5P
 
 
059WL7

Product:  V503 
55
Protocol/Amendment No.:  017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Sample Size and Power Calculations
10.9
Sample Size and Power for Immunogenicity Analysis
10.9.1
This study will enroll 200 participants to be vaccinated with 9vHPV vaccine and has 
approximately 97% power at an overall one-sided 2.5% alpha-level (ie, 1-sided Type I error 
equal to 0.025) to establish that the 9vHPV vaccine induces among participants >90% 
seroconversion to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 at 4 weeks post Dose 3.  
The overall study power corresponding to the sample size of 200 participants is based on the 
following assumptions: 1) approximately 24% to 34% of participants enrolled will be 
ineligible for the per-protocol analysis of seroconversion to the 9 HPV types; and 2) the 
underlying true seroconversion across the 9 HPV types is ≥98% (see Table 6).  The power 
calculation was based on the exact binomial method of Clopper and Pearson [Clopper, C. J. 
and Pearson, E. S. 1934] and was done using PASS 2008.  The minimum criterion for 
success for each HPV type is that the lower limit of the 95% CI of percent seroconversion be 
>90%.  Given the number of participants eligible for the per-protocol analysis expected from 
this study, this may occur when the point estimate of percent seroconversion observed during 
the study is >96% in each of the 9 HPV types.  The numbers of seroconversions across the 9 
HPV types relative to the expected number of participants eligible for the per-protocol 
analysis that will yield a point estimate of seroconversion >96% are shown in Table 6.
 
 
04TB5P
 
 
059WL7

Product:  V503 
56
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Table 6
Power for Testing the Primary Immunogenicity Hypothesis
HPV Type
Participants 
Enrolled
(N)
Expected to be Observed in the 
Study
Assessment of Power for Testing
H0: P = P0 versus Ha: P > P0
Minimum 
Number of 
Seroconversions 
Needed to 
Attain a Point 
Estimate of 
Percent 
Seroconversion 
>96%c
Exclusions 
from PPI 
Analysisa
Evaluable 
for PPI 
Analysis
(n)
Percent 
Sero-
conversiona
P0
b
PE
b
Type I Error (α)
Power
Target
Expected 
Actual 
6
200
34%
132
98.3%
0.90
0.98
0.025
0.018
0.9826
127
11
34%
132
99.7%
0.99
0.018
0.9996
127
16
30%
140
100%
0.99
0.011
0.9994
135
18
27%
146
99.2%
0.99
0.018
0.9999
140
31
25%
150
99.0%
0.99
0.014
0.9999
144
33
26%
148
99.1%
0.99
0.016
0.9999
142
45
24%
152
98.4%
0.98
0.012
0.9881
146
52
32%
137
99.4%
0.99
0.013
0.9995
132
58
31%
139
99.4%
0.99
0.012
0.9995
134
Overall Study Power: 
0.9687
a Historical data from the Asian cohort (Korean and Taiwanese) of the V503-001 study.
b For each HPV type, the null hypothesis that the seroconversion proportion is 0.90 (P=P0) is being tested against the alternative hypothesis that the seroconversion proportion is 
greater than 0.90 (P>P0).  In the calculation of power corresponding to the expected number of participants evaluable for the PPI analysis, a proportion of seroconversion that is 
expected (PE) to be observed during the study is required.  The values of PE used in the calculation of power are obtained from the historical percent seroconversion observed from 
the Asian cohort of the V503-001 study.
c Assuming the number of participants contributing to the PPI analysis is equal to (n), a point estimate of percent seroconversion >96% will yield a corresponding lower limit of 
95% CI of percent seroconversion >90%.
CI=confidence interval; PPI=Per-Protocol Immunogenicity.
 
 
04TB5P
 
 
059WL7

Product:  V503 
57
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Sample Size and Power for Safety Analyses
10.9.2
The probability of observing a specific AE in this study depends on the number of vaccinated 
participants with safety follow-up and the underlying incidence of that specific AE in the 
study population.  In seven clinical studies in the 9vHPV program, 356 of 15,778 (2.3%) 
individuals who were administered 9vHPV vaccine and had safety follow-up reported a SAE; 
7 (0.04%) reported at least one SAE determined to be vaccine related [Moreira, E. D., et al 
2016].  Assuming that all 200 participants enrolled in this study will have safety follow-up, 
then there is a 99% chance of observing at least one SAE; and 7.7% chance of observing at 
least one vaccine related SAE, on at least one of the 200 participants.  If no vaccine-related 
SAEs are observed among the 200 participants, this study will provide 97.5% confidence that 
the underlying percentage of participants with vaccine-related SAE is <1.8% (1 in every 56 
participants) among 9vHPV vaccinated participants.  This is based on calculation of a 1-sided 
97.5% upper confidence limit of a binomial proportion using the exact binomial method of 
Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934].
Subgroup Analyses
10.10
To determine whether immune response to 9vHPV vaccination is consistent across various 
subgroups, the percent seroconversion and Month 7 GMTs (with corresponding nominal 95% 
CIs) will be estimated and Forest plots will be produced for the age subgroups of 9 to 15 
years old; 16 to 26 years old. 
The consistency of immune response to 9vHPV vaccination will be assessed descriptively via 
summary statistics by category for the classification variables listed above.
Analysis of immune response to 9vHPV vaccination by gender is not required because in
previous studies of the 9vHPV vaccine (Protocols V503-002 and V503-003 [Van Damme, P., 
et al 2015] [Castellsague, X., et al 2015]), HPV antibody response was similar between 
genders.
Compliance (Medication Adherence)
10.11
Compliance in this study is defined as receipt of all 3 doses of 9vHPV vaccine.  To 
summarize compliance, the numbers of participants who receive each vaccination will be 
tabulated.  For each of vaccination doses 2 and 3, histograms of the time (in days) of 
administration of the vaccine relative to the target vaccination visit will be provided.
Extent of Exposure
10.12
Each study participant is planned to be administered 0.5 mL of 9vHPV vaccine at each of 
3 vaccination visits (Day 1, Month 2, and Month 6).  Thus, each participant is expected to be 
administered a total of 1.5 mL of 9vHPV vaccine over a 6 months duration.
 
 
04TB5P
 
 
059WL7

Product:  V503 
58
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
11. References
[Alemany, L., et al 
2015]
Alemany L, Saunier M, Alvarado-Cabrero I, 
Quiros B, Salmeron J, Shin HR, et al. Human 
papillomavirus DNA prevalence and type 
distribution in anal carcinomas worldwide. Int J 
Cancer. 2015 Jan 1;136(1):98-107.
0409ZR
[Castellsague, X., et al 
2015]
Castellsague X, Giuliano AR, Goldstone S, 
Guevara A, Mogensen O, Palefsky JM, et al. 
Immunogenicity and safety of the 9-valent HPV 
vaccine in men. Vaccine. 2015 Nov 
27;33(48):6892-901.
04FD2G
[Center for Drug 
Evaluation and 
Research 2014]
Center for Drug Evaluation and Research 
(CDER). Summary basis for regulatory action -
Gardasil 9 [Internet]. Maryland: Department of 
Health and Human Services, Food and Drug 
Administration; 2014. Available from: 
http://www.fda.gov/downloads/BiologicsBloodVa
ccines/Vaccines/ApprovedProducts/UCM428239.
pdf .
04LNXC
[Clopper, C. J. and 
Pearson, E. S. 1934]
Clopper CJ, Pearson ES. The use of confidence or 
fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26(4):404-13.
03Q0LW
[European Medicines 
Agency 2016]
European Medicines Agency. Gardasil 9 - Human 
papillomavirus 9-valent vaccine (recombinant,
adsorbed) (EMA/192711/2016) [Internet]. 
London: European Medicines Agency; 2016. 4 p. 
Available from: 
http://www.ema.europa.eu/docs/en_GB/document
_library/EPAR_-
_Summary_for_the_public/human/003852/WC50
0189114.pdf .
04LNX8
[Forman, D., et al 
2012]
Forman D, de Martel C, Lacey CJ, Soerjomataram 
I, Lortet-Tieulent J, Bruni L, et al. Global burden 
of human papillomavirus and related diseases. 
Vaccine 2012;305:F12-F23.
04BBPB
[Garland, S. M., et al 
2009]
Garland SM, Steben M, Sings HL, James M, Lu S, 
Railkar R, et al. Natural history of genital warts: 
analysis of the placebo arm of 2 randomized phase 
III trials of a quadrivalent human papillomavirus 
(types 6, 11, 16, and 18) vaccine. J Infect Dis 
2009;199:805-14.
03RMDR
 
 
04TB5P
 
 
059WL7

Product:  V503 
59
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
[Joura, E. A., et al 
2015]
Joura EA, Giuliano AR, Iversen OE, Bouchard C, 
Mao C, Mehlsen J, et al. A 9-valent HPV vaccine 
against infection and intraepithelial neoplasia in 
women. N Engl J Med. 2015 Feb 19;372(8):711-
23.
044RDM
[Luxembourg, A., et al 
2015]
Luxembourg A, Brown D, Bouchard C, Giuliano 
AR, Iversen OE, Joura EA, et al. Phase II studies 
to select the formulation of a multivalent HPV L1 
virus-like particle (VLP) vaccine. Hum Vaccin 
Immunother. 2015;11(6):1313-22.
04LPSP
[McKeage, K. 2016]
McKeage K, Lyseng-Williamson KA. 9-Valent 
human papillomavirus recombinant vaccine 
(Gardasil 9): a guide to its use in the EU. Drugs 
Ther Perspect. 2016 Aug 20;32:414-421.
04LMFS
[Moreira, E. D., et al 
2016]
Moreira ED Jr, Block SL, Ferris D, Giuliano AR, 
Iversen OE, Joura EA, et al. Safety Profile of the 
9-Valent HPV Vaccine: A Combined Analysis of 
7 Phase III Clinical Trials. Pediatrics. 2016 
Aug;138(2). pii: e20154387.
04HBHT
[Neuzil, K. M., et al 
2011]
Neuzil KM, Canh DG, Thiem VD, Janmohamed 
A, Huong VM, Tang Y, et al. Immunogenicity and 
reactogenicity of alternative schedules of HPV 
vaccine in Vietnam: a cluster randomized 
noninferiority trial. JAMA 2011;305(14):1424-31.
03RKFN
[Parkin, D. Maxwell 
and Bray, Freddie 
2006]
Parkin DM, Bray F. Chapter 2: The burden of 
HPV-related cancers. Vaccine 2006;24(Suppl 
3):S11-S25.
03QZ7V
[Pitisuttithum, P., et al 
2015]
Pitisuttithum P, Velicer C, Luxembourg A. 9-
Valent HPV vaccine for cancers, pre-cancers and 
genital warts related to HPV. Expert Rev 
Vaccines. 2015 Sep 14:1-15.
047XK8
[Schiller, J. T., et al 
2012]
Schiller JT, Castellsague X, Garland SM. A 
review of clinical trials of human papillomavirus 
prophylactic vaccines. Vaccine 2012;305:F123-
F138.
03RTYW
[Serrano, B., et al 
2015]
Serrano B, de Sanjose S, Tous S, Quiros B, 
Munoz N, Bosch X, et al. Human papillomavirus 
genotype attribution for HPVs 6, 11, 16, 18, 31, 
33, 45, 52 and 58 in female anogenital lesions. Eur 
J Cancer. 2015 Sep;51(13):1732-41.
04F4S3
 
 
04TB5P
 
 
059WL7

Product:  V503 
60
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
[Stanley, M., et al 
2012]
Stanley M, Pinto LA, Trimble C. Human 
papillomavirus vaccines - immune responses. 
Vaccine. 2012 Nov 20;30 Suppl 5:F83-7.
04LNWV
[Van Damme, P., et al 
2015]
Van Damme P, Olsson SE, Block S, Castellsague 
X, Gray GE, Herrera T, et al. Immunogenicity and 
Safety of a 9-Valent HPV Vaccine. Pediatrics. 
2015 Jul;136(1):e28-39.
04885H
 
 
04TB5P
 
 
059WL7

Product:  V503 
61
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
12. Appendices
Appendix 1: Study Governance Considerations
12.1
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (eg, contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
04TB5P
 
 
059WL7

Product:  V503 
62
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
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.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck 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
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck 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.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
04TB5P
 
 
059WL7

Product:  V503 
63
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
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.
Data Protection
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 which 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.
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 institutional review board, ethics review committee (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.
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 in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
 
 
04TB5P
 
 
059WL7

Product:  V503 
64
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
verifying worksheet/case report form 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.
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.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (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 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.
 
 
04TB5P
 
 
059WL7

Product:  V503 
65
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
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 Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); 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 Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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 
 
 
04TB5P
 
 
059WL7

Product:  V503 
66
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
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 
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. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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 may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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 will 
promptly notify that study site’s IRB/IEC.
 
 
04TB5P
 
 
059WL7

Product:  V503 
67
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
12.2
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, 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, or are 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 treatment 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 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose of study treatment without any associated clinical symptoms or 
abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.”
●
Any new cancer or progression of existing cancer.
 
 
04TB5P
 
 
059WL7

Product:  V503 
68
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
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 9.3.5 for protocol specific exceptions
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 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of an MSD product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
04TB5P
 
 
059WL7

Product:  V503 
69
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
A SAE is defined as any untoward medical occurrence that, at any dose:
e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one 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.
Additional Events Reported
Additional Events which require reporting 
●
In addition to the above criteria, adverse events 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.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
04TB5P
 
 
059WL7

Product:  V503 
70
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.  (for pediatric studies, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes 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 utilized 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 redness or swelling from the day of vaccination through Day 5 
post-vaccination will be evaluated by maximum size.
Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event 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 initialed 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 adverse event based upon the available 
information
●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the adverse event:
●
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?
 
 
04TB5P
 
 
059WL7

Product:  V503 
71
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
●
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 this 
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 one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH 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 INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.  
●
Consistency with Study treatment 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 case report forms /worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence 
of the AE onset relative to the administration of the Sponsor's product is 
reasonable.  The AE is more likely explained by the Sponsor's product than by 
another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
 
 
04TB5P
 
 
059WL7

Product:  V503 
72
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
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 one 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.
Reporting of AE, SAE, 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 electronic data collection 
(EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information 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 electronic data collection 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 electronic data collection 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 Trial File Binder (or equivalent).
 
 
04TB5P
 
 
059WL7

Product:  V503 
73
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection 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 Trial File Binder (or equivalent).
 
 
04TB5P
 
 
059WL7

Product:  V503 
74
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Appendix 3: Clinical Laboratory Tests
12.3
The tests detailed in Table 7 will be performed by the local laboratory.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 6.1 and 6.2 of the protocol.
Table 7
Protocol-Required Safety Laboratory Assessments
Laboratory Test
Study Visits Performed 
Serum or urine beta human chorionic gonadotropin (β-hCG)
pregnancy test
(for all female participants at all vaccination visits)
Day 1
Month 2
Month 6
Month 7
The serum pregnancy test or urine pregnancy test must be sensitive to 25 mIU/ML β-hCG 
and performed prior to vaccination.  Results should be negative prior to vaccination.  
Pregnancy testing is required for all female participants. 
Any female participant with a positive pregnancy test at Day 1 will not be vaccinated and 
will not be allowed to participate in the study.  Female participants with a positive pregnancy 
test after Day 1 will not be vaccinated until after pregnancy outcome.  
Investigators must document their review of each laboratory safety report.
 
 
04TB5P
 
 
059WL7

Product:  V503 
75
Protocol/Amendment No.: 017-01 
V503-017-01 Final Protocol
19-Dec-2017
Confidential
Appendix 4: Abbreviations
12.4
9vHPV
9-valent human papillomavirus
AAHS
amorphous aluminium hydroxyphosphate sulfate
AE
adverse event
APaT
All Participants as Treated
β-hCG
β-hCG=beta human chorionic gonadotropin
CI
confidence interval
cLIA
competitive Luminex immunoassay
CRF
case report form
DNA
deoxyribonucleic acid
eCRF
electronic case report form
GCP
Good Clinical Practice
GMT
geometric mean titer
HIV
human immunodeficiency virus
HPV
human papillomavirus
HPV-9 cLIA
9-valent HPV competitive Luminex immunoassay
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
interactive response technology
LLOQ
lower limit of quantification
PPI
Per-Protocol Immunogenicity
qHPV
quadrivalent human papillomavirus HPV
RNA
ribonucleic acid
SAE
serious adverse event
SoA
schedule of activities
STI
sexually transmitted infection
SUSAR
suspected unexpected serious adverse reactions
V503
9vHPV vaccine
VLP
virus-like particle
VRC
Vaccination Report Card
 
 
04TB5P
 
 
059WL7