A Phase I Randomized, Double-Blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Immunogenicity of V160 (Human Cytomegalovirus Vaccine) in Healthy Japanese Men
Phase: PHASE1
Conditions: Cytomegalovirus Infections
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03840174 
Document Date: 
19-NOV-2018
A Phase I Randomized, Double-Blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability and Immunogenicity of V160 (Human 
Cytomegalovirus Vaccine) in Healthy Japanese Men

PRODUCT: V160
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Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME 
CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase I Randomized, Double-Blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability and Immunogenicity of V160 (Human Cytomegalovirus Vaccine) in Healthy 
Japanese Men
Protocol Number: 003-00
Compound Number: V160
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
Not Applicable
Approval Date: 19-November-2018
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study File 
Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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Table of Contents
1
PROTOCOL SUMMARY ............................................................................................10
1.1
Synopsis.................................................................................................................10
1.2
Schema ..................................................................................................................14
1.3
Schedule of Activities (SoA) ................................................................................15
2
INTRODUCTION..........................................................................................................17
2.1
Study Rationale....................................................................................................17
2.2
Background ..........................................................................................................17
2.2.1
Pharmaceutical and Therapeutic Background .............................................18
2.2.2
Preclinical and Clinical Studies ...................................................................18
2.2.2.1
Preclinical Studies..............................................................................18
2.2.2.2
Clinical Studies..................................................................................19
2.3
Benefit/Risk Assessment......................................................................................20
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................20
4
STUDY DESIGN............................................................................................................22
4.1
Overall Design ......................................................................................................22
4.2
Scientific Rationale for Study Design.................................................................22
4.2.1
Rationale for Endpoints ...............................................................................22
4.2.1.1
Immunogenicity Endpoints................................................................22
4.2.1.2
Safety Endpoints ................................................................................23
4.2.1.3
Future Biomedical Research..............................................................23
4.2.2
Rationale for the Use of Placebo .................................................................24
4.2.3
Rationale for Adjuvant.................................................................................24
4.3
Justification for Dose ...........................................................................................24
4.3.1
Rationale for Dose Interval and Study Design ............................................24
4.4
Beginning and End of Study Definition .............................................................24
4.4.1
Clinical Criteria for Early Study Termination .............................................25
5
STUDY POPULATION ................................................................................................25
5.1
Inclusion Criteria.................................................................................................25
5.2
Exclusion Criteria ................................................................................................26
5.2.1
Participant Deferment Criteria before Vaccination .....................................28
5.2.2
Criteria to be Checked for Excluding Participants from Receiving 
Subsequent Doses ........................................................................................29
5.3
Lifestyle Considerations ......................................................................................29
5.4
Screen Failures.....................................................................................................29
5.5
Participant Replacement Strategy......................................................................29
6
STUDY INTERVENTION............................................................................................30
 
 
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6.1
Study Intervention(s) Administered...................................................................31
6.1.1
Medical Devices...........................................................................................32
6.2
Preparation/Handling/Storage/Accountability .................................................32
6.2.1
Dose Preparation..........................................................................................32
6.2.2
Handling, Storage, and Accountability........................................................33
6.3
Measures to Minimize Bias: Randomization and Blinding..............................33
6.3.1
Intervention Assignment..............................................................................33
6.3.2
Stratification.................................................................................................33
6.3.3
Blinding........................................................................................................33
6.4
Study Intervention Compliance..........................................................................34
6.5
Concomitant Therapy..........................................................................................34
6.5.1
Rescue Medications and Supportive Care ...................................................35
6.6
Dose Modification (Escalation/Titration/Other)...............................................35
6.7
Intervention After the End of the Study............................................................35
6.8
Clinical Supplies Disclosure................................................................................35
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................35
7.1
Discontinuation of Study Intervention...............................................................35
7.2
Participant Withdrawal From the Study...........................................................36
7.3
Lost to Follow-up .................................................................................................36
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................37
8.1
Administrative and General Procedures ...........................................................38
8.1.1
Informed Consent.........................................................................................38
8.1.1.1
General Informed Consent.................................................................38
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................38
8.1.2
Inclusion/Exclusion Criteria ........................................................................39
8.1.3
Participant Identification Card.....................................................................39
8.1.4
Medical History ...........................................................................................39
8.1.5
Prior and Concomitant Medications Review ...............................................39
8.1.5.1
Prior Medications...............................................................................39
8.1.5.2
Concomitant Medications ..................................................................39
8.1.6
Assignment of Screening Number...............................................................40
8.1.7
Assignment of Treatment/Randomization Number .....................................40
8.1.8
Study Intervention Administration ..............................................................40
8.1.8.1
Timing of Dose Administration.........................................................41
8.1.9
Discontinuation and Withdrawal .................................................................41
8.1.9.1
Withdrawal From Future Biomedical Research ................................41
 
 
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8.1.10
Participant Blinding/Unblinding..................................................................42
8.1.11
Distribution of Vaccination Report Card.....................................................42
8.1.12
Calibration of Equipment.............................................................................43
8.2
Immunogenicity Assessments .............................................................................43
8.2.1
Viral Neutralizing Antibody Assay .............................................................43
8.3
Safety Assessments...............................................................................................43
8.3.1
Physical Examinations (Full and Targeted Examinations)..........................43
8.3.2
Vital Signs and Body Temperature..............................................................43
8.3.3
Safety Assessments Using the VRC ............................................................44
8.3.4
Clinical Laboratory Assessments.................................................................44
8.3.4.1
CMV IgG Testing ..............................................................................45
8.3.4.2
CMV PCR Testing.............................................................................45
8.3.4.2.1
Plasma......................................................................................45
8.3.4.2.2
Swab.........................................................................................46
8.3.4.2.3
Urine and Saliva.......................................................................46
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................46
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information.............................................................................46
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......48
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...48
8.4.4
Regulatory Reporting Requirements for SAE .............................................49
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................49
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ................................................................................................49
8.4.7
Events of Clinical Interest (ECIs) ................................................................49
8.5
Treatment of Overdose........................................................................................49
8.6
Pharmacokinetics.................................................................................................50
8.7
Pharmacodynamics..............................................................................................50
8.8
Future Biomedical Research Sample Collection...............................................50
8.9
Planned Genetic Analysis Sample Collection ....................................................50
8.10
Visit Requirements...............................................................................................50
9
STATISTICAL ANALYSIS PLAN .............................................................................50
9.1
Statistical Analysis Plan Summary.....................................................................51
9.2
Responsibility for Analyses/In-house Blinding .................................................51
9.3
Hypotheses/Estimation ........................................................................................52
9.4
Analysis Endpoints...............................................................................................52
9.4.1
Immunogenicity Endpoints..........................................................................52
 
 
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9.4.2
Safety Endpoints ..........................................................................................52
9.5
Analysis Populations............................................................................................52
9.5.1
Immunogenicity Analysis Populations ........................................................52
9.5.2
Safety Analysis Populations ........................................................................53
9.6
Statistical Methods...............................................................................................53
9.6.1
Statistical Methods for Immunogenicity Analyses......................................53
9.6.2
Statistical Methods for Safety Analyses ......................................................54
9.6.3
Demographic and Baseline Characteristics .................................................57
9.7
Interim Analyses ..................................................................................................57
9.8
Multiplicity ...........................................................................................................57
9.9
Sample Size and Power Calculations .................................................................57
9.10
Subgroup Analyses...............................................................................................57
9.11
Compliance (Medication Adherence).................................................................57
9.12
Extent of Exposure...............................................................................................57
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................58
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........58
10.1.1
Code of Conduct for Clinical Trials.............................................................58
10.1.2
Financial Disclosure.....................................................................................60
10.1.3
Data Protection.............................................................................................60
10.1.3.1
Confidentiality of Data ......................................................................61
10.1.3.2
Confidentiality of Participant Records...............................................61
10.1.3.3
Confidentiality of IRB/IEC Information............................................61
10.1.4
Publication Policy........................................................................................61
10.1.5
Compliance with Study Registration and Results Posting Requirements ...62
10.1.6
Compliance with Law, Audit, and Debarmen .............................................62
10.1.7
Data Quality Assurance ...............................................................................63
10.1.8
Source Documents .......................................................................................63
10.1.9
Study and Site Closure.................................................................................64
10.2
Appendix 2: Clinical Laboratory Tests..............................................................65
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................69
10.3.1
Definition of AE ..........................................................................................69
10.3.2
Definition of SAE ........................................................................................70
10.3.3
Additional Events Reported.........................................................................71
10.3.4
Recording AE and SAE ...............................................................................71
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor75
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................76
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................77
10.5.1
Definitions....................................................................................................77
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................78
10.7
Appendix 7: Country-specific Requirements ....................................................83
10.8
Appendix 8: Abbreviations .................................................................................84
11
REFERENCES...............................................................................................................86
 
 
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LIST OF TABLES
Table 1
Study Interventions ....................................................................................31
Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...........................................................................48
Table 3
Analysis Strategy for Key Efficacy Variables ...........................................54
Table 4
Safety Analyses of Adverse Events Endpoints..........................................56
Table 5
Protocol-required Laboratory Assessments ...............................................68
 
 
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LIST OF FIGURES
Figure 1
Study Design Diagram...............................................................................14
 
 
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase I Randomized, Double-Blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability and Immunogenicity of V160 (Human Cytomegalovirus Vaccine) in Healthy 
Japanese Men
Short Title: Phase I Study for Safety and Immunogenicity of V160 in Healthy Japanese Men
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for the study.
The following objectives will be evaluated in healthy Japanese male participants 20 years to 64 
years of age inclusive.
Primary Objectives
Primary Endpoints
To assess the safety and tolerability of a 3-dose 
regimen of V160 administered intramuscular 
(IM) by cytomegalovirus (CMV) serostatus.
- Solicited injection site adverse events (AEs) 
within Days 1 through 5 after each vaccination 
visit, and solicited systemic AEs, and vaccine-
related serious adverse events (SAEs) within 
Days 1 through 14 after each vaccination visit
Secondary Objectives
Secondary Endpoints
To evaluate CMV-specific neutralizing 
antibody (NAb) geometric mean titers (GMTs) 
at 1 month postdose (PD)3  in initially CMV-
seronegative participants vaccinated with a 3-
dose regimen of V160 administered IM.
- CMV-specific NAb titers
To evaluate viral detection, viral shedding, and 
viral leakage of V160 by the number and 
proportion of the participants with positive
viral detection in plasma up to 14 days PD1, in 
urine and saliva up to 1 month PD3, and in 
injection-site swab and adhesive tape swab up 
to 30 minutes PD1 by CMV serostatus.
- Viral detection of V160 in plasma, urine and 
saliva, and injection-site swab and adhesive 
tape swab
 
 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Prevention
Indication
Prevention of CMV infection in vaccinated women, and 
congenital CMV infection (cCMVi)/congenital CMV disease
(cCMVd) in children born to vaccinated women
Population
Healthy Japanese male, 20 years to 64 years of age inclusive.
Study Type
Interventional
Intervention Model
Parallel
This is a single-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Investigator, Participant, and Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 9.5 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
For purposes of analysis and reporting, the overall study 
ends when the Sponsor receives the last serology assay 
result.
Number of Participants:
Approximately 18 participants will be allocated/randomized as described in Section 9.9.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Intervention 
Name
Dose 
Formulation
Unit Dose 
Strength
Dosage 
Level
Route 
of 
Admin.
Vaccination 
Regimen
Use
V160 
V160
Lyophilized
Cake
200 
Units/mL
100 Units 
with 225 
μg 
aluminum 
per
0.5mL 
dose
IM 
Day 1, 
Month 2, 
Month 6
Experimental
APA 
Diluent
Sterile 
Suspension
for 
reconstitution
450 μg/mL
Adjuvant
Placebo
Sterile 
Saline 
Placebo
Sterile 
Solution
Not 
applicable
0.5 mL
IM 
Day 1, 
Month 2, 
Month 6
Placebo
Abbreviations: APA Diluent = Aluminum Phosphate Adjuvant (APA) Diluent, Sterile Saline Placebo = V160
Sterile Saline Placebo, Unit Dose Strength = Strength of the V160 and APA product after reconstitution, 
Dosage level = post reconstitution per 0.5 mL dose, IM = Intramuscular
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 7.5 months from 
the time the participant signs the Informed Consent Form (ICF) through the final 
contact. After a screening phase of approximately 21 days, each participant will be 
receiving assigned intervention for approximately 6 months. After the end of 
vaccination each participant will be followed for 1 month.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design Diagram
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Intervention
Notes
Visit Number/Title
Visit 1 
Screening
Visit 2
Day 1
Vac 1
Visit 3
Visit 4
Visit 5
Visit6
Month 2
Vac 2
Visit 7
Month 6
Vac 3
Visit 8
Month 7
Scheduled Day
-21 to -1
1
3
7
14
60
180
210
Scheduling Window (Days)
-21 to -1
+/- 1
+/- 2 
+/- 2 
+14
+14
+14
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Check Inclusion/Exclusion Criteria
X
X
Performed prior to vaccination
Participant Identification Card
X
Medical History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Vaccine Randomization
X
V160/Placebo Administration
X
X
X
Distribution of VRC
X
X
X
Review of VRC data
X
X
X
X
X
X
Telephone contacts after 14 
days from Month 2 and Month 
6, respectively to remind the 
subjects: See Section 8.3.3.
Check postdose 1 Deferment/
Exclusion/Discontinuation criteria
X
X
Performed prior to vaccination
Collection of VRC
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
Includes height, weight, vital 
signs and other assessments 
specified in Section 8.3.1.
Directed Physical Examination
X
X
X
X
Includes vital signs and limited
assessments specified in 
Section 8.3.1. Performed prior 
to vaccination for the 
vaccination visits.
30 Minutes Postdose Observation
X
X
X
 
 
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Study Period
Screening
Intervention
Notes
Visit Number/Title
Visit 1 
Screening
Visit 2
Day 1
Vac 1
Visit 3
Visit 4
Visit 5
Visit6
Month 2
Vac 2
Visit 7
Month 6
Vac 3
Visit 8
Month 7
Scheduled Day
-21 to -1
1
3
7
14
60
180
210
Scheduling Window (Days)
-21 to -1
+/- 1
+/- 2 
+/- 2 
+14
+14
+14
AE Monitoring
X
X
X
X
X
X
X
X
Detailed reporting time periods 
for AEs are indicated in 
Table 2; See Section 8.4.1.
Laboratory Procedures/Assessments
Screening for CMV Serostatus by 
IgG
X
Blood (DNA) for Future 
Biomedical Research
X
Collect sample prior to 
vaccination; See Section 8.8.
Blood(Serum) for Neutralizing 
Antibody titer
X
X
Collect sample prior to 
vaccination on Day 1; See 
Section 8.2.1.
Blood(Plasma) for Viral 
Assessment
X
X
X
X
Collect samples at 3 points on 
Day 1; See Section 8.3.4.
Swab Sampling from Injection-site 
for Viral Assessment
X
Collect samples at 4 points on 
Day 1; See Section 8.3.4.
Swab Sampling from Adhesive 
Tape (Inside and Outside, 
respectively) for Viral Assessment 
X
Collect samples from each side 
at 3 points on Day 1; See 
Section 8.3.4.
Urine and Saliva Collection for 
Viral Assessment
X
X
X
X
X
X
X
Collect sample prior to 
vaccination; See Section 8.3.4.
AE: Adverse Events, CMV:cytomegalovirus, DNA:deoxyribonucleic acid, IgG:immunoglobulin G, Vac:vaccination, VRC:Vaccination Report Card
 
 
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2
INTRODUCTION
2.1
Study Rationale
Merck is developing an investigational CMV vaccine (referred to as V160) for the prevention 
of infection and disease caused by CMV in vulnerable populations. Although CMV infection 
(CMVi) is asymptomatic in healthy individuals, CMV is an important pathogen for 
congenitally infected infants and immunosuppressed individuals, such as solid organ 
transplant or hematopoietic stem cell transplant recipients.
Congenital CMV infection (cCMVi) is the most frequent infectious cause of newborn 
malformation in developed countries. Congenital CMVi, which can lead to congenital CMV 
disease (cCMVd), presents as sensorineural hearing loss (responsible for almost one-third of 
all cases), and neurodevelopmental abnormalities. Congenital CMVd occurs more frequently 
than Down's syndrome, Spina Bifida, Fetal Alcohol Syndrome and, non-epidemic Congenital 
Rubella Syndrome (prior to preventing onset of rubella with wide use of a vaccine).  
Development of a vaccine for prevention of cCMVi has been rated a high priority by the 
National Academy of Medicine [Institute of Medicine 2000].
V160 is initially being developed worldwide for use in women of childbearing age 
independent of CMV serostatus. This study is being conducted to evaluate the safety, 
including biodistribution in human, and immunogenicity of V160 in healthy Japanese men, 
prior to a planned study in Japanese women of childbearing age in near future.
2.2
Background
Human CMV, also known as human herpesvirus 5 is a double-stranded deoxyribonucleic 
acid (DNA) virus belonging to the beta-herpesvirus family of Herpesviridae. Acquisition 
appears to require close or intimate contact with persons who are excreting CMV in their 
urine, saliva or other secretions. CMV can also be transmitted via blood transfusion, breast 
milk, sexual intercourse, and transplanted organs. 
In most healthy individuals, CMVi is asymptomatic. When symptoms are present, they are 
often mild, can be confused with other illnesses, and include fever, sore throat, fatigue, 
and/or swollen glands. After infection, the virus establishes lifelong latency, the evidence of 
which is the detection of anti-CMV antibodies in the blood (CMV seropositivity). Healthy 
individuals with latent CMV infection can reactivate to shed the virus in their saliva or urine, 
which is also predominantly asymptomatic.
It is known that CMV can cause serious disease in congenitally infected newborns and 
immunocompromised individuals. The spectrum of disease in newborns with cCMVi ranges 
from fetal/infant death to neurological and sensory impairments which are diagnosed later in 
childhood [Hahn, G., et al 1998] [Just-Nubling, G., et al 2003] [Sinclair, J. 2008] [Lanzieri, 
T. M., et al 2014].
 
 
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Congenital CMVi is a significant public health problem. Following the widespread use of 
rubella vaccine and the elimination of endemic rubella and congenital rubella syndrome in 
many developed countries [Reef, S. E, et al 2006], cCMVi is now the most common 
congenital viral infection in these countries, and is estimated that approximately 0.6%-0.7% 
will have cCMVi at birth [Dollard, S. C., et al 2007]. Approximately 10%-15% of cCMVi 
will develop symptoms of central nervous system damage either at birth or progressively in 
the first few years of life, with clinical manifestations including sensorineural hearing loss, 
mental retardation, and cerebral palsy [Sung, H., et al 2010]. In Japan, rates of cCMVi have 
been reported to be approximately 0.3% of the newborns [Koyano 2011]. It was also reported 
in Japan that 30% of cCMVi had typical clinical manifestations and/or showed abnormalities 
in brain images at birth [Koyano 2011].
Maternal immunity from naturally acquired infection can protect a fetus from cCMVi. In 
developed countries, maternal seropositivity/seroprevalence (IgG positivity) for CMV is 
approximately 50% and the prevalence of cCMVi among infants is estimated to be 
approximately 0.7% among live births [Dollard, S. C., et al 2007]. In Japan, maternal 
seropositivity for CMV is approximately 71% in 2009 [Azuma 2010], and seropositivity in 
women of child bearing age has been decreasing by year [Iida 2015]. 
Refer to the Investigator’s Brochure (IB) for detailed background information on V160.
2.2.1
Pharmaceutical and Therapeutic Background
There is no effective CMV vaccine to protect women from acquiring CMVi during 
pregnancy or any recognized intervention that can effectively reduce transmission of CMV 
from newly infected pregnant women to the fetus.
Immune responses to natural CMVi can partially protect individuals against re-infection 
[Plotkin, S. A., et al 1989] [Adler, S. P., et al 1995]. Maternal immunity from naturally 
acquired infection can also partially protect a fetus from cCMVi [Fowler, K. B., et al 2003]. 
In addition, CMV-seropositivity is associated with a lower incidence of severe CMV disease 
post-transplantation [Opelz, G., et al 2004] [Griffiths, P. D., et al 2011]. An effective CMV 
vaccine could therefore be designed to parallel the immune response commonly seen in 
healthy CMV seropositive individuals and should induce both humoral and cellular immunity
[Wang, D., et al 2016]. Such a vaccine could protect women from acquisition of CMVi, and 
thereby prevent vertical transmission to their baby, and would be a major medical advance 
that addresses a critical unmet public health need.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Preclinical Studies
The AD169 strain of CMV was originally isolated at the National Institutes of Health from
the adenoids of a 7-year-old girl. The isolate was attenuated through multiple passages in
human fibroblasts. This live attenuated virus was tested as a vaccine in a Phase-1 study in 24
CMV seronegative male participants [Neff, B. J., et al 1979]. The vaccine was well tolerated 
 
 
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and did not cause any serious adverse events (SAEs). No virus could be recovered either 
from peripheral lymphocytes or urine of the vaccinated participants.
The V160 vaccine was created using the Merck variant of AD169 virus (MAD169). The
vaccine virus was genetically modified to be conditionally replication defective in the 
absence of a synthetic molecule called Shield-1 through the ddFKBP-mediated 
destabilization of two viral proteins critical for viral replication. With Shield-1 present, viral 
stocks for V160 can be grown; but in vivo with no Shield-1, replication of V160 is prevented. 
In order to facilitate broad immune responses, the pentameric complex (gH/gL/pUL128-131) 
was restored on the V160 virus. This restores elicitation of antibodies against the gH 
antigens, as well as viral tropism of V160 for epithelial and endothelial cells, permitting entry 
and some protein production without replication (in the absence of Shield-1). Cell-mediated 
and humoral antibody responses are thereby enhanced.
Since there is no relevant animal model available to assess CMV vaccine efficacy, the key 
immunological parameters for preclinical evaluations were based on neutralizing antibodies 
(NAbs) and T-cell responses in animals. V160 has been extensively evaluated in rhesus 
macaques, and can elicit potent NAbs superior to those seen with the gB/MF59 candidate 
CMV vaccine as well as balanced CD4 and CD8 T cell responses. V160 was well tolerated in 
toxicology studies in animals, which supports the administration of this vaccine to humans.
A biodistribution study in rats was conducted to investigate the distribution of V160 to blood 
and tissues after vaccination. The results of this study demonstrated that V160 was reported 
as negative in any samples collected just after injection through 1 month, except for IM 
injection site samples. The V160 strain at IM injection site disappeared at a month after 
vaccination.
2.2.2.2
Clinical Studies
Phase 1 Clinical Study
The first-in-human study was a Phase 1 dose ranging study to assess the safety and
immunogenicity of various antigen dose levels, formulations, and routes of administration in
healthy volunteers 18 years of age and older (V160-001) in United States. In study V160-001, 
the safety and tolerability as well as the immunogenicity of V160 was evaluated in both 
CMV seronegative and seropositive participants and is briefly summarized below. Refer to 
the IB for more detailed information.
Participants in study V160-001 received a 3-dose vaccination regimen (0-1-6 month
schedule) at various doses (10-250 units) administered intramuscularly or intradermally, with
and without aluminum phosphate adjuvant. A saline placebo was used as the control.
In initially CMV seronegative participants, all vaccination groups receiving V160 with and
without aluminum phosphate adjuvant exhibited statistically significant higher CMV-specific 
NAb titers compared with the placebo group. The NAb geometric mean titer (GMT) at 
Month 7 was highest in recipients of V160 100 unit dose + aluminum phosphate adjuvant. 
 
 
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Robust cell mediated immune responses were also noted among CMV seronegative 
participants but no differences across dose groups of V160 were observed. Overall, cell 
mediated immune responses at all doses, and NAb responses at some doses (including 
100U+ aluminum phosphate adjuvant) in CMV seronegative participants approximated those 
observed in naturally infected CMV seropositive participants.
All tested V160 formulations were safe and generally well-tolerated. No SAEs and no events 
of clinical interest (ECIs) (overdoses, pre-defined elevated hepatic enzyme, and autoimmune 
conditions) were reported. Overall, adjuvant-containing formulations were more reactogenic 
than unadjuvanted irrespective of dose. Across the different vaccination groups, the majority 
of AEs were the solicited injection site AEs (pain/tenderness, erythema/redness, and 
swelling) and the solicited systemic AEs (headache, fatigue, muscle pain, and joint pain); all 
of these events were transient and most were mild to moderate in intensity. No vaccine strain 
CMV was detected by polymerase chain reaction (PCR) in the saliva or urine of vaccine 
recipients.
Refer to the IB for further details regarding viral replication, virological characteristics of the 
vaccine virus, as well as detailed background information on animal studies.
Phase 2 Clinical Study (Ongoing)
A global Phase 2b study (V160-002) is currently being conducted to further evaluate the 
V160 formulation containing 100 units/dose + aluminum phosphate adjuvant, which elicited 
high CMV-specific NAb in study V160-001. Both humoral and cellular immune responses as
well as protection against CMVi in CMV seronegative vaccine recipients are being assessed.
The study population in study V160-002 is women of child-bearing age and thus, healthy 
females between 16 and 35 years of age are included in the study. Infant outcomes of any 
study participant who becomes pregnant will be assessed to evaluate protection against 
cCMVi as well.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
intervention during participation, as clinical studies are designed to provide information 
about the safety and immunogenicity of an investigational vaccine.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IB and Informed Consent Form (ICF) documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for the study.
The following objectives will be evaluated in healthy Japanese male participants 20 years to 
64 years of age inclusive.
 
 
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Objectives
Endpoints
Primary
To assess the safety and tolerability of a 
3-dose regimen of V160 administered 
intramuscular (IM) by cytomegalovirus
(CMV) serostatus.
•
Solicited injection site adverse events 
(AEs) within Days 1 through 5 after 
each vaccination visit, and solicited 
systemic AEs, and vaccine-related 
serious adverse events (SAEs) within 
Days 1 through 14 after each 
vaccination visit
Secondary
To evaluate CMV-specific neutralizing 
antibody (NAb) geometric mean titers 
(GMTs) at 1 month postdose (PD)3  in 
initially CMV-seronegative participants 
vaccinated with a 3-dose regimen of 
V160 administered IM.
•
CMV-specific NAb titers
To evaluate viral detection, viral 
shedding, and viral leakage of V160 by 
the number and proportion of the 
participants with positive viral detection 
in plasma up to 14 days PD1, in urine and 
saliva up to 1 month PD3, and in 
injection-site swab and adhesive tape 
swab up to 30 minutes PD1 by CMV 
serostatus.
•
Viral detection of V160 in plasma, 
urine and saliva, and injection-site swab
and adhesive tape swab
Exploratory
To evaluate seroconversion rate based on 
the NAb titers at 1 month PD3 in initially 
CMV-seronegative participants 
vaccinated with a 3-dose regimen of 
V160 administered IM.
•
Seropositivity based on the NAb titers
To evaluate NAb GMT and geometric 
mean of CMV-specific NAb fold-rise 
(GMFR) at 1 month PD3 relative to Day 
1 in initially CMV-seropositive 
participants vaccinated with a 3-dose 
regimen of V160 administered IM.
•
CMV-specific NAb titers
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1, randomized, placebo-controlled, parallel-group, single-site, double-
blinded, safety and immunogenicity study of V160 in healthy Japanese men 20 years to 64 
years of age inclusive.
This study will evaluate the safety and immunogenicity of 3-dose regimen of V160 
administered IM over 6 months in CMV-seropositive and CMV-seronegative of healthy 
Japanese men.
In this study, approximately 18 Japanese healthy male participants will be randomized in a 
2:1 ratio with stratification by CMV serostatus  (seropositive vs seronegative) to receive 3 IM
injections of either 100 units/dose of V160 adjuvanted with aluminum phosphate adjuvant or 
placebo (saline solution) administered on Day 1, Month 2, and Month 6. 
Participants will be considered to have completed the study if they received all 3 doses of 
study vaccine at the time points specified in the SoA and have completed the Month 7 study 
visit.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The primary objective of the study is to assess the safety and tolerability profiles of a 3-dose 
regimen of V160 administered IM in Japanese male participants 20 years to 64 years of age 
inclusive who are in good medical health at the start of the study. The selected population for 
this first study in Japanese participants is consistent with the population typically used in 
Phase I clinical studies, namely healthy adult male at low risk for disease, prior to include 
Japanese women of childbearing age in near future study. Considering possibility of future 
use in CMV seropositive population, this study will enroll CMV seropositive participants to 
collect safety and immunogenicity data as well as CMV seronegative ones. Approximately 
18 participants will be enrolled in this study to include 9 CMV-seropositive and 9 CMV-
seronegative individuals.
4.2.1
Rationale for Endpoints
4.2.1.1
Immunogenicity Endpoints
The purpose of the CMV-specific NAb assay is to assess humoral immunity by quantifying 
NAb titers to CMV before and after vaccination. This assay provided the primary serological 
readout in study V160-001, allows quantitative comparison of responses to different doses, 
and provides a functional characterization of the vaccine response. Also, seropositivity based 
on the Nab assay in initially CMV-seronegative participants will be assessed that is defined 
as NAb titer ≥assay defined cutoff level.
 
 
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4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the product’s safety 
profile demonstrated in study V160-001.
In this study, as in study V160-001, solicited injection site AEs will be collected Days 1 to 5 
following each dose of V160/placebo, and oral temperatures and pre-specified solicited 
systemic AEs including tiredness (fatigue), muscle pain (myalgia), headache, and joint pain 
(arthralgia) will be collected Days 1 to 14 following each dose of V160/placebo. SAEs will 
be collected for the duration of the participant’s study participation (up to Month 7/Visit 8). 
The vaccine is conditionally replication defective and the vaccine virus will not replicate in 
the human body because Shield-1 is not present, regardless, specific safety measurements are 
being collected as outlined in Section 8.4.
The time points chosen for safety assessment are based on peak occurrence of AEs generally 
observed following vaccination in clinical studies with multi-dose vaccines. The investigator 
(or medically-qualified designee) will assess the vaccine relatedness of all serious and non-
serious AEs, the intensity of all serious and non-serious AEs. During the Vaccination Report 
Card (VRC)-specified safety follow-up period (Day 1 through Day 14), clinical AEs will be 
recorded on a VRC by the participant on the day of occurrence. The investigator will use the 
information provided by the participant both on the VRC, and verbally at the time of VRC 
review.
Details on AEs, including definitions and reporting requirements, can be found in 
Appendix 3.
In addition, samples of saliva, urine, injection-site swab and adhesive tape swab will be 
collected at pre-specified times according to the SoA to evaluate the possible shedding, and 
leakage from the injection-site using a sensitive PCR assay. Furthermore, samples of blood 
(plasma) will be collected at pre-specified times up to Day 14 (SoA) as well to evaluate the 
possible biodistribution of vaccine virus in plasma using PCR assay.
4.2.1.3
Future Biomedical Research
The Sponsor will conduct future biomedical research on DNA specimens for which consent
was provided during this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
 
 
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4.2.2
Rationale for the Use of Placebo
There is no commercially available CMV vaccine to serve as a comparator. A concurrent 
placebo control (sterile saline) is included in this study in order to compare safety profile and 
immunogenicity with those V160.
4.2.3
Rationale for Adjuvant
The aluminum phosphate adjuvant was assessed in study V160-001 where formulations 
containing aluminum phosphate adjuvant tended to be more immunogenic than those 
without, particularly at the 100 unit dose. Therefore, aluminum phosphate adjuvant is 
included in the V160 formulation for this Japan Phase 1 study. The dose level of aluminum 
phosphate adjuvant in the V160 formulation to be used in this study is consistent with the 
amount of aluminum phosphate adjuvant (125 μg/dose to 500 μg/dose) used in many other 
licensed vaccines.
4.3
Justification for Dose
The V160 formulation selected for this study is 100 Units/0.5 mL dose +225 μg of aluminum 
phosphate adjuvant as this formulation provided a safe and generally well tolerated profile 
with the greatest immunogenicity (measured by the NAb response) compared to the other 
dose groups in study V160-001. All participants randomized to the vaccine group will be 
given 3 injections of the V160 100 units/0.5 mL + aluminum phosphate adjuvant. The 
maximum dose at each dosing time point is the same as the minimum dose.
4.3.1
Rationale for Dose Interval and Study Design
The proposed dosing interval is intended to provide early induction of CMV-specific immune 
responses (with a second dose given within 2 months) and establishment of long term 
immunogenicity by providing a third dose at a later time (6 months). A 3-dose schedule of 
V160 administered at Day 1, Month 1, and Month 6 was used for study V160-001. For this 
Japan Phase 1 study, a Day 1, Month 2, and Month 6 schedule was selected to be consistent 
with the 3-dose regimen in the ongoing Phase 2b, proof of concept study in women of child-
bearing age (V160-002). In Phase 2b, 2-dose regimen (Day 1, Month 6) will also be 
evaluated because it would allow greater compliance. Based on the results of Phase 2b, 
2-dose or 3-dose regimen will be selected for Phase 3 studies.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last assay result.
 
 
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4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Healthy Japanese male participants between the ages of 20 and 64 (inclusive) will be enrolled 
in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Participant is healthy, based on medical history and physical examination.
2. Participant is serologically confirmed with CMV IgG as either CMV seropositive or 
CMV seronegative at Visit 1. Subjects who are indeterminate for CMV serostatus at 
randomization will be excluded from the study.
Demographics
3. Participant is Japanese Male.
4. Participant is from 20 years to 64 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
5. A male participant are eligible to participate if they agree to the following from 
randomization through at least 4 weeks after the last dose of V160/placebo (from Day 1 
through Month 7):

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
OR

Must agree to use contraception unless confirmed to be azoospermic (Vasectomized 
or secondary to medical cause) as detailed below:
o
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a woman of childbearing 
potential (WOCBP) [Appendix 5]
who is not currently pregnant. Note: Men 
with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
 
 
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Informed Consent
6. The participant provides written informed consent for the study. The participant may also 
provide consent for future biomedical research. However, the participant may participate 
in the main study without participating in future biomedical research.
Protocol Adherence
7. The participant is able to read, understand, and complete study questionnaires (ie, the 
VRC).
8. The participant is able to complete all scheduled visits and to comply with the study 
procedures.
9. The participant agrees to provide study personnel with a primary telephone number as 
well as an alternate form of contact (eg, other telephone number, mailing address), if 
available, for follow-up purposes.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
For items with an asterisk (*), if the subject meets these but not other exclusion criteria, the 
Day 1 Visit may be rescheduled for a time when these criteria are not met.
Medical Conditions
1. The participant has a history or current evidence of any condition, therapy, laboratory 
abnormality or other circumstance that might expose the participant to risk by 
participating in the study, confound the results of the study, or interfere with participation 
for the full duration of the study, as assessed by the investigator.
2. The participant has a history of any allergic reaction or an anaphylactic/anaphylactoid 
reaction to any vaccination that required medical intervention, or of any severe allergic 
reaction (eg, swelling of the mouth and throat, difficulty breathing, hypotension, or 
shock), to any vaccine component that required medical intervention.
3. *The participant has a recent (<72 hours prior to receipt of V160/placebo) history of 
febrile illness (temperature ≥38ºC, oral or equivalent).
4. The participant is planning donation of sperm at any time from signing the informed 
consent through 1 month after receiving the last dose of V160/placebo.
 
 
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5. The participant is currently immunocompromised or has been diagnosed as having a 
congenital or acquired immunodeficiency, human immunodeficiency virus (HIV) 
infection, lymphoma, or leukemia. The participant with autoimmune conditions that 
require immunosuppressive medications (eg, systemic lupus erythematosus, rheumatoid 
arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease) is also to be excluded.
No testing for HIV will be required in the study.
6. The participant has a condition in which repeated venipuncture or injections pose more 
than minimal risk for the subject, such as hemophilia, thrombocytopenia, other severe 
coagulation disorders, or significantly impaired venous access.
7. The participant has major psychiatric illness including: any history of schizophrenia or 
severe psychosis, bipolar disorder requiring therapy, or any subject with suicidal ideation 
within 3 years.
Prior/Concomitant Therapy
8. The participant has previously received any CMV vaccine.
9. *The participant had any live virus vaccine administered or scheduled to be administered 
in the period from 4 weeks prior to, and 4 weeks following receipt of V160/placebo.
10. *The participant had any inactivated vaccine administered or scheduled within the period 
from 14 days prior to, through 14 days following V160/placebo.
11. The participant had administration of any immune globulin or blood product within 90 
days prior to injection with V160/placebo or scheduled within 30 days thereafter.
12. The participant has received systemic corticosteroids (equivalent of ≥2 mg/kg total daily 
dose of prednisone or ≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days 
and has not completed treatment at least 30 days prior to study entry.
13. The participant has received systemic corticosteroids exceeding physiologic replacement 
doses (≈5 mg/d prednisone equivalent) within 14 days prior to the first vaccination 
(participants using inhaled, nasal, or topical steroids are considered eligible for the study).
14. *The participant has received any anti-viral agent with proven or potential activity 
against CMV 14 days prior to vaccination or is likely to receive such an agent within 14 
days after vaccination. Anti-viral agents prohibited include letermovir, ganciclovir, 
valganciclovir, foscarnet, and valacyclovir.
 
 
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15. *The participant is receiving or has received in the year prior to enrollment 
immunosuppressive therapies including but not limited to rapamycin (also sirolimus), 
tacrolimus (also FK-506), or other therapies used for solid organ/cell transplant, radiation 
therapy, immunosuppressive/cytotoxic immunotherapy, chemotherapy and other 
immunosuppressive therapies known to interfere with the immune response. Topical 
tacrolimus is allowed provided that it is not used within 14 days prior to, or 14 days
following V160/placebo.
Prior/Concurrent Clinical Study Experience
16. *The participant has participated in another clinical study in the past 4 weeks, or plans to 
participate in a treatment-based study or a study in which an invasive procedure is to be 
performed while enrolled in this study. (Participation in a safety surveillance or non-
interventional study is acceptable).
Other Exclusions 
17. The participant has a recent history (within the past 5 years) or current evidence of drug 
or alcohol abuse.
18. The participant is legally or mentally incapacitated.
19. Participant meets all eligibility criteria however, the number of participants required for 
enrollment based on CMV serostatus has been met.
20. Any other reason that in the opinion of the investigator might interfere with the
evaluation required by 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.
5.2.1
Participant Deferment Criteria before Vaccination
These deferment criteria must be reviewed for each participant before each of second and 
third vaccination to ensure that none of the criteria apply to the participant and or that 
vaccination is deferred for an appropriate period of time. The participant would only be 
permitted to continue with a delayed vaccination if the vaccine can be administered within 
the allowed window. The participant should be deferred if:
1. Has a recent (<72 hours prior to receipt of V160/placebo) history of febrile illness 
(temperature ≥38.0°C, oral or equivalent).
2. Had any live virus vaccine administered or scheduled to be administered in the period
from 4 weeks prior to, through 4 weeks following receipt of V160/placebo.
3. Had any inactivated vaccine administered or scheduled within the period from 14 days 
prior to, through 14 days following V160/placebo.
 
 
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4. Had administration of any immune globulin or blood product within 90 days prior to 
injection with V160/placebo or scheduled within 30 days thereafter.
5. Had received systemic corticosteroids (equivalent of ≥2 mg/kg total daily dose of 
prednisone or ≥20 mg/d for persons weighing >10 kg) for ≥14 consecutive days and has 
not completed treatment at least 30 days prior to any dose of study vaccination.
6. Had received systemic corticosteroids exceeding physiologic replacement doses (≈5 mg/d 
prednisone equivalent) within 14 days prior to any dose of study vaccination (use of
inhaled, nasal, or topical steroids is allowed for the study).
7. Had administration of any anti-viral agent with proven or potential activity against CMV 
within 14 days prior to injection with V160/placebo or scheduled within 14 days 
thereafter. Anti-viral agents prohibited include letermovir, ganciclovir, valganciclovir, 
foscarnet, and valacyclovir.
8. Had administration of topical tacrolimus within 14 days prior to injection with 
V160/placebo or scheduled within 14 days thereafter.
5.2.2
Criteria to be Checked for Excluding Participants from Receiving Subsequent 
Doses
Specific exclusion criteria must be reviewed for each participant before administration of any 
subsequent dose of V160/placebo to ensure that none of the criteria apply to the participant. 
If any apply, the participant will be excluded from receiving the scheduled vaccination (and 
therefore be excluded from the per protocol analysis) but will continue in the study for all 
other follow-up procedures. A complete list of criteria to be checked prior to Dose 2 and 
Dose 3 are provided in Section 7.1.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. 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 AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study vaccination or withdraws from the study will not 
be replaced.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
Table 1
Study Interventions
Inter-
vention 
Group
Name
Arm Type
Inter-
vention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength
Dosage Level
Route of 
Administra
tion
Vaccination 
Regimen
Use
IMP/N
IMP
Sourcing
V160
Experi-
mental
V160
Biological/
Vaccine
Lyophilized 
Cake (vial)
200 
Units/mL
100 Units 
with 225 μg 
aluminum per 
0.5 mL dose
IM
Day 1, 
Month 2, 
Month 6
Experi-
mental
IMP
Sponsor
APA 
Diluent
Other
Sterile 
Suspension 
(Vial) for 
reconstitution
450 
μg/mL
Adjuvant
IMP
Sponsor
Placebo
Placebo 
Comparator
Sterile 
Saline 
Placebo
Other
Sterile 
Solution(vial)
Not 
applicable
0.5 mL
IM
Day 1, 
Month 2, 
Month 6
Placebo
IMP
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Abbreviations: APA Diluent = Aluminum Phosphate Adjuvant (APA) Diluent, Sterile Saline Placebo = V160 Sterile Saline Placebo, Unit Dose Strength = Strength of the V160 
and APA product after reconstitution, Dosage level = post reconstitution per 0.5 mL dose, IM = Intramuscular, IMP = Investigational Medicinal Product, NIMP = Non-
Investigational Medicinal Product
All supplies indicated in Table 1 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
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
V160 (after reconstitution) and placebo will be prepared and administered in a blinded 
fashion by an unblinded qualified study site personnel because the two products are visually 
different (the vaccine is opaque and the placebo is clear). Unblinded personnel will be 
responsible for reconstitution of study vaccine in order to produce the final study vaccine 
formulation that will be administered to the participant. Blinded personnel will not be present 
during vaccine preparation and administration.
Reconstitution of V160 Lyophilized Cake:
Reconstitution of the V160 lyophilized cake should be completed within 90 minutes after 
removal from the refrigerated storage unit.
1. Remove V160 and aluminum phosphate adjuvant diluent vials from the refrigerated 
storage unit.
2. Mix the contents of the aluminum phosphate adjuvant diluent vial by shaking 
thoroughly to get a homogeneous mixture.
3. Using a syringe and needle, withdraw 0.7 mL of aluminum phosphate adjuvant
diluent from the diluent vial, and inject immediately into the V160 lyophilized cake 
vial. 
4. Gently swirl the V160 vial and examine for undissolved material. Continue swirling 
until the lyophilized cake has completely dissolved and the appearance is opalescent. 
Disregard any bubbles that may be present.  
5. Withdraw and administer 0.5 mL of the reconstituted V160 vial.
Study vaccine should be administered immediately following dose preparation. If the 
reconstituted product is not used immediately, the vial/syringe contents should be mixed by 
inverting several times to get a homogeneous mixture of the product immediately prior to 
use. If the study vaccine or placebo is not administered within 60 minutes, it should be 
disposed of as a biohazardous medical waste and a new study vaccine should be prepared.
Preparation of Placebo:
The sterile saline placebo will be used as supplied.
 
 
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6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule. There are 2 study intervention arms. Participants will be assigned randomly in a 
2:1 ratio to V160 group and placebo group, respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified to 1:1 according to the CMV 
serostatus (seropositive : seronegative).
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. V160 (after reconstitution) 
and placebo will be prepared and administered in a blinded fashion by an unblinded qualified 
study site personnel because the two products are visually different (the vaccine is opaque 
and the placebo is clear). The participant, the investigator, and Sponsor personnel or 
 
 
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delegate(s) who are involved in the clinical evaluation of the participants are unaware of the 
intervention assignments.
In order to avoid bias, the unblinded individual/s will not be involved in any postdose safety 
assessment procedures. The unblinded individual/s also must not disclose any information 
regarding the allocation of the clinical supplies or the appearance of the V160/placebo to any 
blinded member of the site staff or to the participant. No blinded member of the site staff 
should have contact with the clinical supplies at any point during the course of the study. 
Note that participants must be discontinued from vaccination if they become unblinded 
(Section 7.1).
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.4
Study Intervention Compliance
Study compliance is defined in this study as participants who received all 3 doses of 
scheduled study vaccinations/placebo.
Interruptions from the protocol specified vaccination plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
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 medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy rests with the investigator and/or the participant’s primary physician. 
However, the decision to continue the participant on study intervention requires the mutual 
agreement of the investigator, the Sponsor, and the participant.
See the exclusion criteria for specific restrictions for prior and concomitant medications at 
Day 1 (Section 5.2) and prerequisites for other vaccination visits (Section 5.2.1).
Participants may receive allergen desensitization therapy and tuberculin skin testing while 
participating in the study.
Topical tacrolimus is allowed provided that it is not used 14 days prior to, or 14 days
following a V160/placebo dose.
Use of prior and concomitant medications/vaccination should be recorded as described in 
Section 8.1.5.
 
 
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Dose modification is not allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This  study is blinded but supplies are provided as open label; therefore, an unblinded 
pharmacist or qualified study site personnel will be used to blind supplies. Study intervention
identity (name, strength, or potency) is included in the label text; random code/disclosure 
envelopes or lists are not provided.
The emergency unblinding call center will use the intervention allocation/randomization 
schedule for the study to unblind participants and to unmask study intervention identity. The 
emergency unblinding call center should only be used in cases of emergency (see Section 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the vaccination regimen will still 
continue to participate in the study as specified in Section 1.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
 
 
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A participant must be discontinued from study intervention 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 intervention.
•
The participant’s intervention assignment has been unblinded by the investigator, 
Sponsor, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, placed the participant at unnecessary 
risk from continued administration of study intervention.
•
The participant had an allergic reaction or an anaphylactic/anaphylactoid reaction 
that required medical intervention following Dose 1 or Dose 2 administration
•
The participant enrolled in another interventional clinical study following Dose 1 or 
Dose 2 administration.
•
The participant has received any prohibited medications or vaccinations since Dose 
1 or Dose 2 administration (See Section 5.2.1 for prerequisites for the second and 
third vaccination visits).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, see Section 1.3 and Section 8.1.9 for those procedures to be completed at each 
specified visit.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9.1. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
 
 
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•
The site must attempt to contact the participant and reschedule the missed visit. If 
the participant is contacted, the participant should be counseled on the importance 
of maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Study 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.
•
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 60.5 mL (Appendix 2).
 
 
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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or future biomedical research.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 is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
 
 
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study. An additional review of 
deferment/exclusion/discontinuation criteria will be done at the second and the third 
vaccination visits (Visit 6 and 7). These criteria are listed in Section 5.2.1, 5.2.2 and 7.1.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/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 healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at the screening 
visit in order to ensure that the participant satisfies the inclusion and exclusion criteria of the 
study. The participant's medical conditions will be reported on the appropriate electronic case 
report form (eCRF), including any chronic or serious conditions.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication/vaccination use and 
record prior medication taken by the participant to assess inclusion and exclusion criteria 
including time windows for medication/vaccination use.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. As outlined in the exclusion criteria, there are specific restrictions for prior
medications and vaccines, as well as concomitant medications and vaccines that are
anticipated throughout the duration of the study. Investigators should make every attempt to
adhere to the entry criteria concerning prior, concomitant, and anticipated medications and
vaccines.
 
 
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Note that participants who meet screening eligibility 
may be randomized outside of the 21-day window; however, all screening procedures must 
be repeated when a participant is not randomized within 21 days of Visit 1 (Screening). 
Participants who are re-screened must be randomized within 21 days of the re-screening visit.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
V160/placebo will be prepared and administered by an unblinded pharmacist/qualified study 
site personnel, who will do no further assessment of clinical outcomes in the participants. 
Open-label, single dose vials will be supplied to the unblinded individual/s at the clinical site. 
Supplies will be affixed with a clinical label in accordance with regulatory requirements, 
including the information as a genetically modified live vaccine. 
Note that the V160/placebo should be administered within 60 minutes of preparation. Refer 
to Section 6.2.1 for details. 
The V160/placebo will be administered intramuscularly in the deltoid muscle using the 
syringe by the unblinded physician. Injections of V160/placebo should be administered at a 
90° angle into the muscle tissue using a needle long enough to ensure IM deposition of 
V160/placebo. A separate, sterile disposable unit should be used for the administration of 
V160/placebo to each participant. Needles should not be recapped. Safe disposal procedures 
should be handled in accordance with medical waste management regulations and infectious 
waste management regulations. Study participants will be observed for 30 minutes (for 3 
hours on Visit 2 for another blood sampling) following each vaccination for any immediate 
AEs and longer if necessary. Adequate treatment provision, including epinephrine, should be 
available for immediate use should an anaphylactic or anaphylactoid reaction occurs. 
 
 
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Participants who meet any of the deferred exclusion criteria (criteria with asterisk in Section 
5.2, and 5.2.1) should not be administered, and may subsequently return to the clinic to 
determine eligibility status prior to vaccination. 
Prior to each subsequent vaccination, exclusion criteria for subsequent vaccination (Section 
5.2.2 and Section 7.1) will be assessed. 
8.1.8.1
Timing of Dose Administration
Dose 1 of study intervention for both V160 and placebo groups will begin on the day of 
intervention randomization at Visit 2 (Day 1). A second dose of study intervention will be 
given at Visit 6 (Month 2) and a third dose will be given at Visit 7 (Month 6).
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the 3-dose vaccination 
regimen should be encouraged to continue to be followed for all remaining study visits.
Those procedures related to the following vaccination (i.e., to check postdose 1 exclusion 
criteria, vaccination, distribution of VRC, postdose observation) are not required for the 
participants at the following visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Visit 8/Month 7 visit should be performed (at the time of withdrawal). Any 
AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4 .
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
 
 
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8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity grade of the AEs observed, the relation to study intervention, the reason thereof, 
etc., in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Only the primary investigator or delegate and the respective participant’s code should be 
unblinded. Other study site personnel and Sponsor personnel directly associated with the 
conduct of the study should not be unblinded.
Once an emergency unblinding that is part of the study design has taken place, the 
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
Participants whose intervention assignment has been unblinded by the investigator or 
medically qualified designee and/or nonstudy treating physician must be discontinued from 
study intervention, but should continue to be monitored in the study.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Distribution of Vaccination Report Card
The VRC was structured as recommended in the final FDA Patient Reported Outcome
Guidance. The investigator or delegate will train the participant in the use of the VRC at 
Visit 2 (Day 1). Oral temperatures, injection site reactions, vaccine specific complaints, other 
complaints or illnesses and medications/vaccinations will be recorded on the VRC following 
each vaccination (refer to Section 8.3.3 for safety assessments using the VRC).
 
 
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Immunogenicity Assessments
Sera collected from all participants on Visit 2 (Day 1) and Visit 8 (Month 7) will be used to 
measure humoral immune responses to V160 using viral NAbs. Blood collection, storage and 
shipment instructions for serum samples will be provided in the operations/laboratory 
manual.
8.2.1
Viral Neutralizing Antibody Assay
The viral NAb assay measures the functional antibodies blocking viral entry, and is 
considered the primary assay for immunogenicity. Note that all blood samples collected on 
the day of vaccination will be drawn prior to V160/placebo administration. Refer to 
Appendix 2 for additional details of the assay and volume of blood collected.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood and other samples to be drawn/collected over the 
course of the study (from prestudy to poststudy visits), including approximate blood/fluid 
volumes drawn/collected by visit and by sample type per participant, can be found in 
Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations (Full and Targeted Examinations)
A full physical examination including vital signs (heart rate, respiratory rate, seated blood 
pressure, and oral temperature), height and weight will be conducted per institutional 
standard and recorded at the screening visit (Visit 1). Any clinically significant abnormality 
should be recorded on the appropriate eCRF. Special attention should be paid to clinical 
signs related to a previous serious illness.
A directed physical examination including vital signs should be performed prior to each 
vaccination and at the Month 7 visit.
8.3.2
Vital Signs and Body Temperature
•
Heart rate, respiratory rate, blood pressure, and oral temperature will be assessed.
 
 
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•
Blood pressure and heart rate measurements will be assessed after the participant 
has at least 5 minutes of rest in a quiet setting without distractions, and from a 
sitting position with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
•
Oral temperatures will also be documented by participants using their VRC during 
the VRC-specified postvaccination follow-up period.
8.3.3
Safety Assessments Using the VRC
All participants will be observed for 30 minutes after each vaccination for any immediate 
reactions.If any immediate AEs are observed during this period, the time at which the event 
occurred within this timeframe, as well as the event itself, any concomitant medications that 
were administered, and resolution of the event, must be recorded on the appropriate eCRF.
Participants will use the VRC (Section 8.1.11) to document the following information:
•
Oral temperatures measured from Day 1 (day of vaccination) through Day 14 
postdose; any temperature ≥38.0ºC oral or equivalent, will be considered an AE of 
fever. 
•
Solicited injection site AEs (pain/tenderness, erythema/redness, and swelling) from 
Day 1 through Day 5 postdose;
•
Solicited systemic AEs (headache, tiredness, muscle pain, and joint pain) from Day 
1 through Day 14 postdose;
•
Any other injection-site or systemic AEs from Day 1 through Day 14 postdose; and 
•
Concomitant medications from Day 1 to Day 14 postdose.
In order to ensure that the VRC is being filled out without delay, telephone contacts to 
remind the subject will be conducted after 14 days from the second and the third vaccination, 
respectively.
The investigator or delegate will review the data captured on the VRC with the participant at 
the subsequent visit after each vaccination (refer to the SoA).
For AEs reported on the VRC, the investigator will use the information provided by the 
participant both on the VRC, and verbally at the time of VRC review, to apply the 
appropriate intensity grade as described in Appendix 3. 
8.3.4
Clinical Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to 
the SoA for the timing and frequency.
 
 
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•
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the operations/laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed 
at the institution’s local laboratory require a change in study participant 
management or are considered clinically significant by the investigator (eg, SAE or 
AE or dose modification), then the results must be recorded in the appropriate CRF 
(eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
8.3.4.1
CMV IgG Testing
For stratification, serum CMV IgG will be assessed by Enzyme immunoassay and the 
participant will be determined whether the serum is IgG (+) or IgG (-) at screening visit 
(Visit 1).
8.3.4.2
CMV PCR Testing
Plasma, swab from injection-site and adhesive tapes (inside and outside, respectively), urine 
and saliva will be collected from all participants at time points specified below and 
Appendix 2.
DNA will be extracted from each samples and assayed for the presence of CMV by a PCR 
assay. If CMV is detected, distinction between V160 vaccine virus and non-vaccine virus 
will be performed in a separate PCR assay, except swab samples.
Refer to Appendix 2 for a summary of the CMV PCR assay.
8.3.4.2.1
Plasma
Plasma samples will be collected at 3 points on Day 1 (prior to vaccination, 0-min and 3-hour 
post vaccination), and each 1 point on Day 3, 7, and 14 as shown in Appendix 2 in order to 
evaluate biodistribution of V160 in the human body. Blood will be drawn from the other arm 
from the vaccinated arm at the time point of just after vaccination on Day 1.
 
 
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8.3.4.2.2
Swab
Swab samples will be collected at 4 points on Day 1 (0-min, 10-min, 20-min and 30-min post 
vaccination) from injection-site, and 3 points on Day 1 (10-min, 20-min and 30-min post 
vaccination) from adhesive tapes (inside and outside, respectively) as shown in Appendix 2, 
in order to evaluate viral leakage from injection-site to assess risk for horizontal infection of 
V160. Injection-site will be covered with an adhesive tape just after vaccination (after swab 
sampling from injection-site), and the adhesive tape will be changed by 10 minutes (after 
swab sampling from injection-site), ie, at 10 minutes and at 20 minutes after vaccination on 
Day 1. At 30 minutes after vaccination on Day 1, Month 2 and Month 6, the investigator or 
delegate should confirm that the injection-site of the participant is no longer bleeding prior to 
be free from covering with the adhesive tapes.
8.3.4.2.3
Urine and Saliva
Urine and saliva samples will be collected at each visit (7 points prior to vaccination from
Day 1 through Month 7) specified in the SoA and Appendix 2 for evaluation of viral 
shedding.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator, 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 8.4.3.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before 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.
 
 
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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.
OR
2. An SAE 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 intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 2.
 
 
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Table 2
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
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 from 
the time of each 
vaccination 
through 14 days 
thereafter.
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all for the 
duration of an 
individual’s study 
participation.
Report if:
- drug/vaccine related.
- any death until 
participant completion of 
study
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all for the 
duration of an 
individual’s study 
participation.
Not required
Within 5
calendar days 
of learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all for the 
duration of an 
individual’s study 
participation.
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including cancer, and overdose will be followed until resolution, stabilization, until the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
 
 
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randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are males and partner 
pregnancy/lactation information is not required.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease related outcomes not qualifying as AEs or 
SAEs for this study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
There are no ECIs for this study.
8.5
Treatment of Overdose
In this study, an overdose is defined as receipt of more than 1 dose of study vaccine in a 
24-hour period.
Sponsor does not recommend specific treatment for an overdose.
 
 
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8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
DNA for future research
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase I Randomized, Double-Blind, Placebo-controlled Study 
to Evaluate the Safety, Tolerability and Immunogenicity of 
V160 (Human Cytomegalovirus Vaccine) in Healthy Japanese 
Men
Intervention
Assignment
Participants will be randomized in a 2:1 ratio to either V160 or 
Placebo, stratified by CMV serostatus.
Analysis Populations
Efficacy: Per Protocol Immunogenicity (PPI) population
Safety: All participants as treated (APaT) population
Primary Endpoint

Solicited injection site AEs within Days 1 through 5 after 
each vaccination visit

Solicited systemic AEs within Days 1 through 14 after each 
vaccination visit

Vaccine-related SAEs within Days 1 through 14 after each 
vaccination visit
Secondary Endpoint

CMV-specific NAb titers at 1 month PD3

Viral detection of V160 in plasma, urine and saliva, and 
injection-site swab and adhesive tape swab
Statistical Methods for 
Key Efficacy Analyses
CMV-specific NAb GMT at 1 month PD3 will be analyzed for 
seronegative participants using analysis of variance (ANOVA) 
model. The model will include term for intervention. The GMT 
ratio and 95% confidence intervals (CIs) will be estimated from 
this model.
Statistical Methods for 
Key Safety Analyses
Incidence of solicited injection site AEs, solicited systemic AEs 
and vaccine-related SAEs will be summarized for each 
serostatus, respectively.
Interim Analyses
No interim analyses are planned in this study.
Multiplicity
No multiplicity adjustment is planned in this study.
Sample Size and Power A total of 9 participants will be enrolled for each CMV 
serostatus. Assuming a discontinuation rate of approximately 
20%, 7 participants are expected to complete intervention. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
SPONSOR. This study will be conducted as a double-blind study under in-house blinding 
procedures.  The official, final database will not be unblinded until medical/scientific review 
has been performed, protocol deviations have been identified, and data have been declared 
final and complete.
 
 
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9.3
Hypotheses/Estimation
There are no hypotheses for the study. Objectives are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Immunogenicity Endpoints
Secondary Endpoint

Geometric mean of CMV-specific NAb titers at 1 month PD3 in initially CMV-
seronegative participants
Exploratory Endpoints

Percent Seropositivity (Defined by NAb titer ≥assay defined cutoff level) at 1 month 
PD3 in initially CMV-seronegative participants

Geometric mean of CMV-specific NAb titer at 1 month PD3 in initially CMV-
seropositive participants

Geometric mean of CMV-specific NAb fold-rise at 1 month PD3 relative to Day 1 
(GMFR) in initially CMV-seropositive participants
9.4.2
Safety Endpoints

Solicited injection site AEs within Days 1 through 5 after each vaccination visit, 
solicited systemic AEs and vaccine-related SAEs within Days 1 through 14 after each 
vaccination visit

Viral detection of V160 in plasma, urine and saliva, and injection-site swab and adhesive 
tape swab
9.5
Analysis Populations
9.5.1
Immunogenicity Analysis Populations
Per Protocol Immunogenicity (PPI) population
The PPI population will serve as primary immunogenicity analysis. To be eligible for 
inclusion in the PPI population, study participants must satisfy the following criteria:

Participants have received all 3 vaccinations within the vaccination visit window 
specified in the SoA (Section 1.3).

Have not deviated from protocol in ways that could affect the immune response to 
vaccination
 
 
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The final determination of protocol deviations that could affect immune response to 
vaccination, and thereby the composition of the PPI population, will be made prior to the 
final unblinding of the database and will be documented in a separate memo.
Participants will be included in the intervention group to which they are randomized for the 
analysis of immunogenicity.  Details on the approach to handling missing data are provided 
in Section 9.6 Statistical Methods.
Full Analysis Set (FAS)
The FAS will serve as a supportive analysis population for Immunogenicity. The FAS 
population consists of all randomized participants who received at least 1 vaccination and
have at least one post-randomization observation for the analysis endpoint.
9.5.2
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety in 
this study. The APaT population consists of all randomized participants who received at least 
one vaccination and defined according to the regimen of clinical material actually received 
(ie, received only vaccine, or received only placebo). Participants who received a mixture of 
vaccine and placebo are deemed ineligible for inclusion in the APaT population. Safety data 
of participants ineligible for inclusion in the APaT population will be summarized in listings.
9.6
Statistical Methods
9.6.1
Statistical Methods for Immunogenicity Analyses
CMV-specific NAb GMT at 1 month PD3 will be analyzed for seronegative participants 
using an ANOVA model. The NAb titers will be log-transformed prior to analysis. The 
model will include term for intervention. The treatment difference and corresponding 95% 
confidence interval (CI) will be estimated at 1 month PD3 on the log-transformed data.  
Estimates of treatment difference and corresponding 95% CI will then be back-transformed 
to get the GMT ratio and the 95% CI for GMT ratio. Methods related to exploratory endpoint 
will be described in sSAP.
 
 
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Table 3 summarizes the analysis plans relating to the immunogenicity endpoints.
Table 3
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(1 month PD3)
Primary vs. 
Supportive 
Approach†
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Secondary 
CMV-specific NAb GMT 
at 1 month PD3
P
ANOVA
PPI
(seronegative 
participants)
observed data
CMV-specific NAb GMT 
at 1 month PD3
S
ANOVA
FAS
(seronegative 
participants)
observed data
 † P=Primary approach, S=Supportive approach.
ANOVA: analysis of variance, PPI:Per Protocol Immunogenicity, FAS: Full Analysis 
Set
Handling of Missing Data
All analyses will be conducted based on the observed data only.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and vital signs. All participants who are vaccinated and eligible for inclusion in the 
APaT population as defined in Section 9.5.2 will be included in the safety analyses and 
summaries. Incidence of AEs will be summarized as frequencies and percentages by 
vaccination group. 
To provide an overall assessment, safety measures such as the incidence of the following 
events occurring throughout the study will be summarized for each serostatus, respectively:
1) any AE,
2) any injection-site AE,
3) any systemic AE,
4) any SAE,
5) any vaccine-related SAE, 
6) any discontinuation due to an AE within 14 days of receipt of any study vaccination
 
 
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AEs will be summarized by vaccination visit and across all vaccination visits.  Specific AEs 
for which summaries will be provided are identified in Table 4.
-The number and percent of the participants with positive viral shedding in urine and saliva
up to 1 month postdose 3 (defined by viral load in saliva/urine ≥ assay defined threshold 
cutoff value) will be also summarized for generic CMV and for vaccine-type virus 
separately, by vaccination group by CMV serostatus. 
-The number and percent of the participants with positive viral detection in plasma up to 14 
days postdose 1 (defined by viral load in plasma ≥ assay defined threshold cutoff value) will 
be also summarized for generic CMV and for vaccine-type virus separately, by vaccination 
group by CMV serostatus.
-The number and percent of the participants with positive viral leakage in injection-site swab
and adhesive tape swab up to 30 minutes postdose 1 (defined by viral load in injection-site 
swab/adhesive tape swab ≥ assay defined threshold cutoff value) will be also summarized 
for generic CMV by vaccination group by CMV serostatus.
-The oral temperatures recorded on the VRC will also be summarized.  
 
 
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Table 4
Safety Analyses of Adverse Events Endpoints
Adverse Events endpoints
Time Window
Day1 to Day 5†
Day 1 to Day 14†
Any Time during Study
-Solicited Injection site AEs of pain/tenderness, 
erythema/redness, and swelling
●
-Unsolicited injection site AEs 
●
-Solicited systemic AEs of fatigue, myalgia, 
headache and arthralgia
●
-Unsolicited systemic AEs
●
-Serious AEs
●
-VR SAEs
●
- Discontinuation due to an AE
●
-Elevated temperature§
●
-Death
●
-Any AE
●
-Saliva/Urine viral Shedding* 
●
-Viral detection from plasma*
●
-Viral leakage from swab sampling of injection-
site/adhesive tape*
●
Summaries will be provided by vaccination group separately for the participants in each serostatus.
†
The day of vaccination is counted as Day1. Day 1 to Day 5 refers to the day of vaccination plus 4 days immediately post-vaccination.  
Day 1 to Day 14 refers to the day of vaccination plus 13 days immediately post-vaccination.
*
The viral shedding, viral detection from plasma, and viral leakage data will be summarized as percentage of positivity by Visit; the 
duration for collecting viral shedding is shown in SoA.
§
Defined as ≥38.0ºC oral or equivalent.
AE=Adverse Events, SAE=Serious Adverse Events, VR=Vaccine-Related.
 
 
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9.6.3
Demographic and Baseline Characteristics
The comparability of the vaccination groups for each relevant characteristic will be assessed 
by the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of participants screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed.  Demographic variables (eg, age), baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by vaccination and 
serostatus either by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No multiplicity adjustment is planned for this study.
9.9
Sample Size and Power Calculations
Nine participants will be randomized in a ratio of 2:1 into V160 and placebo for each CMV 
serostatus cohort. 
If a specific AE is not observed in any of the 6 participants in V160, then the true incidence 
of that event is 46% or less with 90% confidence.
9.10
Subgroup Analyses
No subgroup analyses are planned for this study.
9.11
Compliance (Medication Adherence)
Compliance to vaccination will be summarized by number and percent of subjects in each 
vaccination group who received vaccination dose 1, vaccination dose 2, and vaccination 
dose 3.
9.12
Extent of Exposure
The summary of the number and percent of subjects in the V160 group who received 
vaccination dose 1, vaccination dose 2, and vaccination dose 3 also serve as the summary of 
subjects who received 100 units, 200 units, and 300 units, respectively, of V160.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
 
 
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
 
 
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Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
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.
 
 
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10.1.5
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 study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.6
Compliance with Law, Audit, and Debarmen
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: 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 Code of 
Conduct for Clinical Studies.
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 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
 
 
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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.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
 
 
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Table 5
Protocol-required Laboratory Assessments
Visit Number/Title
Visit 1
Screening
Visit 2/Day 1
Visit 3
Day 3
Visit 4
Day 7
Visit 5
Day 14
Visit 6
Month 2
(Day 60)
Visit 7
Month 6
(Day 180)
Visit 8
Month 7
(Day 210)
Approx.
Blood 
Volume 
Collected
Assay
Sample
prior 
to vac
0 min 
after 
vac
10 min 
after 
vac
20 min 
after 
vac
30 min 
after 
vac
3 hour 
after 
vac
Scheduling Window
-21 to -1 
days
- 1 hr
+ 
5min
+/-
5min
+/-
5min
+/-
5min
+/-
10min
+/- 1 
day
+/- 2 
days
+/- 2 
days
+14 days
+14 days
+14 days
Not 
applicable
CMV IgG 
testing
Blood (Serum)
X
2.0 ml
Future 
Biomedical 
Research
Blood
X
8.5 ml
Neutralizing 
Antibody 
assay
Blood(Serum)
X
X
20 ml
(10 ml/
time point)
CMV PCR 
assay
Blood (Plasma)
X
X
X
X
X
X
30 ml
(5 ml/
time point)
Swab from 
injection-site 1
X
X
X
X
Not 
applicable
Swab from 
adhesive tape 
(inside)2
X
X
X
Not 
applicable
Swab from 
adhesive tape 
(outside) 2
X
X
X
Not 
applicable
Urine
X
X
X
X
X
X
X
Not 
applicable
Saliva
X
X
X
X
X
X
X
Not 
applicable
Total Blood Volume Collected
60.5 ml
CMV: cytomegalovirus, IgG: immunoglobulin G, PCR: polymerase chain reaction ,vac: vaccination
1 Wipe the skin with an alcohol swab AFTER collection of the injection-site swab and the Band-Aid.
2 Collect samples from inside and outside of 3 adhesive tapes covered over injection-site, changed by 10 min.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, 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, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
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 an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
 
 
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories: 
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category 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 erythema/redness or swelling from the day of vaccination through Day 5 
postvaccination will be evaluated by maximum size.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
 
 
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (diary, 
etc.), seroconversion or identification of vaccine virus in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in the study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose vaccine study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
 
 
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-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
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.
 
 
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10.3.5
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 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study vaccination, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note:  Documentation can come from the site personnel’s review of the participant’s
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition. 
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
 
 
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3.
Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
 
 
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At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5.
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
 
 
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answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10.
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
 
 
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12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13.
References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ANOVA
analysis of variance
APaT
all participants as treated
BAC
bacterial artificial chromosome
cCMVd
congenital cytomegalovirus disease
cCMVi
congenital cytomegalovirus infection
CI
confidence interval
CMV
cytomegalovirus 
CMVi
cytomegalovirus infection
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form 
CSR
Clinical Study Report
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
EMA
European Medicines Agency
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GFP
green-fluorescent protein
GMFR
geometric mean fold rise
GMT
geometric mean titer
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IM
intramuscular
IND
Investigational New Drug 
IRB
Institutional Review Board 
NAb
neutralizing antibody
PCR
polymerase chain reaction
PD
postdose
PK
pharmacokinetic
PPI
Per Protocol Immunogenicity
qPCR
quantitative polymerase chain reaction
RNA
ribonucleic acid
RT-PCR
real time quantitative polymerase chain reaction
SAE
serious adverse event 
SLAB
Supplemental Lab
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
 
 
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Abbreviation
Expanded Term
SUSAR
suspected unexpected serious adverse reaction
VRC
Vaccination Report Card
WOCBP
woman/women of childbearing potential 
 
 
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