Clinical trial NCT05763823
Conditions: Cytomegalovirus Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2023-03-24; Completion date: 2024-04-18
Enrollment: 120 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of a once-a-day oral or intravenous (IV) dose of Letermovir (MK-8228) in Chinese adult hematopoietic stem cell transplant (HSCT) recipients for the prevention of clinically significant cytomegalovirus (CMV) infection.

Detailed description:

Arms: arm 1: Chinese HSCT recipients will receive 240 mg of Letermovir \[for participants on Cyclosporin A (CsA)\] or 480 mg of Letermovir (for participants not on CsA) either orally or IV once daily through week 14 (\~100 days) post-transplant.
Interventions: intervention 1: Letermovir
Intervention descriptions: intervention 1: Daily 240 mg or 480 mg oral tablets or IV dose

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date: 
     24-Jan-2023
NCT05763823
A Phase 3, Open label, Single-Arm Clinical Trial to 
Evaluate the Efficacy and Safety of MK-8228 
(Letermovir) for the Prevention of Clinically Significant 
Cytomegalovirus (CMV) Infection in Chinese Adult, 
CMV-Seropositive Allogeneic Hematopoietic Stem Cell 
Transplant Recipients


PRODUCT: MK-8228
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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 LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Open label, Single-Arm Clinical Trial to Evaluate the Efficacy 
and Safety of MK-8228 (Letermovir) for the Prevention of Clinically Significant 
Cytomegalovirus (CMV) Infection in Chinese Adult, CMV-Seropositive Allogeneic 
Hematopoietic Stem Cell Transplant Recipients
Protocol Number: 045-01
Compound Number: MK-8228
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not Applicable
EU CT
Not Applicable
EudraCT
Not Applicable
JAPIC-CT
Not Applicable
WHO
Not Applicable
UTN
Not Applicable
IND
Not Applicable
Approval Date: 24 January 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 1
24-JAN-2023
To remove the CMV resistant testing due to 
operational considerations.
Original Protocol
03-AUG-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
To remove the CMV resistant testing due to operational considerations.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
1.3 Schedule of Activities
8.2.3 CMV Disease Assessment
8.2.4 CMV DNA Resistance 
Analysis
10.2 Appendix 2: Clinical 
Laboratory Tests
Removed the CMV resistant testing.
This change was made to address 
operational considerations. The rationale is 
further supported by new data, considering 
that the resistance pattern of CMV has 
been characterized in other studies.
Other Changes in Amendment
1.1 Synopsis
6.1 Study Intervention(s) 
Administered
The oral and IV infusion formulations of 
letermovir are presented in separate rows.
To ensure the clarity of IMP dose 
formulations and route of administration.
1.1 Synopsis
3 Hypotheses, Objectives, and 
Endpoints
Switched the order of the following secondary 
endpoints: “CMV disease” comes before 
“initiation of PET for document CMV viremia”.
The order of secondary endpoints should 
be consistent with the definition of 
clinically significant CMV infection.
1.3 Schedule of Activities
Clarified the definition of Week No. and Visit 
Window. Deleted the row of FU Week No..
To ensure clarity of the SoA and accurate 
conduct of the trial.
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Section Number and Name
Description of Change
Brief Rationale
10.2 Appendix 2 Clinical 
Laboratory Tests 
Removed pH, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase tests from the routine 
urinalysis. Routine Urinalysis will include 
specific gravity, glucose, protein, blood, and 
microscopic examination (if blood or protein is 
abnormal). 
Clinical laboratory analysis method 
changes.
Throughout the document
Minor administrative, formatting, grammatical, 
and typographical changes were made 
throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.........................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
2
INTRODUCTION..........................................................................................................27
2.1
Study Rationale....................................................................................................27
2.2
Background ..........................................................................................................28
2.2.1
Pharmaceutical and Therapeutic Background .............................................28
2.2.2
Preclinical and Clinical Studies ...................................................................29
2.2.3
Ongoing Clinical Studies.............................................................................29
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................32
4.1
Overall Design......................................................................................................32
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................36
4.2.1.1
Efficacy Endpoints.............................................................................36
4.2.1.2
Safety Endpoints................................................................................38
4.2.2
Rationale for Sample Size............................................................................38
4.3
Justification for Dose...........................................................................................38
4.3.1
Starting Dose for This Study........................................................................38
4.3.2
Maximum Dose Exposure for This Study ...................................................40
4.3.3
Rationale for Dose Interval and Study Design ............................................40
4.4
Beginning and End-of-Study Definition ............................................................40
4.4.1
Clinical Criteria for Early Study Termination .............................................40
5
STUDY POPULATION ................................................................................................41
5.1
Inclusion Criteria.................................................................................................41
5.2
Exclusion Criteria................................................................................................42
5.3
Lifestyle Considerations......................................................................................45
5.3.1
Meals and Dietary Restrictions....................................................................45
5.4
Screen Failures.....................................................................................................45
5.5
Participant Replacement Strategy......................................................................45
6
STUDY INTERVENTION............................................................................................46
6.1
Study Intervention(s) Administered...................................................................46
6.2
Preparation/Handling/Storage/Accountability .................................................48
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6.2.1
Dose Preparation..........................................................................................48
6.2.2
Handling, Storage, and Accountability........................................................48
6.3
Measures to Minimize Bias: Randomization and Blinding..............................49
6.3.1
Intervention Assignment..............................................................................49
6.3.2
Stratification.................................................................................................49
6.3.3
Blinding........................................................................................................49
6.4
Study Intervention Compliance..........................................................................49
6.5
Concomitant Therapy..........................................................................................49
6.5.1
Allowed Medications/Therapies to be Administered with Clinical 
and/or Drug Level Monitoring when Coadministered with Study 
Intervention..................................................................................................50
6.5.2
Prohibited Medications................................................................................52
6.5.2.1
Medications Prohibited with Study Medication ................................52
6.5.2.2
Additional Medications Prohibited When Study Medication is 
Coadministered with CsA..................................................................53
6.5.3
Rescue Medications and Supportive Care ...................................................54
6.6
Dose Modification (Escalation/Titration/Other)...............................................54
6.7
Intervention After the End of the Study............................................................54
6.8
Clinical Supplies Disclosure................................................................................54
6.9
Standard Policies..................................................................................................54
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................55
7.1
Discontinuation of Study Intervention...............................................................55
7.2
Participant Withdrawal From the Study...........................................................56
7.3
Lost to Follow-up .................................................................................................57
8
STUDY ASSESSMENTS AND PROCEDURES........................................................58
8.1
Administrative and General Procedures ...........................................................58
8.1.1
Informed Consent.........................................................................................58
8.1.1.1
General Informed Consent.................................................................59
8.1.2
Inclusion/Exclusion Criteria ........................................................................59
8.1.3
Participant Identification Card.....................................................................59
8.1.4
Medical History ...........................................................................................59
8.1.5
Prior and Concomitant Medications Review...............................................60
8.1.5.1
Prior Medications...............................................................................60
8.1.5.2
Concomitant Medications..................................................................60
8.1.6
HSCT Details Review..................................................................................60
8.1.7
Assignment of Screening Number...............................................................60
8.1.8
Assignment of Treatment/Randomization Number.....................................60
8.1.9
Study Intervention Administration ..............................................................61
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8.1.9.1
Timing of Dose Administration.........................................................61
8.1.9.2
Study Medication Diary and Recording the Study Intervention........62
8.1.10
Discontinuation and Withdrawal .................................................................62
8.1.11
Participant Blinding/Unblinding..................................................................62
8.1.12
Calibration of Equipment.............................................................................63
8.2
Efficacy Assessments ...........................................................................................63
8.2.1
CMV DNA PCR Testing .............................................................................63
8.2.2
CMV Serology (IgG) Testing......................................................................63
8.2.3
CMV Disease Assessment...........................................................................63
8.3
Safety Assessments...............................................................................................65
8.3.1
Physical Examinations.................................................................................65
8.3.2
Vital Signs....................................................................................................65
8.3.3
Electrocardiograms ......................................................................................65
8.3.4
Child-Pugh Score.........................................................................................65
8.3.5
Birth Control Confirmation (WOCBP Only)...............................................66
8.3.6
Clinical Safety Laboratory Assessments .....................................................66
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................67
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................67
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......69
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...69
8.4.4
Regulatory Reporting Requirements for SAE .............................................69
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................70
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................70
8.4.7
Events of Clinical Interest............................................................................70
8.5
Treatment of Overdose........................................................................................71
8.6
Pharmacokinetics.................................................................................................71
8.7
Pharmacodynamics..............................................................................................71
8.8
Biomarkers ...........................................................................................................71
8.9
Future Biomedical Research Sample Collection...............................................71
8.10
Visit Requirements...............................................................................................71
8.10.1
Screening......................................................................................................71
8.10.2
Treatment Period..........................................................................................72
8.10.2.1
Day 1 Visit.........................................................................................73
8.10.2.2
Study Intervention Administration ....................................................73
8.10.3
Follow-up Period/Visits...............................................................................74
8.10.4
CMV Infection or Early Discontinuation Visit............................................75
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8.10.5
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................76
8.10.5.1
Discontinuation for Reasons Other Than CMV Infection.................76
8.10.6
Survival Status .............................................................................................76
9
STATISTICAL ANALYSIS PLAN .............................................................................77
9.1
Statistical Analysis Plan Summary.....................................................................77
9.2
Responsibility for Analyses/In-house Blinding .................................................78
9.3
Hypotheses/Estimation ........................................................................................78
9.4
Analysis Endpoints...............................................................................................78
9.4.1
Efficacy Endpoints.......................................................................................78
9.4.2
Safety Endpoints..........................................................................................79
9.5
Analysis Populations............................................................................................79
9.5.1
Efficacy Analysis Populations.....................................................................79
9.5.2
Safety Analysis Populations ........................................................................80
9.6
Statistical Methods...............................................................................................80
9.6.1
Statistical Methods for Efficacy Analyses...................................................80
9.6.2
Statistical Methods for Safety Analyses ......................................................82
9.6.3
Summaries of Baseline Characteristics and Demographics.........................83
9.7
Interim Analyses ..................................................................................................83
9.8
Multiplicity ...........................................................................................................83
9.9
Sample Size and Power Calculations .................................................................83
9.9.1
Sample Size and Power for Efficacy Analysis ............................................83
9.9.2
Sample Size and Power for Safety Analysis................................................84
9.10
Subgroup Analyses...............................................................................................85
9.11
Compliance (Medication Adherence).................................................................85
9.12
Extent of Exposure...............................................................................................85
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................86
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........86
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................86
10.1.2
Financial Disclosure.....................................................................................89
10.1.3
Data Protection.............................................................................................90
10.1.3.1
Confidentiality of Data ......................................................................90
10.1.3.2
Confidentiality of Participant Records...............................................90
10.1.3.3
Confidentiality of IRB/IEC Information............................................91
10.1.4
Committees Structure...................................................................................91
10.1.4.1
Clinical Adjudication Committee (CAC) ..........................................91
10.1.5
Publication Policy........................................................................................91
10.1.6
Compliance with Study Registration and Results Posting Requirements ...91
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10.1.7
Compliance with Law, Audit, and Debarment ............................................92
10.1.8
Data Quality Assurance ...............................................................................93
10.1.9
Source Documents .......................................................................................93
10.1.10
Study and Site Closure.................................................................................94
10.2
Appendix 2: Clinical Laboratory Tests..............................................................95
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................97
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................97
10.3.2
Definition of AE ..........................................................................................97
10.3.3
Definition of SAE ........................................................................................98
10.3.4
Additional Events Reported.........................................................................99
10.3.5
Recording AE and SAE ...............................................................................99
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................103
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................104
10.5
Appendix 5: Contraceptive Guidance..............................................................105
10.5.1
Definitions..................................................................................................105
10.5.2
Contraceptive Requirements......................................................................106
10.5.3
Pregnancy Testing......................................................................................107
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................108
10.7
Appendix 7: Country-specific Requirements..................................................109
10.8
Appendix 8: Definition of CMV Disease in Hematopoietic Stem Cell 
Transplant (HSCT) Recipients.........................................................................110
10.9
Appendix 9: Child-Pugh Classification for Severity of Liver Disease ..........113
10.10 Appendix 10: Abbreviations .............................................................................114
11
REFERENCES.............................................................................................................118
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................47
Table 2
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................68
Table 3
Analysis Strategy for Key Efficacy Variables.................................................81
Table 4
Analysis Strategy for Safety Parameters..........................................................82
Table 5
Two-Sided 95% Confidence Intervals for the Proportion of Participants 
with Clinically Significant CMV Infection through Week 24 (~6 Months) 
Post-Transplant (FAS Population)...................................................................84
Table 6
Estimate of Incidence of AEs and Upper Bound of 95% CI Based on 
Hypothetical Numbers of Participants with AEs.............................................84
Table 7
Protocol-required Laboratory Assessments.....................................................95
Table 8
Contraceptive Methods ..................................................................................106
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LIST OF FIGURES
Figure 1
Study Design................................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Open label, Single-Arm Clinical Trial to Evaluate the Efficacy 
and Safety of MK-8228 (Letermovir) for the Prevention of Clinically Significant 
Cytomegalovirus (CMV) Infection in Chinese Adult, CMV-Seropositive Allogeneic 
Hematopoietic Stem Cell Transplant Recipients
Short Title: MK-8228 (Letermovir) for Prevention of CMV infection in Chinese HSCT 
Recipients
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses to be tested in this study.  
The following objectives and endpoints will be evaluated in Chinese adult CMV-seropositive 
allogeneic HSCT recipients:
Primary Objective
Primary Endpoint
To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by the proportion of 
participants with clinically significant CMV 
infection through Week 24 (~6 months) 
post-transplant.
Clinically significant CMV infection, 
defined as onset of CMV disease and/or 
initiation of PET for documented CMV 
viremia 
Secondary Objectives
Secondary Endpoints
To evaluate the safety and tolerability of 
letermovir based on the proportion of 
participants with AEs.

AEs

AEs resulting in study medication 
discontinuation 
To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by the proportion of 
participants with clinically significant CMV 
infection through Week 14 (~100 days) 
post-transplant.
Clinically significant CMV infection, 
defined as onset of CMV disease and/or 
initiation of PET for documented CMV 
viremia
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To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by:

proportion of participants with CMV 
disease through Week 14 (~100 
days) post-transplant and Week 24 
(~6 months) post-transplant.

proportion of participants with 
initiation of PET for documented 
CMV viremia through Week 14 
(~100 days) post-transplant and 
Week 24 (~6 months) post-
transplant.

proportion of participants with all-
cause mortality through Week 14 
(~100 days) post-transplant and 
Week 24 (~6 months) post-
transplant.

CMV disease 

Initiation of PET for document 
CMV viremia

All-cause mortality
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Cytomegalovirus prophylaxis
Population
Adult Chinese CMV-seropositive allogeneic 
HSCT recipients
Study Type
Interventional
Intervention Model
Single Group
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 23 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
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Number of Participants:
Approximately 120 participants will be allocated.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Letermovir
Letermovir
240 mg
240 mg
(for 
participants 
on CsA)
OR
480 mg 
(for 
participants 
not on CsA)
Oral
Through 
Week 14 
(~100 days)
post-
transplant
Test Product
Letermovir
Letermovir
240 mg
240 mg
(for 
participants 
on CsA)
OR
480 mg 
(for 
participants 
not on CsA)
IV Infusion
Through 
Week 14 
(~100 days)
post-
transplant
Test Product
Note: This is a single-arm study. Both oral (tablet) and IV formulations of letermovir will be available for study 
intervention. Participants will be initiated with the oral formulation of study intervention provided they are able to 
swallow and do not have a condition that may interfere with the absorption of the tablets. For participants who cannot 
swallow and/or have a condition that may interfere with the absorption of the oral formulation, study intervention can 
be initiated with or switched to the IV formulation. The IV formulation should be switched to oral study intervention 
(i.e., at the next planned dose) as soon as such participants are able to swallow and/or the condition necessitating the 
use of the IV formulation resolves.
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Total Number of Intervention Groups/Arms
1 (single-arm study)
Duration of Participation
Each participant will participate in the study 
for approximately 25 weeks from the time 
the participant signs the informed consent 
form (ICF) through the final contact. 
Participants can be screened from up to 15 
days prior to receipt of HSCT to 28 days 
post-HSCT. Allocation of study 
intervention can be initiated as early as the 
day of transplant but must be completed 
within 28 days post-transplant. All 
participants will receive study treatment 
until Week 14 (~100 days) post-transplant. 
After the end of study treatment, each 
participant will be followed until Week 24 
post-transplant.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
* For participants who cannot tolerate swallowing and/or develop a condition that may interfere with the absorption of the 
oral formulation of letermovir, study intervention can be initiated/switched to the IV formulation of letermovir. The IV 
formulation should be switched to oral study therapy (i.e., at the next planned dose) as soon as such participants are 
able to swallow and/or the condition necessitating the use of the IV formulation resolves.
CsA = cyclosporin A
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1.3
Schedule of Activities
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Administrative Procedures
Informed Consent
X
Inclusion/
Exclusion Criteria
X
X
Confirm 
inclusion/exclusion 
prior to 1st dose of 
study intervention.
Participant 
Identification Card
X
Medical History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Intervention 
Allocation
X
HSCT Details 
Review
X
Study Medication 
Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/ Assessments
Full Physical 
Examination
X
X
08RXZX


PRODUCT: MK-8228
19
PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Targeted Physical 
Examination
Performed only when clinically indicated
Weight
X
X
X
Height
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram
X
X
X
Read locally. 
Values collected 
within 1 week prior 
to screening are
acceptable for Visit 
1.
ECG will be 
obtained after 
participants resting 
for at least 
10 minutes.
Child-Pugh Score 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Refer to 8.3.4 and 
Appendix 9.
08RXZX


PRODUCT: MK-8228
20
PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Participant 
Confirmation of 
Birth Control
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For male 
participants, no 
contraception 
measures are needed 
during letermovir 
treatment. 
For female 
participants of 
child-bearing 
potential, acceptable 
methods of 
contraception 
should be used from 
the time of consent 
through 28 days 
after the last dose of
study intervention.
08RXZX


PRODUCT: MK-8228
21
PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Adverse Events 
Monitoringf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All AEs will be 
reported through 14 
days after last dose 
of study medication.  
Thereafter, only 
SAEs will be 
reported through 
Week 24 post-
transplant (see 
Section 8.4)
Laboratory Procedures/ Assessments
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening values 
from the 
participant’s chart 
within 5 days prior 
to allocation for 
required chemistry, 
hematology, 
coagulation, and 
urinalysis tests are 
acceptable.  
Refer to 
Section8.3.6 for 
further details 
regarding the 
laboratory safety 
tests.
08RXZX


PRODUCT: MK-8228
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PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation INR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
Serum 
β-hCG in women of 
childbearing 
potential
X
Urine Pregnancy Test 
in women of 
childbearing 
potential
X
X
X
X
X
Performed locally; 
serum pregnancy 
test must be 
performed to 
confirm a positive 
urine test result.
HIV/Hepatitis B, C 
Screen
X
Screening values 
from the 
participant’s chart 
within 90 days prior 
to allocation for 
required tests are 
acceptable.  
08RXZX


PRODUCT: MK-8228
23
PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
CMV Procedures/ Assessments
CMV DNA PCR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CMV DNA will be 
tested weekly 
during the screening 
period (time 
between Screening 
and Day 1) by 
central lab after 
establishing absence 
of CMV viremia.
CMV Serology (IgG)
X
Perform locally per 
SOC at the site. 
This testing is not 
required if a 
previous 
documented 
positive IgG testing 
result within 1 year 
before HSCT is 
available.
08RXZX


PRODUCT: MK-8228
24
PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
CMV Disease 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All clinical signs 
and symptoms of 
CMV disease and 
review of relevant 
laboratory 
parameters
Survival Assessment
X
X
Study Intervention Administration
Letermovir 
dispensing (oral 
formulation)
X
X
X
X
X
X
X
For participants 
receiving the oral 
formulation of study 
intervention, 
letermovir tablets 
will be dispensed on 
Day 1 and every 2 
weeks starting from 
Week 2. Contact 
IRT at all 
dispensing visits.
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PRODUCT: MK-8228
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PROTOCOL/AMENDMENT NO.: 045-01
MK-8228-045-01 FINAL PROTOCOL
24-JAN-2023
Study Period
Screen
Treatment 
(W1)
Treatment
(W2 to W14 post-transplant)
Post-treatment FU
(W15 to W24 post-
transplant)
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Notes
Week No. 
SCRa
D1b
D7
2
3
4
5
6
7
8
9
10c
11c
12c
13c
EoT  
14c
16
18
20
22
24
CMV Infection 
or Early 
Discontinuation 
Visitd,e
Week No. of 
Treatment period is 
relative to the day of 
first dose of study 
intervention.
Visit Window 
(Days)
±2
±3
±4
±3 days every 2 
week during 
treatment period to 
align with drug 
dispensation.
Letermovir 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IV formulation 
available for 
participants unable 
to tolerate 
swallowing and/or 
have a condition 
that may interfere 
with the absorption 
of oral formulation. 
Study medication 
reconciliation and 
diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diary should be 
completed for 
participants 
receiving the oral 
formulation of study 
intervention only.
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24-JAN-2023
β-HCG = β-Human Chorionic Gonadotropin CMV = cytomegalovirus; D = Day; DNA = deoxyribonucleic acid; EoT = End-of-Treatment; FU = follow up; HIV = human 
immunodeficiency virus; HSCT = hematopoietic stem cell transplant; PCR = polymerase chain reaction; SCR = screening; W = week. 
a.
Participants may be screened during a period starting from 15 days prior to transplantation through 28 days post-transplant. The screening test results must be available within 
5 days prior to the planned allocation (start of study intervention) day. The following tests are to be performed within 5 days prior to allocation and results must be available
prior to allocation:  coagulation (INR), serum AST, ALT, and total bilirubin; creatinine clearance. For CMV DNA PCR, results of the assay done at a local laboratory will be 
acceptable for initial screening purposes.
b.
Allocation (start of study intervention) day is Day 1.  On the day of allocation, eligibility for enrollment into the study should be confirmed (including confirmation that 
HSCT has taken place) prior to start of study intervention. At that time, participants should have NO documented CMV viremia, as confirmed by CMV DNA PCR assay at 
the central laboratory in a plasma sample collected within 5 days prior to allocation. In addition, creatinine clearance and liver function test results within 5 days prior to 
allocation should also be available and within the range allowable in this study as outlined in Section 5.2 (Participant Exclusion Criteria). Study intervention may begin as 
early as the day of transplant and no later than 28 days post-transplant. Study intervention will continue through Week 14 (~100 days) post-transplant. Day 1 
procedures/assessments must be performed prior to initiation of study intervention.
c.
End of Study Therapy Visit may occur on Week 10, 11, 12, 13, or 14 depending on when study therapy was started during the 28-day post-transplant window.  For example, 
if study therapy was started on the day of transplant, the End of Study Therapy Visit would be the Week 14 Visit (which corresponds to Week 14 post-transplant).  If study 
therapy was started 28 days post-transplant, the End of Study Therapy Visit would be the Week 10 Visit (which corresponds to Week 14 post-transplant).  Any per protocol 
procedure listed under the Week 14 Visit should be conducted at the true End of Study Therapy Visit (at Week 10, 11, 12, 13, or 14 post-transplant, depending on when study 
therapy was started).
d.
The visit will be a CMV Infection Visit for all participants who discontinue study intervention due to clinically significant CMV infection defined as the occurrence of CMV 
disease or the initiation of PET, or for participants who are either diagnosed with CMV disease or require initiation of PET after study intervention completion during the 
follow-up period (through Week 24 post-transplant).  All procedures should be performed at this visit immediately prior to the initiation of treatment of CMV diseases or 
initiation of PET (i.e., on the day anti-CMV therapy is initiated).  Most importantly, a confirmatory plasma sample for CMV PCR testing at the central laboratory should be 
collected at this visit.  Refer to Section 8.2.1 and Section 8.10.4 for detailed requirements.
e.
The visit will be an Early Discontinuation Visit for those participants who are prematurely discontinued from the trial up to Week 24 post-transplant.
f.
Adverse event (AE) monitoring prior to allocation (Day 1) is limited to AEs resulting from protocol-related procedures or interventions, those resulting in death, and those 
resulting in a participant not being allocated. After initiating study intervention, all AEs should be collected from Day 1 through 14 days after last dose of study medication. 
Thereafter, only serious adverse events (SAEs) will be collected through Week 24 post-transplant in all participants.
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PRODUCT: MK-8228
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2
INTRODUCTION
Letermovir (also known as MK-8228) is an inhibitor of the CMV viral terminase complex. 
As of July 2022, letermovir has been approved for prophylaxis of CMV infection or disease 
in adult CMV-seropositive recipients (R+) of an allogeneic HSCT in several markets, 
including US, EU, Japan, Korea, Singapore, China Taiwan, and China Hong Kong. 
Letermovir tablet and IV formulations received approval in China for prophylaxis of CMV 
infection or disease in adult CMV-seropositive recipients (R+) of an allogeneic HSCT on 31 
December 2021 and 10 May 2022, respectively. 
The efficacy and safety of letermovir for CMV prophylaxis in adult CMV-seropositive 
recipients (R+) of an allogeneic HSCT has been established in the global pivotal double-
blinded, placebo-controlled Phase 3 trial (P001). However, as no Chinese participants were 
included in Study P001, the P045 study will be conducted to evaluate the efficacy and safety 
of letermovir for the prevention of clinically significant CMV infection in Chinese adult, 
CMV-seropositive allogeneic HSCT recipients. Of note, in this study, “Chinese participants” 
refer to participants who live in mainland China and who are ethically Chinese.
2.1
Study Rationale
CMV continues to be an important complication after allogeneic HSCT [Ljungman, P., et al
2002] [Boeckh, M. 2011].  The clinical effects of CMV can be divided into direct and 
indirect effects [Ljungman, P., et al 2002] [Boeckh, M. 2011].  The direct effects which have 
been extensively described include the spectrum of CMV disease (ie, end-organ 
manifestation).  CMV gastroenteritis is the most common clinical presentation in this 
population. While CMV pneumonia is the most serious manifestation, it has become 
relatively infrequent with current preventive strategies for CMV disease in HSCT recipients 
[Boeckh, M. 2011] [Boeckh, M. and Geballe, A. P. 2011].  Other rare manifestations of 
CMV disease include hepatitis, retinitis, and encephalitis [Ljungman, P., et al 2002] [Boeckh, 
M. 2011]. The indirect effects of CMV include its immunosuppressive effects, which can 
lead to an increased risk of systemic bacterial and invasive fungal disease as well as acute 
and chronic GVHD [Boeckh, M. 2011] [Boeckh, M. and Nichols, W. G. 2004].
Between 65% and 80% of adult HSCT recipients have evidence of prior CMV seropositivity 
globally and are therefore at risk for CMV reactivation (also referred to as CMV infection) 
and CMV disease post-transplantation [Ljungman, P. 2014] [Razonable, R. R. 2005] [Zhou, 
W., et al 2009]. In China, CMV seropositive (R+) patients account for about 95% of 
allogeneic HSCT patients, which is higher than the Western population [Xuan, L., et al 
2012]. Among R+ HSCT recipients, approximately 80% of recipients develop CMV 
infection and 20% to 35% progress to CMV disease without preventive measures [Boeckh, 
M. 2011] [Boeckh, M. and Geballe, A. P. 2011] [Boeckh, M. and Nichols, W. G. 2004]. The 
highest risk period for developing CMV infection (ie, virus isolation or detection of viral 
proteins (antigens) or nucleic acid in any body fluid or tissue specimen) is during the first 
100 days post-transplant [Boeckh, M. 2011] [Boeckh, M. and Geballe, A. P. 2011] [Boeckh, 
M. and Nichols, W. G. 2004] [Nakamae, H., et al 2009].
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Recipients with CMV seropositivity remain associated with poor outcomes especially in high 
risk HSCT patients, ie, unrelated donors or cord blood recipients [Boeckh, M. 2011] 
[Nakamae, H., et al 2009].  The source of stem cells and the conditioning regimens may also 
influence both the time to reactivation as well as the severity of disease [Nakamae, H., et al
2009] [Marty, F. M., et al 2011] [Sauter, C., et al 2011]. There are currently 2 approaches to 
prevent CMV disease in HSCT recipients: 1) prophylaxis with antivirals, and 2) pre-emptive 
therapy (PET), the practice of active surveillance for viral replication and initiating treatment 
with anti-CMV agents when CMV viremia is detected [Ljungman, P., et al 2002]. Prior to the 
availability of letermovir, all available anti-CMV agents were associated with significant 
toxicity, and resistance and cross-resistance across these antiviral agents is increasingly being 
reported. Thus, antivirals were not routinely used for the prophylaxis of CMV infection in 
HSCT patients, and there was a clear need for safe and well-tolerated drugs with novel 
mechanisms of action against CMV that can be used for prophylaxis in HSCT patients.
Letermovir is a novel anti-CMV agent that has been shown to be generally well tolerated in 
32 Phase 1 trials, 2 Phase 2 clinical trials (P019 and P020, respectively), and a single, pivotal 
Phase 3 efficacy and safety trial (P001). The results of the pivotal global Phase 3 trial (P001) 
establish the efficacy and safety of letermovir for CMV prophylaxis in adult CMV-
seropositive recipients (R+) of an allogeneic HSCT. In this randomized, placebo-controlled 
Phase 3 study, letermovir prophylaxis when started within 28 days posttransplant and 
continued until Week 14 (~100 days) posttransplant effectively prevented clinically 
significant CMV viremia through Week 24 posttransplant.  At Week 14 posttransplant (end 
of study treatment), 19.1% participants on letermovir developed clinically significant CMV 
infection compared to 50% participants on placebo. Letermovir was well-tolerated with no 
evidence of myelotoxicity.
This post-approval commitment study is planned to evaluate the efficacy and safety of 
letermovir in preventing clinically significant CMV infection in Chinese adult CMV 
seropositive allogeneic HSCT recipients.
2.2
Background
Refer to the IB for detailed background information on letermovir.
2.2.1
Pharmaceutical and Therapeutic Background
Prior to the availability of letermovir, there was no oral anti-CMV drug approved for 
prophylaxis of CMV disease in HSCT patients.  Use of GCV, VGCV, and foscarnet are 
limited by their toxicity profiles (prolonged myelosuppression, renal toxicity, and electrolyte 
abnormalities, respectively) [Boeckh, M. 2009]. Acyclovir and valacyclovir have limited 
efficacy against the virus [Boeckh, M. 2011] [Pollack, M., et al 2011] [Biron, K. K. 2006].  
Additionally, there is increasing emergence of resistance and cross-resistance to currently 
available antiviral agents [Boeckh, M. 2009] [Lurain, N. S. and Chou, S. 2010].  Thus, there 
is an urgent need for newer efficacious agents with better tolerability and novel mechanisms 
of action for CMV prophylaxis in HSCT patients.  
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Letermovir, which belongs to a new class of anti-CMV agents, has a novel mechanism of 
action.  It has demonstrated potent, selective, and reversible inhibition of CMV activity in 
preclinical studies in vitro and efficacy against the virus in vivo [Lurain, N. S. and Chou, S. 
2010] [Lischka, P., et al 2010].  It inhibits the viral terminase complex (UL56/UL89), an 
enzyme that plays an important role in cleavage of viral DNA into unit-length genome and 
packaging it into procapsids [Lischka, P., et al 2010] [Goldner, T., et al 2011].
While drug resistance remains rare, most resistance arises during treatment with GCV (or 
VGCV) as they are used in ~90% of patients as first-line agents.  Drug resistance is usually 
seen after treatment with these antiviral agents for duration of weeks to months [Boeckh, M. 
2009].  GCV and VGCV undergo intracellular phosphorylation by a viral kinase, which is 
encoded by the CMV gene UL97 during infection and the majority of resistance mutations 
with use of these therapies map to this gene [Lurain, N. S. and Chou, S. 2010].  It has been 
postulated that UL97 mutations arise first and confer moderate resistance to GCV (or 
VGCV) but not to other CMV antivirals, such as cidofovir or foscarnet. However, all current 
anti-CMV agents (with the exception of letermovir) act through the viral polymerase (UL54) 
and resistance mapping to this gene product leads to cross-resistance among all available 
agents [Lurain, N. S. and Chou, S. 2010].  To date, no cross-resistance has been 
demonstrated between letermovir and GCV, foscarnet, cidofovir, or acyclovir [Kaul, D. R., et 
al 2011].
2.2.2
Preclinical and Clinical Studies
Details of preclinical studies and completed clinical studies conducted with letermovir can be 
found in the accompanying IB.
2.2.3
Ongoing Clinical Studies
There are two ongoing clinical studies involving letermovir for HSCT patients: 1) P040, a 
Phase 3 randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy 
and safety of letermovir prophylaxis when extended from 100 days to 200 days post-
transplant in CMV R+ at high risk for CMV infection and/or disease after ~100 days post-
transplant of an allogenic HSCT; 2) P030, a Phase 2b open-label, single-arm study to 
evaluate pharmacokinetics, efficacy, safety and tolerability of letermovir in pediatric 
participants from birth to less than 18 years of age. Additionally, there are 2 ongoing clinical 
studies involving letermovir for adult solid organ transplant patients:1) P002, a Phase 3 
randomized, multi-site, double-blind active comparator trial to evaluate the efficacy and 
safety of letermovir versus VGCV in adult kidney transplant recipients; 2) P042, a Phase 3, 
open-label, single-arm study to evaluate the safety, efficacy and pharmacokinetics of 
letermovir for the prevention in adult Japanese kidney transplant recipients.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Efficacy data from the global Phase 2 and 3 studies have demonstrated that letermovir is 
highly efficacious in preventing CMV infection and disease in HSCT patients [Turner, N., et 
al 2019] [Marty, F. M., et al 2017]. Safety data (cut-off date: 1 May 2022) from 1,759 
participants exposed to letermovir across the clinical program indicated that overall 
letermovir has a favorable safety profile that is generally similar to placebo.  The effect of
race on letermovir exposure is not considered to be clinically relevant, and no dose 
adjustment is required. Based on available clinical data from non-Chinese patients, the study 
participants may potentially benefit from prevention of clinically significant CMV infection.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this study.  
The following objectives and endpoints will be evaluated in Chinese adult CMV-seropositive 
allogeneic HSCT recipients:
Primary Objective
Primary Endpoint
To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by the proportion of 
participants with clinically significant CMV 
infection through Week 24 (~6 months) post-
transplant.
Clinically significant CMV infection, 
defined as onset of CMV disease 
and/or initiation of PET for 
documented CMV viremia 
Secondary Objectives
Secondary Endpoints
To evaluate the safety and tolerability of 
letermovir based on the proportion of 
participants with AEs.

AEs

AEs resulting in study 
medication discontinuation 
To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by the proportion of 
participants with clinically significant CMV 
infection through Week 14 (~100 days) post-
transplant.
Clinically significant CMV infection, 
defined as onset of CMV disease 
and/or initiation of PET for 
documented CMV viremia
To evaluate the efficacy of letermovir in the 
prevention of clinically significant CMV 
infection, as measured by:

proportion of participants with CMV 
disease through Week 14 (~100 days) 
post-transplant and Week 24 (~6 months) 
post-transplant.

proportion of participants with initiation 
of PET for documented CMV viremia 
through Week 14 (~100 days) post-
transplant and Week 24 (~6 months) 
post-transplant.

proportion of participants with all-cause 
mortality through Week 14 (~100 days) 
post-transplant and Week 24 (~6 months) 
post-transplant.

CMV disease 

Initiation of PET for document 
CMV viremia

All-cause mortality
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4
STUDY DESIGN
4.1
Overall Design
This is an open label, single-arm, multi-site trial of letermovir in the prevention of clinically 
significant CMV infection in Chinese adult, CMV-seropositive allogeneic HSCT recipients. 
Clinically significant CMV infection is defined as the occurrence of either one of the 
following outcomes:
•
Onset of CMV end-organ disease, or
•
Initiation of anti-CMV PET based on documented CMV viremia (as measured by the 
central laboratory) and the clinical condition of the participant.
Approximately 120 eligible HSCT recipients will be allocated to receive letermovir at any 
time from the day of transplant until 28 days post-transplant. Both oral (tablet) and IV 
formulations of letermovir will be available for study intervention. Participants will be 
initiated with the oral (tablet) formulation of study intervention provided they are able to 
swallow and do not have a condition (e.g., vomiting, diarrhea, or a malabsorptive condition) 
that may interfere with the absorption of the tablets. For participants who cannot swallow 
and/or have a condition that may interfere with the absorption of the oral formulation (e.g., 
vomiting, diarrhea, or a malabsorptive condition), study intervention can be initiated with or 
switched to the IV formulation. The IV formulation should be switched to oral study 
intervention (i.e., at the next planned dose) as soon as such participants are able to swallow 
and/or the condition necessitating the use of the IV formulation resolves.
The dose of letermovir will either be 240 mg QD, for participants receiving concomitant 
CsA, or 480 mg QD, if the participant is not on CsA. As CsA has been shown to increase 
letermovir exposure, the dose of letermovir must be adjusted for participants taking CsA 
(concomitant use of other immunosuppressive agents like tacrolimus does not require this 
adjustment).
Participants will be grouped by the following risk categories for CMV reactivation and/or 
disease to observe the efficacy of letermovir based on risk category (see Section 4.2.1.1), as 
participants in the high-risk category are more likely to develop clinically significant CMV 
infection than those in the low-risk group. 
High risk: Participants meeting one or more of the following criteria at the time of 
allocation:
1. HLA-related (sibling) donor with at least one mismatch at one of the following three 
HLA-gene loci: HLA-A, -B or -DR, 
2. Haploidentical donor,
3. Unrelated donor with at least one mismatch at one of the following four HLA-gene loci: 
HLA-A, -B, -C and -DRB1,
4. Use of umbilical cord blood as stem cell source,
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5. Use of ex vivo T-cell-depleted grafts (including ex vivo use of alemtuzumab 
[Campath™]),
6. Grade 2 or greater GVHD, requiring the use of systemic corticosteroids (defined as the 
use of ≥1 mg/kg/day of prednisone or equivalent dose of another corticosteroid).
Low risk: All participants not meeting definition of high risk.
Participants must have documented seropositivity for CMV (recipient CMV IgG 
seropositivity [R+]) at screening or within one year prior to transplantation to be eligible for 
the study. Donor CMV serostatus may either be positive (D+) or negative (D−). Screening of 
potential eligible participants may begin within 15 days prior to transplantation. Screening 
may also occur after the transplant, but allocation (start of study intervention) must occur no 
later than 28 days post-transplant. Participants will have plasma samples tested for CMV 
viremia using the CMV DNA PCR assay, conducted by the central laboratory (Note: for 
initial screening purposes, results of the assay done at a local laboratory will be acceptable.) 
After establishing absence of CMV viremia, participants will be tested once a week by the 
central laboratory using the CMV DNA PCR assay until allocation in order to minimize 
enrollment of those with active CMV replication in the study. Note: the screening test results 
must be available within 5 days prior to the planned allocation date. Any participant who 
tests positive for CMV viremia (as documented by central laboratory results) prior to 
allocation at any time point will be excluded from the study, even if subsequent tests are 
negative for CMV viremia. Once allocated, CMV viremia will be monitored at the time 
intervals detailed in the Schedule of Activities (Section 1.3).
Study intervention (with letermovir) may begin as early as the day of transplant and no later 
than 28 days post-transplant. Study intervention will continue through Week 14 (~100 days) 
post-transplant with the primary intent of preventing clinically significant CMV infection. On 
the day of allocation, eligibility for enrollment into the study should be confirmed (including 
confirmation that HSCT has taken place). At that time, participants should have no 
documented CMV viremia (as confirmed by the central laboratory) from a plasma sample 
collected within 5 days prior to allocation. In addition, creatinine clearance and liver function 
test values from testing performed within 5 days prior to allocation should also be available 
and within the range allowable in this study as outlined in Section 5.2 (Participant Exclusion 
Criteria).
Once enrolled in the study, participants will have study visits scheduled at weekly intervals 
during the treatment period which will be through Week 14 (~100 days) post-transplant. For 
participants receiving the oral formulation of study intervention, letermovir tablets will be 
dispensed on Day 1 and every 2 weeks starting from Week 2. Visit schedules must align the 
weekly visits with the drug dispensation every 2 weeks. Thereafter, participants will be 
followed through Week 24 (~6 months) post-transplant. At all study visits through Week 24 
post-transplant, plasma samples will be collected for CMV DNA PCR testing (for testing by 
central laboratory) and the investigator must assess the participant to determine if the 
participant meets one of the criteria for clinically significant CMV infection (as defined 
above).
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Participants who are enrolled and start study treatment (letermovir) should not be 
discontinued from the study if the Day 1 CMV DNA PCR results are subsequently positive. 
In the event test results from the central laboratory are not available within the timeframe the 
investigator wishes to initiate anti-CMV therapy, the investigator may use local laboratory 
test (CMV DNA PCR) results in order to make the decision. However, plasma samples for 
CMV DNA PCR testing must also be sent to the central laboratory on the day anti-CMV 
agents are initiated for PET or for treatment of CMV disease.  The local laboratory result 
must also be reported in such instances.
For participants who develop clinically significant CMV infection during the study 
treatment period (up to Week 14 post-transplant): When the investigator intends to 
initiate either treatment for CMV disease or PET, the participant should have a CMV 
Infection Visit. It is very important to ensure that all procedures, as outlined in the Schedule 
of Activities (Section 1.3), are performed at the CMV Infection Visit immediately prior to
the initiation of treatment of CMV diseases or initiation of PET (i.e., on the day anti-CMV 
therapy is initiated). Most importantly, a confirmatory plasma sample for CMV PCR testing 
at the central laboratory should be collected at this visit. Thereafter, the participant should be 
discontinued from study intervention and treated according to the local standard of care 
(outside the context of the study). Such participants will, however, continue to be followed in 
the study (despite discontinuing study intervention and initiating anti-CMV therapy) and 
complete all remaining study visits (including all subsequent treatment period visits). At such 
subsequent visits, all procedures specified in the Schedule of Activities should be completed 
with the exception of study intervention administration and study medication diary review.
Note on reinitiation of study intervention: There may be instances where confirmatory 
central lab test results for CMV DNA PCR obtained on the day of PET initiation may be 
negative (i.e., CMV DNA not detected) and the investigator may wish to discontinue PET. 
The decision to stop PET in the event of a negative (CMV not detectable) confirmatory 
central laboratory result collected on the day of PET initiation resides with the investigator 
caring for the participant. Therefore, in the event the confirmatory CMV DNA sample at PET 
initiation is negative for CMV viremia, the Sponsor will allow for letermovir to be restarted 
at the investigator’s discretion, once PET is discontinued. In such instances, study 
intervention should be restarted within 7 days from the date on which study intervention is 
stopped. It is important to note that the status of the participant’s study intervention in IVRS 
should NOT be changed until the CMV DNA PCR result is confirmed and the investigator is 
certain that study intervention will be permanently discontinued.
For participants with clinically significant CMV infection during the post-treatment 
[follow-up] period (after Week 14 and through Week 24 post-transplant): When an 
investigator intends to initiate either treatment for CMV disease or PET, the participant 
should have a CMV Infection Visit. It is very important to ensure that all procedures, as 
outlined in the Schedule of Activities (Section 1.3), are performed at the CMV Infection Visit 
immediately prior to the initiation of treatment of CMV diseases or initiation of PET (i.e., 
on the day anti-CMV therapy is initiated). Most importantly, a confirmatory plasma sample 
for CMV PCR testing at the central laboratory should be collected at this visit. Thereafter, 
the participant can be treated according to the local standard of care (outside the context of 
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the study). Such participants will, however, continue to be followed in the study (despite 
initiation of anti-CMV therapy) and complete all remaining study visits). At such subsequent 
visits, all procedures specified in the Schedule of Activities should be completed.
Note: It is mandatory to send a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (i.e., on the day of) initiating treatment for 
CMV disease or PET in ALL instances. In the event that the confirmatory result obtained on 
the day of PET initiation is NOT available (e.g., sample is lost or mishandled by the 
investigator site prior to shipment, or is inadequate upon receipt at the central laboratory), 
local lab may be used in the interest of clinical management, but a subsequent sample must 
be obtained and sent to the central laboratory within 7 days after PET initiation (preferably 
within 48-72 hours). The participant will be considered to have met the primary efficacy 
endpoint if this confirmatory laboratory result is positive.
In the event confirmatory test results from the central laboratory are not available within the 
timeframe the investigator wishes to initiate anti-CMV therapy, the investigator may use a 
positive local laboratory test result (CMV DNA PCR) in order to make the decision. 
However, as described above, plasma samples for CMV DNA PCR testing must also be sent 
to the central laboratory. The local laboratory result must also be reported in such instances.
Participants who are discontinued from the study for any reason will not be replaced. 
Participants who discontinue the study early up to Week 24 post-transplant should complete 
an Early Discontinuation Visit. 
An independent CAC will be established. Investigators will report all “probable” and 
“proven” cases of CMV disease using the definitions in Appendix 8. All investigator-
reported diseases will be confirmed by the independent CAC. This CAC will review clinical, 
virologic, and histopathological data as well as the investigator’s assessments for 
adjudicating all potential cases of CMV end-organ disease, as defined in Appendix 8 
throughout the trial. The adjudication of cases by the CAC will take precedence over the 
investigator’s assessment.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The P045 study is designed as a single-arm and open-label study for CMV-seropositive 
allogeneic HSCT recipients as a large global double-blinded placebo-controlled trial 
demonstrating the safety and efficacy of letermovir has previously been conducted.  As 
letermovir is now approved for CMV prophylaxis, and no other approved anti-CMV agent is 
available for CMV prophylaxis in this population, it is not appropriate for this post approval 
study to be conducted with a placebo/active comparator.
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint of the study will be the proportion of participants with 
clinically significant CMV infection through Week 24 (~6 months) post-transplant, defined 
as the occurrence of either one of the following outcomes: 
•
Onset of CMV end-organ disease 
OR
•
Initiation of anti-CMV PET based on documented CMV viremia (as measured by the
central laboratory) and the clinical condition of the participant. Initiation of PET in this 
study refers to the practice of initiating therapy with the following approved anti-CMV 
agents when active CMV viral replication is documented: ganciclovir, valganciclovir, 
foscarnet, and/or cidofovir.
Note: in this document, below terms are used interchangeably: CMV disease and CMV end-
organ disease.
As detection of CMV in plasma or blood is associated with an increased risk of CMV disease 
[Gerna, G., et al 2011] [Lowance, D., et al 1999] [Gor, D., et al 1998] [Atkinson, C. and 
Emery, V. C. 2011], CMV viral DNA as a measure of CMV infection is already used 
routinely in China and global clinical practice to initiate and monitor PET [Boeckh, M. 2011] 
[Boeckh, M. 2009] [Winston, D. J., et al 2008] [Härter, G. and Michel, D. 2012] [Emery, V. 
C., et al 2000].  Patients with high viral loads or with cumulative high viral loads are at an 
increased risk of developing disease than those with lower viral loads [Härter, G. and Michel,
D. 2012] [Emery, V. C., et al 2000].  However, there is no clinically validated viral load 
threshold for initiating pre-emptive therapy at this point in time. 
In this study, CMV viremia (viral load) will be measured on plasma samples using the Roche 
COBAS® 6800 System, which will be performed by the central laboratory.  The lower limit 
of quantification (LLoQ) for this assay is 34.5 IU/ml (1 IU/ml = 1.1 copy/ml).  Results will 
be reported as:
•
Not detected (<34.5 IU/mL)
•
Detected, not quantifiable (<34.5 IU/mL)
•
Detected (numeric value provided)
Documented viremia is defined as any detectable (includes reporting of PCR results as 
“detected, not quantifiable” or “detected” with a numeric value provided) CMV viral 
DNA on a confirmatory sample obtained immediately prior to (i.e., on the day of) the 
initiation of treatment for CMV disease or PET, as measured by the Roche COBAS® 6800 
System in the central laboratory.  While any detectable CMV viral DNA results in the Roche 
COBAS® 6800 assay from confirmatory plasma sample sent to the central laboratory is 
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acceptable for the purpose of documenting viremia as a component of the primary endpoint, 
it is strongly recommended that investigators should not initiate PET when CMV viral load is 
below the LLoQ, but detectable (detected, not quantifiable [<34.5 IU/mL]). 
The following guidance regarding viral load thresholds for initiation of PET is being 
provided based on risk as defined in Section 4.1 as well as consideration of standard practice 
described by [Boeckh, M. 2009], which was also used in the global pivotal Phase 3 study 
(P001), and are as follows:
During the study treatment period [through Week 14 (~100 days) post-transplant] 
•
High risk: viral DNA ≥150 copies/mL
•
Low risk:  viral DNA >300 copies/mL
After Week 14 (~100 days) post-transplant
•
High risk: viral DNA >300 copies/mL
•
Low risk:  viral DNA >300 copies/mL
These thresholds for initiation of PET are provided as guidance based on the participant’s 
risk for CMV disease at baseline. However, specific thresholds for initiating PET are not 
mandated per protocol as a participant’s risk status and clinical condition may change during 
the course of the trial and is best assessed by the investigator taking care of the participant.
Note:  All study-related CMV DNA PCR samples must be sent to the central laboratory at 
the designated time points in the Schedule of Activities (Section 1.3).  It is strongly 
recommended that investigators use quantifiable viremia levels (at levels ≥LLoQ) detected 
by the central laboratory to drive decisions for initiating PET. It is mandatory to send a 
confirmatory plasma sample for CMV DNA PCR testing to the central laboratory 
immediately prior to (i.e., on the day of) initiating treatment for CMV disease or PET in 
ALL instances. In the event that the confirmatory result obtained on the day of PET initiation 
is NOT available (e.g., sample is lost or mishandled by the investigator site prior to 
shipment, or is inadequate upon receipt at the central laboratory), a subsequent sample must 
be obtained and sent to the central laboratory within 7 days after PET initiation (preferably 
within 48-72 hours). The participant will be considered to have met the primary efficacy 
endpoint if this confirmatory laboratory result is positive.
In the event test results from the central laboratory are not available within the timeframe the 
investigator wishes to initiate anti-CMV therapy, the investigator may use positive local 
laboratory test (CMV DNA PCR) results in order to make the decision. However, as 
described above, plasma samples for CMV DNA PCR testing must also be sent to the central 
laboratory on the day anti-CMV agents are initiated for PET or for treatment of CMV 
disease.  The local laboratory result must also be reported in such instances.
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4.2.1.2
Safety Endpoints
The safety and tolerability of letermovir will be assessed by a clinical evaluation of adverse 
experiences and evaluation of other study parameters including vital signs, physical 
examination, 12-lead ECGs, and standard laboratory safety tests at appropriate time points as 
specified in the Schedule of Activities (Section 1.3) and Section 8.4. Adverse experiences 
should be graded and recorded. Participants may be asked to return for unscheduled visits for 
additional safety monitoring.
4.2.2
Rationale for Sample Size
This is an estimation study with no hypotheses to be tested. This study will allocate 
approximately 120 participants to receive letermovir and will allow estimation of the 
proportion of participants with clinically significant CMV infection through Week 24 (~6 
months) post-transplant among participants receiving letermovir with a 95% confidence 
interval with a half-width of ~10 percentage points. Refer to Section 9.9.1 for detailed 
method of sample size calculation.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
This clinical study will evaluate:
Letermovir 
•
Oral/IV 480 mg QD, if given without concomitant CsA, or 
•
Oral/IV 240 mg QD, if given concomitantly with CsA
Rationale for Dose of Letermovir
Letermovir belongs to a new class of anti-CMV agents which have a novel mechanism of 
action compared to currently available drugs for the treatment of CMV infection. By 
inhibiting the viral terminase complex, the drug plays a key role in disrupting the normal 
process of cleavage and packaging of genomic viral DNA into provirions and subsequently 
prevents the completion of viral replication.
Letermovir has been generally safe and well tolerated in 32 Phase 1 studies in which 
participants received oral letermovir single doses ranging from 5 mg to 720 mg and multiple 
doses ranging from 40 mg QD to 720 mg BID or received IV letermovir single doses ranging 
from 30 mg to 960 mg and multiple doses ranging from 120 mg QD to 480 mg QD. In the 
Phase 2b study (Protocol 020), letermovir doses of 60 mg, 120 mg, or 240 mg or placebo, 
were given once daily in 131 HSCT recipients.  Letermovir 240 mg QD, during an 84-day 
treatment period, was well tolerated with a safety profile similar to placebo. A dose response 
was observed. One primary endpoint, the incidence of overall failure of CMV prophylaxis, 
was significantly reduced in the primary efficacy analyses with both the 120 mg and 240 mg 
doses of letermovir (32%, p=0.014 and 29%, p=0.007, respectively) when compared to 
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placebo (63.6%). However, the second primary efficacy endpoint, the time to onset of overall 
failure of CMV prophylaxis, was significantly reduced in the 240 mg group (p=0.002), but 
not in the 120 mg group (p=0.126), when compared to placebo. All sensitivity analyses 
confirmed the statistical significance of both the primary endpoints for the 240 mg QD dose 
of letermovir when compared to placebo. Letermovir was generally well-tolerated at all three 
doses in P020.
Phase 1 studies demonstrated that co-dosing with CsA increases letermovir exposure.  
Further analyses using the Phase 2b study (P020) data indicated that exposure with the 240 
mg QD dose of letermovir administered alone overlaps exposure levels of the 60 and 120 mg 
QD doses, which are associated with virologic failures. Based on the Phase 2b efficacy and 
safety data as well as the exposure-response data, a dose of 480 mg QD was proposed in 
participants who are not receiving CsA concomitantly, and 240 mg QD was proposed as the 
dose for participants receiving CsA concomitantly. The dose of letermovir for evaluation in 
the Phase 3 pivotal study was 480 mg with a dose adjustment to 240 mg when given 
concomitantly with CsA.
The efficacy and safety of letermovir 480 mg QD (or 240 mg QD with concomitant CsA) 
was demonstrated in a Phase 3, randomized, placebo-controlled study (P001) in adult CMV 
seropositive allogeneic HSCT recipients including Asian participants[Marty, F. M., et al 
2017]. Treatment with letermovir or placebo was started as early as the day of transplant and 
no later than 28 days post-transplant and continued through Week 14 post-transplant; 
participants were followed through Week 48 post-transplant. Overall, the results showed a 
robust and efficacious response for letermovir compared to placebo. Letermovir was superior 
to placebo in the prevention of clinically significant CMV infection through Week 24 post-
transplant, and the proportion of participants with clinically significant CMV infection was 
substantially lower in the letermovir group compared to the placebo group. All-cause 
mortality was substantially lower in the letermovir group compared to the placebo group 
through Week 24 post-transplant, with a continued trend in favor of letermovir through and 
Week 48 post-transplant.  Letermovir was well tolerated in HSCT recipients and had a safety 
profile which was generally similar to placebo with no evidence of myelotoxicity, 
nephrotoxicity, or hepatotoxicity.
For the P045 study, the doses of letermovir that were previously used in the Phase 3 
evaluation in global HSCT recipients including Asian participants will be used. The 
letermovir doses that have shown to be effective in the global HSCT recipient population is 
anticipated to be effective in the Chinese population.
The IV formulation of letermovir contains the excipient hydroxypropyl betadex. There is a 
possibility that in participants with renal impairment, worsening of renal function and other 
untoward effects might occur due to accumulation of the excipient hydroxypropyl-β-
cyclodextrin in the intravenous infusion therefore, the duration of use with the intravenous 
infusion should be kept to a minimum. Oral administration should be selected for participants 
for whom oral administration is possible. Also, the effect of renal impairment on letermovir 
PK was evaluated in participants with moderate (eGFR ≥30 to 59 mL/min/1.73 m2) or severe 
renal impairment (eGFR <30 mL/min/1.73 m2; actual range:  11.86-28.14 mL/min/1.73 m2) 
[Kropeit, D., et al 2017]. Based on the P006 study results, no dose adjustment is 
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recommended for participants with moderate or severe renal impairment. The approved 
letermovir dose for IV formulation is the same as PO dosing of 480 mg QD (or 240 mg QD 
with concomitant CsA). IV formulation should only be used when participants are either 
unable to swallow or have a condition that may interfere with the absorption of the oral 
formulation. Use of the IV formulation should generally be limited to 4 weeks or less in 
duration per participant.
4.3.2
Maximum Dose Exposure for This Study
The maximum dose of letermovir in this study will not exceed 480 mg once daily.
4.3.3
Rationale for Dose Interval and Study Design
Most HSCT patients are at highest risk for CMV disease within 14 weeks (~100 days) after 
transplantation.  Antiviral prophylaxis with letermovir was efficacious when used for 84 days 
in the Phase 2b (MK-8228-020) study, and it had also been confirmed that it’s efficacious 
when used for 100 days in the Phase 3 (P001) study, Therefore, study intervention with 
letermovir will be used for antiviral prophylaxis through Week 14 (~100 days) post-
transplant in this study. Participants will then be followed through Week 24 post-transplant 
(additional 10 weeks following completion of study intervention) in order to evaluate the 
incidence of late-onset CMV infection/disease during the post-treatment period.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
Male/Female Chinese adult participant of an allogeneic HSCT will be eligible for inclusion 
in this trial.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Recipient CMV IgG seropositivity [R+] (have seropositivity for CMV) at screening or 
have documented seropositivity for CMV within 1 year before HSCT.
2. Be receiving a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord 
blood transplant).
3. Have undetectable CMV DNA (as confirmed by the central laboratory) from a plasma 
sample collected within 5 days prior to allocation.
4. Be within 28 days post-HSCT at the time of allocation.
Demographics
5. Is an individual of any sex/gender, from 18 years to any years of age inclusive, at the 
time of providing the informed consent.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Not a WOCBP
OR
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•
A WOCBP and:
-
Uses an acceptable contraceptive method, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 28 days after the last dose of study intervention. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. Contraceptive use by 
women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.
-
Has a negative highly sensitive pregnancy test (serum as required by local 
regulations) within 24 hours before the first dose of study intervention. 
-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed
consent/assent for the study.
Additional Categories
8. Be able to read, understand, and complete diaries.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Received a previous allogeneic HSCT (Note: Receipt of a previous autologous HSCT is 
acceptable).
2. Has a history of CMV end-organ disease within 6 months prior to allocation.
3. Has evidence of CMV viremia at any time from either signing the ICF or the HSCT 
procedure, whichever is earlier, until the time of allocation. 
(Note: Evidence of CMV viremia as reported by central lab will include reporting of 
CMV DNA test results as “detectable, not quantifiable” or “detected” with a numeric 
value provided.) 
4. Has suspected or known hypersensitivity to active or inactive ingredients of letermovir 
formulations.
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5. Has severe hepatic insufficiency (defined as Child-Pugh Class C [see Appendix 9]) 
within 5 days prior to allocation.
6. Has serum AST or ALT > 5 × the ULN or serum total bilirubin > 2.5 × ULN within 5 
days prior to allocation.
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have one repeat testing done prior to allocation. If the repeat value does not 
meet this criterion, they may continue in the screening process. Only the specific out of 
range value should be repeated (not the entire panel).
7. Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis)  OR b) has end-
stage renal impairment with a creatinine clearance ≤10 mL/min, as calculated by the 
Cockcroft-Gault equation using serum creatinine within 5 days prior to allocation.
Creatinine Clearance (Males) = (weight in kg) (140 – age)(72) (creatinine in mg/dL)
Creatinine Clearance (Females) = 0.85 x the value obtained with formula above
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have one repeat testing done within 5 days prior to allocation. If the repeat 
value does not meet this criterion, they may continue in the screening process. Only the 
specific out of range value should be repeated (not the entire panel).
8. Has both moderate hepatic insufficiency AND moderate to severe renal insufficiency.
Note: Moderate hepatic insufficiency is defined as Child-Pugh Class B (see Appendix 9); 
moderate-to-severe renal insufficiency is defined as a creatinine clearance less than 50 
mL/min, as calculated by the Cockcroft-Gault equation (as above), respectively.
9. Has an uncontrolled infection (such as any infectious process that is associated with 
sepsis, septic shock and/or requires management in the intensive care unit) on the day of 
allocation.
10. Any rapidly-progressing disease or immediately life-threatening illness (including 
respiratory failure and septic shock) necessitating the use of IV fluids and/or vasopressors 
for maintaining blood pressure and/or the use of mechanical ventilation. 
11. Has a documented positive result for human immunodeficiency virus antibody (HIV-Ab) 
test at any time prior to allocation, or for HCV-Ab with detectable HCV RNA, or 
hepatitis B surface antigen (HBsAg) within 90 days prior to allocation. Local HIV, HBV, 
or HCV lab testing using acceptable methods are allowed.
12. Has active solid tumor malignancies with the exception of localized basal cell or 
squamous cell skin cancer or the condition under treatment (e.g., lymphomas).
13. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the 
time of consent through 28 days after the last dose of study intervention.
Prior/Concomitant Therapy
14. Received within 2 days prior to treatment initiation of letermovir or plans to receive 
during the study any of the following:
-
Ganciclovir
-
Valganciclovir
-
Foscarnet
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-
Acyclovir (at doses greater than those recommended for HSV/VZV prophylaxis 
>3200 mg PO per day or >25 mg/kg IV per day; see Section 6.5.2.1)
-
Valacyclovir (at doses greater than those recommended for HSV/VZV prophylaxis, 
such as >3000 mg PO per day; see Section 6.5.2.1)
-
Famciclovir (at doses greater than those recommended for HSV/VZV prophylaxis 
>1500 mg PO per day; see Section 6.5.2.1)
Received within 30 days prior to screening or plans to receive during the study any of the 
following:
-
Cidofovir
-
CMV hyper-immune globulin|
-
Any investigational CMV antiviral agent/biologic therapy
15. Participant is anticipated to be treated with Traditional Chinese Medicine or herbal 
medicine during the study treatment period and for 14 days after study medication.
Prior/Concurrent Clinical Study Experience
16. Is currently participating or has participated in a study with an unapproved investigational 
compound or device within 28 days or 5× half-life of the investigational compound, 
whichever is longer, or 5× half-life of monoclonal antibody of initial dosing in this study.
Note: Investigational chemotherapy regimens involving approved agents and 
investigational antimicrobial regimens involving approved 
antibacterial/antifungal/antiviral agents, investigational radiotherapy or GVHD agents, or 
other observational studies are allowed.
17. Has previously participated or is currently participating in any study involving 
administration of a CMV vaccine or another CMV investigational agent or is planning to 
participate in a study of a CMV vaccine or another CMV investigational agent during this 
study.
Diagnostic Assessments
Not applicable.
Other Exclusions
18. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
circumstance that might confound the results of the study, interfere with participation for 
the full duration of the study, or would be put at undue risk as judged by the investigator, 
such that it is not in the best interest of the participant to participate in this study.
19. 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.
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5.3
Lifestyle Considerations
No lifestyle restrictions are required based on the study procedures.
5.3.1
Meals and Dietary Restrictions
The oral formulation of letermovir demonstrates no clinically significant food effect, thus 
participants may take the study drug orally without regard to food.  
However, there may be restrictions with other nonstudy treatment agents the participant is 
taking during the study and therefore it is important for investigators to refer to the product 
information for those agents (ie, participants who are taking CsA concomitantly with 
letemovir must avoid consumption of grapefruit and grapefruit juice from 2 weeks prior to 
study treatment administration with CsA until 72 hours after the final administration of study 
treatment with CsA).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently allocated in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention 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 provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study is outlined in Table 1. In this study, 
approximately 120 participants will be allocated to receive letermovir once a day from the 
day of allocation (Day 1, within 28 days post-transplant) through 14 weeks (~100 days) post-
transplant.  Both oral (tablet) and IV formulations of letermovir will be used in this study.  
Participants will be initiated with the oral formulation of study intervention provided they are 
able to swallow and do not have a condition (e.g., vomiting, diarrhea, or a malabsorptive 
condition) that may interfere with the absorption of the tablets. Participants requiring the oral 
480 mg dose of letermovir should be initiated with two 240 mg tablets. 
For participants who cannot tolerate swallowing and/or develop a condition that may 
interfere with the absorption of the oral formulation at or after allocation/Day 1, study 
intervention can be initiated/switched to the IV formulation.  Use of the IV formulation 
should generally be limited to 4 weeks or less in duration per participant.  However, it will be 
left to the investigator’s discretion to continue IV administration beyond 4 weeks if the 
benefit/risk ratio supports continued administration. Simultaneous use of IV and oral study 
intervention is not allowed.  The IV formulation should be switched to oral study 
intervention (ie, at the next planned dose) as soon as such participants are able to swallow 
and/or the condition necessitating the use of the IV formulation resolves.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Letermovir Experimental Letermovir
Drug
Tablet
240 mg
240 mg
(for 
participants 
on CsA)
OR
480 mg 
(for 
participants 
not on 
CsA)
Oral
Through 
Week 14 
(~100 days)
post-
transplant
Test 
Product
IMP
Sponsor
Letermovir Experimental Letermovir
Drug
Concentrate
240 mg
240 mg
(for 
participants 
on CsA)
OR
480 mg 
(for 
participants 
not on 
CsA)
IV Infusion
Through 
Week 14 
(~100 days)
post-
transplant
Test 
Product
IMP
Sponsor
CsA = Cyclosporin A; IMP = Investigational Medicinal Product.
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For letermovir oral route of administration, the study intervention will be dispensed every 2 
weeks; one letermovir 240 mg tablet should be taken for the 240 mg dose, and two 240 mg 
letermovir tablets for the 480 mg dose. 
For letermovir IV route of administration, letermovir IV will be provided as a sterile liquid 
concentrate for dilution (20 mg/mL), one vial to be used for the 240-mg dose and two vials 
for the 480-mg dose. The dosing volume will be 250 mL and duration of infusion will be 60 
minutes.Site personnel will administer the IV study medication through a sterile 0.2 micron 
or 0.22 micron PES in-line filter, using only IV bags and infusion set materials that are 
DEHP-free.
The letermovir IV formulation should be switched to oral study intervention (ie, at the next 
planned dose) as soon as participants are able to swallow and/or the condition necessitating 
the use of the IV formulation resolves.
Study intervention may begin as early as the day of transplant to no later than 28 days 
posttransplant, once the participant is determined to be negative for CMV viremia (no 
evidence of CMV viremia confirmed by the central laboratory on a sample collected from the 
participant within 5 days prior to allocation).
All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
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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 in this study will be assigned to a single intervention group.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment for ≥7 consecutive days require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
It is important for investigators to review each medication (prescription and non-prescription) 
the participant is taking before starting the study and at each study visit.
•
At each visit, participants should be questioned about any new drug they are taking.
•
To minimize the risk of adverse drug interactions, every effort should be made to limit 
the number of concomitant drugs to those that are truly essential.
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Given that the lists below are not comprehensive, the investigator should use his/her medical 
judgment when a participant presents with a medication not on the list and consult with the 
Sponsor when appropriate.
6.5.1
Allowed Medications/Therapies to be Administered with Clinical and/or Drug 
Level Monitoring when Coadministered with Study Intervention
Letermovir is both a CYP3A inhibitor and substrate, an OATP1B1/3 inhibitor, and a 
CYP2C9 and CYP2C19 inducer. The following medications/therapies are allowed when 
coadministered with study intervention but should be used with clinical monitoring for AEs 
related to these agents and/or drug level monitoring of these agents (please refer to the 
prescribing information of each product circular). 
Note:  Since the drug-drug interactions may be different when letermovir is 
coadministered with CsA than when drugs are coadministered with letermovir without 
CsA, please refer to Section 6.5.2.2 for additional recommendations when study 
intervention is coadministered with CsA.
•
CYP3A substrates:
-
Coadministration of letermovir with drugs that are CYP3A substrates may result in 
clinically relevant increases in the plasma concentrations of coadministered CYP3A 
substrates (eg, alfentanil, fentanyl, and midazolam).  Therefore, frequent monitoring 
for adverse reactions related to these agents is recommended during coadministration.  
-
Dose adjustment of CYP3A substrates with narrow therapeutic range (NTR) may be 
needed when coadministered with letermovir (a moderate CYP3A inhibitor).  Please 
consult current prescribing information for monitoring and dosing of these products 
with moderate inhibitors of CYP3A.
◦
CsA:  Coadministration of letermovir with CsA increases CsA concentrations.  
Frequent monitoring of CsA whole blood concentrations should be performed 
during and at discontinuation of letermovir with the dose of CsA to be adjusted as 
appropriate. 
◦
Sirolimus: Coadministration of letermovir with sirolimus increases 
concentrations of sirolimus.  Frequent monitoring of sirolimus whole blood 
concentrations should be performed during and at discontinuation of letermovir 
with the dose of sirolimus to be adjusted as appropriate.  When letermovir is 
coadministered with CsA, refer to the sirolimus prescribing information for 
specific dosing recommendations for use of sirolimus with CsA.
◦
Tacrolimus:  Coadministration of letermovir with tacrolimus increases tacrolimus 
concentrations.  Frequent monitoring of tacrolimus whole blood concentrations 
should be performed during and at discontinuation of letermovir with the dose of 
tacrolimus to be adjusted as appropriate.
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◦
Everolimus:  Coadministration of letermovir with everolimus may increase 
everolimus concentrations.  Frequent monitoring of everolimus blood 
concentrations should be performed during and at discontinuation of letermovir 
with the dose of everolimus to be adjusted as appropriate.  (Note: Please see 
Section 6.5.2.2 for recommendation of everolimus when Letermovir is 
coadministered with CsA).
◦
Amiodarone: Letermovir may increase the plasma concentrations of amiodarone 
(CYP3A and CYP2C8 substrates).  Frequent monitoring for adverse reactions 
related amiodarone is recommended during coadministration.  Frequent 
monitoring of amiodarone concentrations should be performed when 
coadministered with letermovir.
•
Certain HMG-CoA reductase inhibitors (statins) as substrates of organic anion-
transporting polypeptide 1B1/3 (OATP1B1/3) and/or CYP3A:
-
Atorvastatin:  The dose of atorvastatin should not exceed a daily dose of 20 mg.  
(Note: Please see Section 6.5.2.2 for recommendation of atorvastatin when letermovir 
is coadministered with CsA).
-
Fluvastatin, lovastatin, rosuvastatin, or pravastatin:  The dose of fluvastatin, 
lovastatin, rosuvastatin, or pravastatin may need to be adjusted when coadministered 
with letermovir.  Monitoring for statin-associated adverse reactions (eg, myalgias, 
rhabdomyolysis) is recommended during coadministration with letermovir. 
•
Substrates of CYP2C9 and CYP2C19 (voriconazole, warfarin, omeprazole, and 
pantoprazole):
-
Voriconazole:  Coadministration of letermovir with voriconazole decreases the 
plasma concentrations of voriconazole likely due to induction of CYP2C9 and/or 
2C19.  If concomitant administration is necessary, close monitoring for reduced 
effectiveness of voriconazole is recommended.
-
Warfarin:  Letermovir may decrease the plasma concentrations of CYP2C9 and/or 
CYP2C19 substrates (eg, warfarin).  Frequent monitoring of international normalized 
ratio (INR) should be performed while warfarin is coadministered with letermovir.
-
Proton Pump Inhibitors, omeprazole, and pantoprazole:  Letermovir may decrease the 
plasma concentrations of CYP2C19 substrates.  Clinical monitoring and dose 
adjustment may be needed.
•
Medications for Diabetes:  
-
Glyburide, repaglinide, or rosiglitazone:  Letermovir may increase the plasma 
concentrations of these diabetic medications.  Frequent monitoring of glucose 
concentrations is recommended during coadministration with letermovir.  (Note:
please see Section 6.5.2.2 for recommendation of repaglinide when letermovir is 
coadministered with CsA).
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6.5.2
Prohibited Medications
Medications/therapies that are prohibited during coadministration with study intervention 
during the time periods specified are outlined in Section 6.5.2.1.  Since the drug-drug 
interaction on coadministered drugs may be different when letermovir is coadministered with 
CsA than when drugs are coadministered with letermovir without CsA, additional prohibited 
medications when study intervention is coadministered with CsA are outlined in Section 
6.5.2.2. 
If there is a clinical indication for one of these or other medications specifically prohibited 
during the study, discontinuation from study intervention may be required.  The investigator 
should discuss any questions regarding this with the Sponsor.  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.  Given that the list below is 
not comprehensive, the investigator should use his/her medical judgment when a participant 
presents with a medication not on the list and consult with the Sponsor.
6.5.2.1
Medications Prohibited with Study Medication
Letermovir use that is not part of study medication is prohibited during treatment 
period and all of follow-up period.
The following medications/therapies are prohibited during treatment period and all of 
follow-up period (except for cases of suspected clinically significant CMV infection):
•
Antiviral drugs or therapies for prevention/treatment of CMV, including but not limited 
to:
-
Ganciclovir or valganciclovir
-
Foscarnet
-
Cidofovir
-
Acyclovir (at doses greater than those recommended for HSV/VZV prophylaxis, such 
as >3200 mg PO per day or >25 mg/kg IV per day)
-
Valacyclovir (at doses greater than those recommended for HSV/VZV prophylaxis, 
such as >3000 mg PO per day)
-
Famciclovir (at doses greater than those recommended for HSV/VZV prophylaxis, 
such as >1500 mg PO per day) 
-
CMV immunoglobulin 
-
ANY investigational CMV antiviral agent/biologic therapy, including CMV vaccines
Note: these agents may be used for other indications while participants are on study 
intervention (eg, foscarnet for the treatment of HHV 6 or acyclovir for treatment of 
disseminated zoster)
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The following medications/therapies are prohibited during the dosing period and for 14 
days after study medication is discontinued: 
•
Investigational Agents:  Unapproved investigational agents or investigational regimens 
involving combinations of approved agents are not permitted except
-
Investigational chemotherapy regimens involving approved agents and 
investigational antimicrobial regimens involving approved
antibacterial/antifungal/antiviral agents, investigational radiotherapy studies, or other 
observational studies are allowed.
•
Traditional Chinese Medicines or Herbal Supplements:  both Traditional Chinese 
medicines and Herbal Supplements are not permitted.
•
CYP3A substrates with NTR, including but not limited to:
-
Pimozide: Concomitant administration of letermovir may result in increased 
concentrations of pimozide due to inhibition of CYP3A by letermovir, which may 
lead to QT prolongation and torsade de pointes.
-
Ergot alkaloids: Concomitant administration of letermovir may result in increased 
concentration of ergot alkaloids (ergotamine and dihydroergotamine) due to 
inhibition of CYP3A by letermovir, which may lead to ergotism.
•
Certain HMG-CoA reductase inhibitors (statins) (Note: See Section 6.5.2.2 for additional 
statins that are prohibited for use when letermovir is coadministered with CsA):
-
Simvastatin and pitavastatin 
•
Strong inducers, such as rifampin, phenytoin, carbamazepine, St John’s wort (Hypericum 
perforatum), rifabutin and phenobarbital 
•
Moderate inducers, such as nafcillin, thioridazine, modafinil and bosentan
6.5.2.2
Additional Medications Prohibited When Study Medication is 
Coadministered with CsA
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on coadministered 
drugs may be different when letermovir is coadministered with CsA than when drugs are 
coadministered with letermovir without CsA.  In addition to the prohibited medications listed 
above in Section 6.5.2.1, medications listed in this section are additional medications that are 
prohibited when coadministered with letermovir and CsA during the dosing period and for 
14 days after the dosing period.  When used together, they should be administered in a 
manner consistent with the Chinese product circulars for CsA, including the complete list of 
prohibited medications including those that are contraindicated or not recommended.  
•
Certain HMG-CoA reductase inhibitors (statins): When letermovir is coadministered with 
CsA, the magnitude of the increase in statin plasma concentrations is expected to be 
greater than with letermovir alone.  
-
atorvastatin and lovastatin (Note: please see Section 6.5.2.1 for additional prohibited 
statins when coadministered with letermovir alone).  
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•
Everolimus (Note: please see Section 6.5.1 for recommendation of everolimus when 
coadministered with letermovir alone)
•
Repaglinide (Note: please see Section 6.5.1 for recommendation of repaglinide when 
coadministered with letermovir alone)
6.5.3
Rescue Medications and Supportive Care
In the event of clinically significant CMV infection (CMV disease or initiation of PET based 
on CMV viremia and the clinical condition of the participant) during the study intervention 
period (ie, prior to completion or early discontinuation of study intervention), study 
intervention will be discontinued, and the participant may be treated according to the 
standard of care (SOC) (outside the context of the study). In this setting, any of the prohibited 
anti-CMV medications (as outlined in Section 6.5.2) may be used.
6.6
Dose Modification (Escalation/Titration/Other)
Please see Section 6.1 for letermovir dose to be used with or without coadministered CsA 
and Section 8.10.2.2 for information regarding dose modifications if CsA is initiated or 
discontinued during study intervention treatment period.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not Applicable. This is a single-arm study.
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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 before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study Section 7.2.
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.
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 develops confirmed or suspected clinically significant CMV infection as 
determined by the investigator (see Section 4.2.1.1).
•
The participant has a confirmed positive pregnancy test.
•
The participant’s investigator feels it is in the best interest of the participant to 
discontinue.
•
An elevated AST or ALT lab value that is greater than or equal to 3 × ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at the same 
time, an alkaline phosphatase lab value that is less than 2 × ULN, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing.
•
The participant develops: 
-
Both moderate hepatic insufficiency (Child-Pugh Class B; Appendix 9) and 
moderate-to-severe renal insufficiency (defined as CrCl <50 mL/min as calculated by 
the Cockcroft-Gault equation; see Section 5.2), 
OR
-
Severe hepatic insufficiency (Child Pugh Class C; Appendix 9),
OR
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-
Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis)  OR b) has 
end-stage renal impairment with a creatinine clearance ≤10 mL/min,  as calculated by 
the Cockcroft-Gault equation
•
The participant may be discontinued from study intervention for any of the following 
reasons:
-
Any AE/SAE assessed by the investigator as possibly or probably related to study 
intervention. The investigator may continue the participant in the study if it is deemed 
to be in the best interest of the participant to stay on study intervention.
-
Failure to comply with the dosing, evaluations, or other requirements of the study.
-
The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, places the participant at unnecessary risk 
through continued participation in the study or does not allow the participant to 
adhere to the requirements of the protocol (eg, if there is a clinical indication for any 
medication or vaccination specifically prohibited during the trial, discontinuation 
from trial therapy may be required [see Section 6.5]).
Specific details regarding procedures to be performed at study intervention discontinuation 
are provided in Section 6.5.
For participants who are discontinued from study medication but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Participants may be allowed to begin study medication again if deemed medically 
appropriate.  There may be instances where confirmatory central laboratory test results for 
CMV DNA PCR results obtained on the day of PET initiation may be CMV DNA 
undetectable or detected, but not quantifiable, and the investigator may wish to discontinue 
PET.  The decision to stop PET resides with the investigator caring for the participant.  
Therefore, in the event the confirmatory CMV DNA sample at PET initiation is CMV DNA 
undetectable or detected, but not quantifiable, the Sponsor will allow for study intervention 
to be restarted at the investigator’s discretion, once PET is discontinued.  In such instances, 
study intervention should be restarted <7 days from the date on which study intervention was 
stopped.  It is important to note that the status of the participant’s study intervention in 
IRT should NOT be changed until the CMV DNA PCR result is confirmed and the 
investigator is certain that study intervention will be permanently discontinued.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.10 The procedures to be performed should a participant 
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repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet 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 
is specified in a separate document.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study at screening and prior to 
allocation on Day 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 documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
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8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement. This includes review of consumption of grapefruit, 
Seville oranges or their respective juices, and other quinine-containing drinks or food. Prior
medication taken by the participant within 30 days prior to the first dose of study intervention 
will be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
through 2 weeks after the study treatment period.
In addition, anti-CMV medications (including letermovir that is not part of the study 
medication, ganciclovir, valganciclovir, acyclovir, valacyclovir, famciclovir, foscarnet, 
cidofovir) administered for treatment of CMV disease or for initiation of PET, and all 
drug/biologic therapies used to prevent/treat GVHD should be recorded at every visit through 
Week 24 posttransplant (Visit 21).  
During the follow-up period through Week 24, concomitant medication review and recording 
of data is limited to anti-CMV medications and, all antimicrobials (antibacterials, antifungals, 
antiparasitic agents, and antivirals), oral hypoglycemic agents, insulin, granulocyte colony-
stimulating factor (G-CSF), and immunosuppressant agents. Refer to the data entry 
guidelines for additional requirements on concomitant medication review and recording of 
data.
8.1.6
HSCT Details Review
All relevant data about the HSCT will be collected on Day 1. This includes details regarding 
conditioning regimen, date and type of transplant, source of stem cells, type of graft 
manipulation, presence of GVHD, and GVHD prophylaxis regimen (if any).
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
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A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.9
Study Intervention Administration
The first dose of study intervention will be administered at the study site at Visit 2 (Day 1; 
within 28 days post transplant).  Subsequent dosing will be performed once daily by the 
participant (ie, unsupervised at his/her home) at approximately the same time each day.
For participants who develop a condition that interferes with their ability to swallow, or a 
condition that interferes with the absorption of the oral formulation (eg, vomiting, diarrhea, 
or a malabsorptive condition), a letermovir IV formulation would be administered. The IV 
administration is for short-course administration (up to approximately 4 weeks).  The study 
pharmacist will be responsible solely for the preparation of the IV study medication.  
Site personnel will administer the IV study medication through a sterile 0.2-micron or 0.22 
micron polyethersulfone (PES) in-line filter, using only IV bags and infusion set materials 
that are diethylhexyl phthalate (DEHP)-free.  Refer to the Pharmacy Manual document for 
further details. 
Participants should be switched from the IV formulation back to oral study intervention as 
soon as such participants are able to swallow and/or the condition necessitating the use of the 
IV formulation resolves and the appropriate oral study drug supply may be obtained for the 
participant.  Use of the IV formulation should generally be limited to 4 weeks or less in 
duration per participant.  However, it will be left to the investigator’s discretion to continue 
IV administration beyond 4 weeks if the benefit/risk ratio supports continued administration.
The study pharmacist will be responsible for the preparation of the IV study intervention. 
The IV study intervention will be administered by site personnel.  Refer to the Pharmacy 
Manual for further details.
Study intervention may be interrupted for any reason for a time period of <7 consecutive 
days (including suspected CMV disease/infection; see Section 8.10.4).  Study intervention 
interruption for a time period of <7 consecutive days due to an AE followed by re-starting of 
study intervention upon resolution of the AE is permitted.
Interruptions from the protocol specified treatment plan for ≥7 consecutive days require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
8.1.9.1
Timing of Dose Administration
Study intervention should be administered/taken at the same time each day.  Tablets are to be 
swallowed whole (ie, no crushing or chewing the tablet is allowed).  Study intervention may 
be administered with or without food (please refer to Section 5.3.1 for food restrictions 
applicable to those participants who are taking concomitant CsA). 
If a participant misses a dose, the missed dose should be given as soon as possible during the 
same day.  If more than 18 hours have gone by after the regular dosing time, then the missed 
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dose should be skipped, and the normal dosing schedule should be resumed.  The next dose 
should not be doubled in order to “make up” what has been missed.  
If a participant vomits within 2 hours of an oral administration, the full oral dose can be 
repeated one time within 6 hours after vomiting.  If a participant vomits and it has been 
longer than 2 hours from the time of oral administration, the dose should not be repeated.  
Take the next dose at the usual time.
8.1.9.2
Study Medication Diary and Recording the Study Intervention
For hospitalized participants receiving either letermovir oral tablets or IV formulation, study 
intervention will be recorded in the participant’s chart; this will serve as the source 
document. For participants receiving oral tablets outside of the hospital setting (ie, receiving 
oral letermovir at home), study intervention will be recorded in a paper study medication 
diary (SMD).  The investigator/study coordinator will review and provide instructions to the 
participant on the use of the SMD, which is to be completed during the treatment period of 
the study.  
At visits when used/unused study therapy are returned, site personnel must verify the 
accuracy of the dosing diary by comparing entries with amounts of returned study therapy.  If 
a discrepancy is noted, the investigator/study coordinator must discuss the discrepancy with 
the participant, and the detailed explanation must be documented in the participant’s study 
record.  The investigator/study coordinator will be responsible for transferring the 
appropriate information to the case report form.  
If oral medication is administered by clinical personnel during any hospitalization, the site 
personnel will be responsible for transferring the appropriate information from the 
participant’s medical record to the case report form.
When administering IV formulation of study medication, the volume and the duration of 
infusion will be documented.  The investigator/study coordinator will be responsible for 
transferring the appropriate information to the case report form.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit 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 and visit requirements as outlined in Section 1.3 (SoA).
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
CMV DNA PCR Testing
Protocol-specified CMV DNA levels will be drawn at prespecified clinical visits and the 
CMV Infection Visit as indicated in the Study SoA (Section 1.3) and sent to the central 
laboratory where CMV DNA PCR testing will be performed using a quantitative CMV 
DNA PCR assay at the central laboratory. In this study, CMV DNA levels may be monitored 
using local laboratory results for the clinical management of participants any time during the 
study.  It is MANDATORY, however, to collect and send a confirmatory plasma sample for 
CMV DNA PCR testing to the central laboratory immediately prior to (ie, on the day of) 
initiating PET or treatment for confirmed or suspected CMV disease (CMV infection visit).  
In the event test results from the central laboratory are not available within the time frame the 
investigator wishes to initiate anti-CMV therapy (including PET), the investigator may use a 
positive local laboratory test (CMV DNA PCR or pp65 antigen only) result in order to make 
the decision.  However, as described above, a confirmatory plasma samples for CMV DNA 
PCR testing must also be sent to the central laboratory prior to initiating PET.  The local 
laboratory result must also be reported in such instances.
In the event that the confirmatory result obtained on the day of anti-CMV treatment 
(including PET) initiation is NOT available (eg, sample is lost or mishandled by the 
investigator site prior to shipment, or is inadequate upon receipt at the central laboratory), a 
subsequent sample must be obtained and sent to the central laboratory within 7 days after 
PET initiation (preferably within 48-72 hours). Sample collection, storage, and shipment 
instructions for plasma samples will be provided in the operations/laboratory manual.
8.2.2
CMV Serology (IgG) Testing
Available CMV serology (IgG) testing data for the participant will be obtained from the 
participant’s chart. For participants whose CMV serology (IgG) testing data are not 
previously documented within 1 year before HSCT, CMV serology (IgG) testing should be 
performed locally per SOC at the site.
8.2.3
CMV Disease Assessment
CMV disease will be assessed at every visit from screening through Week 24 post-transplant.  
Diagnostic criteria for the evaluation of CMV infection are outlined in Appendix 8.  If a 
participant develops suspected or confirmed CMV disease, site should perform the CMV 
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Infection Visit instead of the scheduled visit assessments (see Section 1.3, Schedule of 
Activities).  The investigator will ensure that clinical information, radiology results, and 
specimens for the appropriate diagnostic tests (including, but not limited to, viral culture, 
histopathology, immunohistochemical analysis, in situ hybridization, CMV DNA PCR) as 
outlined in Appendix 8 will be collected.
For participants who develop suspected or confirmed CMV disease:  Clinical and 
laboratory evaluation of participants with suspected or confirmed CMV disease may be 
performed at the discretion of the site investigative team and at any time during the study 
intervention or follow-up period.  During such evaluations, if a blood sample for CMV viral 
DNA testing is collected for processing by a local laboratory by the site investigative team, 
clinical decisions and management will be made based on the results of the local CMV DNA 
PCR results and assessment of the participant’s CMV disease.  When a CMV DNA PCR is 
collected for processing by a local laboratory, it is mandatory that a separate blood sample 
also be collected for CMV DNA PCR and sent to the central laboratory for processing.
Note:  It is mandatory to send a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (ie, on the day of) initiating treatment for 
confirmed or suspected CMV disease.  In the event that the confirmatory result obtained on 
the day of anti-CMV treatment initiation is NOT available (eg, sample is lost or mishandled 
by the investigator site prior to shipment, or is inadequate upon receipt at the central 
laboratory), a subsequent sample must be obtained and sent to the central laboratory within 7 
days after PET initiation (preferably within 48-72 hours).
If the investigator decides to initiate PET or treatment for confirmed or suspected CMV 
disease while the participant is on study treatment, the participant’s study intervention will be 
discontinued (see following bullet) and a CMV Infection Visit (including collection of CMV 
DNA PCR sample; see Section 1.3 [SoA]) will be completed prior to initiating treatment for 
CMV disease.  These participants will complete all remaining treatment-period visits through 
Week 14 as well as all remaining visits through Week 24 as outlined in the SoA (Section 
1.3).  All specified procedures through Week 14 will be completed for these participants with 
the exception of study intervention administration and study medication diary review.
•
Following the CMV Infection Visit, a participant may interrupt study treatment (if the 
participant is on study treatment at the time of the CMV Infection Visit) and receive 
treatment for CMV Disease for up to 7 days before the participant is permanently 
discontinued from study treatment (but remains in the study). If within the 7-day interval, 
CMV Disease is either not confirmed by the site investigator and/or an alternative 
medical condition that is not CMV-related is identified, then the participant may stop 
treatment for CMV disease and resume previously assigned study treatment. 
If CMV disease is suspected or confirmed by the investigator during the post-treatment 
follow-up period (ie, after completion or early discontinuation of study intervention):  
Participants may be started on treatment for CMV disease at the investigator’s discretion and 
will complete all remaining follow-up visits (through Week 24).  See Section 1.3 SoA for 
procedures performed at the CMV Infection Visit.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in in a separate 
document.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
At screening, on Day 1 (allocation), a complete physical examination will be conducted by 
an investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard. Height and weight will also be measured and recorded.
After Day 1, a targeted physical examination should be performed only if a participant has 
any complaints.  Investigators should pay special attention to clinical signs related to 
previous serious illnesses. The content of the targeted physical examination will be at the 
discretion of the investigator. The timing of physical examinations is indicated in the Study 
SoA (Section 1.3).
8.3.2
Vital Signs
Vital signs will be assessed at the time points indicated in the SoA (Section 1.3) and will 
include the following assessments:  
•
Body temperature (oral preferred, see below), heart rate, respiratory rate, and blood 
pressure will be assessed.  
NOTE: Oral temperatures should be taken, but if oral is not possible, tympanic, rectal, 
temporal, or axillary temperatures may be taken. 
•
Blood pressure and heart rate measurements should be preceded by at least 10 minutes of 
rest for the participant in a quiet setting without distractions.
8.3.3
Electrocardiograms 
•
Single 12-lead electrocardiogram (ECG) will be obtained and reviewed by an investigator 
or medically qualified designee (consistent with local requirements) as outlined in the 
SoA (see Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.  Participants should be resting for at least 
10 minutes prior to having ECG readings obtained.
8.3.4
Child-Pugh Score
The Child-Pugh score will be assessed as indicated in the study SoA (Section 1.3) according 
to Appendix 9.  At the screening visit, the clinical assessment and the laboratory parameters 
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(total bilirubin, albumin, and INR) obtained at that visit will be used to calculate the Child-
Pugh score.  Thereafter, at each scheduled assessment of the Child-Pugh score, the clinical 
assessment at the scheduled study visit and the most recently collected and available local 
laboratory parameters (total bilirubin, albumin, and INR) obtained at the corresponding 
scheduled study visit, or up to one week prior to the scheduled study visit, will be used to 
calculate the Child-Pugh score.  As stated in Section 7.1, a participant must be discontinued 
from study treatment but continue to be monitored in the study if the participant develops 
both moderate hepatic insufficiency (Child-Pugh Class B) and moderate-to-severe renal 
insufficiency (defined as CrCl <50 mL/min as calculated by the Cockcroft-Gault equation; 
see Section 5.2), or develops severe hepatic insufficiency (Child-Pugh Class C).
8.3.5
Birth Control Confirmation (WOCBP Only)
WOCBP must use acceptable methods of contraception from the time of consent through 28 
days after the last dose of study intervention (see Appendix 5).  Confirmation must be 
obtained by site personnel that participants and their partner(s) are using acceptable methods 
of contraception.  This assessment must be documented in the participant's study chart at 
each specified visit.
No contraception measures are needed during letermovir treatment for male participants 
(refer to the Investigator’s Brochure).
8.3.6
Clinical Safety 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.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the 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 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 14 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.
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention allocation through 14 days after cessation of treatment, all 
AEs, SAEs, and other reportable safety events must be reported by the investigator.
After 14 days following cessation of study intervention, only SAEs will be reported through 
Week 24 post-transplant.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
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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Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 2
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
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Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) 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
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), or a pregnancy that occurs during the study in a 
nonparticipant whose sexual partner is a participant capable of producing ejaculate is 
reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable. 
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
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value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than two times the prescribed dose specified in 
Section 6.6 (Dose Modification [Escalation/Titration/Other]).
Sponsor does not recommend specific treatment for an overdose.  Overdose during the study 
will be a reportable safety event (see Section 8.4.1 and Appendix 3 for further details).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Future Biomedical Research Sample Collection
FBR samples will not be collected in this study.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Participants may be screened during a period starting from 15 days prior to transplant 
through 28 days post-transplant (laboratory test results necessary for allocation must be 
available within 5 days prior to the planned day of allocation). The informed consent must be 
obtained before any study-specific procedure is performed. It is acceptable that the date of 
obtaining informed consent is earlier than the day of performing screening procedures.  
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However, once informed consent is obtained adverse event reporting must be conducted 
according to Section 8.4.1.
Potential participants will be evaluated to determine if they fulfill the trial entry requirements 
as described in Section 5.1 and Section 5.2.  The investigator will discuss with each potential 
participant the nature of the study and its requirements/restrictions. CMV serology (IgG) 
testing should be performed locally per SOC at the site; CMV seropositivity previously 
documented within 1 year before HSCT is acceptable. Donor CMV serostatus may either be 
positive (D+) or negative (D−). All screening procedures listed under Visit 1 of the SoA 
(Section 1.3) will be performed.  Participants will be instructed that they are required to use 
methods of birth control as indicated in Appendix 5 during the protocol-defined time frame 
in Section 5.1. 
For screening purposes, values from the participant’s chart within 5 days prior to allocation 
for required chemistry, hematology, and urinalysis tests are acceptable. Documented negative 
HIV test results within 90 days prior to allocation of the participant will be acceptable.  A 
copy of report must be available.  If documentation of a previous HIV test is not available, 
the HIV test must be conducted using the local laboratory.  Hepatitis B, and hepatitis C 
screening should only be performed if not previously documented within 90 days at any time 
prior to allocation.  If hepatitis C virus antibody is positive, RNA PCR results should be 
provided (or, if not available, RNA PCR testing will be performed by the local laboratory).  
CMV procedures/assessments will also be performed at screening.  For initial screening, 
results of CMV DNA PCR assay performed at a local laboratory will be acceptable to 
establish absence of CMV viremia.  Thereafter, CMV DNA PCR testing will be performed 
once a week by the central laboratory in order to exclude those with active CMV replication 
prior to study intervention initiation.  
On the day of allocation, eligibility for enrollment into the study should be confirmed. At that 
time, participants have already received their HSCT and will be considered eligible for 
allocation once (a) they are determined to be negative for CMV viremia (NO evidence of 
CMV viremia from a central or local laboratory at any time point and confirmed by the 
central laboratory on a sample collected from the participant within 5 days prior to 
allocation), and (b) have acceptable creatinine clearance and liver function test values (i.e., 
within the range allowable in this study, as outlined in Section 5.2 [Exclusion Criteria]) from 
testing performed within 5 days prior to allocation.  (NOTE:  Evidence of CMV viremia as 
reported by the central lab will include reporting of test results as “detectable, not 
quantifiable” or “detected” with a numeric value provided.)  
Presence of CMV disease in the screening period will be assessed according to Appendix 8.
8.10.2
Treatment Period
Study intervention (letermovir) may begin as early as the day of transplant and no later than 
28 days post-transplant.  Study intervention will continue through Week 14 (~100 days) post-
transplant. For participants receiving the oral formulation of study intervention, letermovir 
tablets will be dispensed on Day 1 and every 2 weeks starting from Week 2. Visit schedules 
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must align the weekly visits with the drug dispensation every 2 weeks. Study intervention 
visits will occur weekly through Week 14 (~100 days) post-transplant.  
The Day 1 Visit (as shown in the SoA, Section 1.3) will be day the participant is allocated 
and study intervention is initiated.  Study intervention will continue through the End of Study 
Intervention Visit.  The End of Study Intervention Visit may occur at the Week 10, 11, 12, 
13, or 14 Visit depending on when study intervention is started during the 28-day post-
transplant window.  For example, if study intervention is started on the day of transplant, the 
End of Study intervention Visit will be the Week 14 Visit (which corresponds to Week 14 
post-transplant).  If study intervention is started 28 days post-transplant, the End of Study 
intervention Visit will be the Week 10 Visit (which corresponds to Week 14 post-transplant).
All procedures listed under the weekly study intervention visits in the SoA (Section 1.3) will 
be performed at the corresponding visit.  After allocation, the physical examination does not 
need to be performed at every visit; a targeted physical exam should be performed only if a 
participant has any complaints. After allocation, vital signs should only be performed if 
targeted physical examination is performed.
8.10.2.1
Day 1 Visit 
Day 1 procedures/assessments listed on the SoA must be performed prior to initiation of 
study intervention.
Laboratory safety evaluations (hematology, chemistry, and urinalysis) specified in Section 
8.3.6 will be performed prior to study intervention initiation. 
For female participants, a urine pregnancy test will be performed at the site prior to study 
intervention initiation.  If the urine pregnancy test result is negative, the participant will be 
eligible for allocation and the remainder of the Day 1 testing/procedures will be performed.  
If the urine pregnancy result is positive, the participant must not be allocated.
8.10.2.2
Study Intervention Administration
Following completion of the Day 1 procedures/assessments and confirmation of eligibility 
(including availability of results from samples for CMV DNA PCR, creatinine clearance, and 
liver function tests), the participant will be allocated. The site pharmacist or study 
coordinator will contact the IVRS for assignment of the study intervention to be 
administered.  Sites should not call the IVRS for study intervention administration until the 
participant has met all criteria for the study and is ready to receive the first dose of study 
intervention on Day 1. 
The first dose of study intervention will be administered at the Day 1 Visit. The oral or IV 
formulation of letermovir will be dispensed via the IVRS.  Participants will be initiated with 
the oral (tablet) formulation of study intervention provided they are able to swallow and do 
not have a condition (e.g., vomiting, diarrhea, or a malabsorptive condition) that may 
interfere with the absorption of the tablets. For participants who cannot swallow and/or have 
a condition that may interfere with the absorption of the oral formulation, study intervention 
can be initiated with or switched to the IV formulation.  The IV formulation should be 
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switched to oral study intervention (i.e., at the next planned dose) as soon as such participants 
are able to swallow and/or the condition necessitating the use of the IV formulation resolves.  
Use of the IV formulation should generally be limited to 4 weeks or less in duration. 
However, it will be left to the investigator’s discretion to continue IV administration beyond 
4 weeks, if the benefit/risk ratio supports continued administration.
The same dose of letermovir will be administered for both formulations. Participants will 
receive either 240 mg letermovir QD, if receiving concomitant CsA, or 480 mg letermovir 
QD, if not on CsA. If CsA is initiated after starting study intervention, the next dose of 
letermovir (administered up to 24 hours later) should be decreased to 240 mg QD.  If CsA is 
discontinued permanently or for the long-term in a participant, the next dose of letermovir 
(administered up to 24 hours later) should be increased from 240 mg to 480 mg QD. If CsA 
is temporarily held due to high levels detected by therapeutic blood monitoring, the dose of 
letermovir need not be adjusted. 
The 240 mg oral (tablet) formulation of letermovir will be available for study intervention 
(two 240 mg letermovir tablets should be taken for the 480 mg dose and one 240 mg tablet 
for the 240 mg dose). After Day 1, study intervention will continue through Week 14 (~100 
days) post-transplant. During this period, samples for CMV DNA PCR should be sent at 
every visit to the central laboratory as per the SoA (Section 1.3). The CMV DNA PCR test 
may be conducted within 3 days prior to a scheduled study visit and no later than the day of 
the scheduled study visit.  (This CMV DNA PCR testing window is not applicable to a CMV 
Infection Visit.  See Section 8.2.1.)
Participants will be trained in the use of the Study Medication Diary. Once the participant is 
discharged from the hospital, he/she will be instructed to enter the number of tablets of study 
intervention taken during the study intervention period.
8.10.3
Follow-up Period/Visits
After the last day of study intervention, participants will continue to be followed though 
Week 24 (~6 months) post-transplant.  Visits will occur every 2 weeks from Week 15 post-
transplant to Week 24 post-transplant, and all procedures listed in the SoA (Section 1.3) 
corresponding to the visits will be performed.  
During the follow-up period, samples for CMV DNA PCR should be sent at every visit to 
the central laboratory as per the SoA (Section 1.3). The CMV DNA PCR test may be 
conducted ±4 days of the scheduled study visit.  (This CMV DNA PCR testing window is not 
applicable to a CMV Infection Visit.  See Section 8.2.1.)
Adverse event monitoring should include the collection of all adverse events while on study 
intervention and for 14 days following completion of study intervention (i.e., through 
Follow-up Week 2 Visit) in all participants, including those who have discontinued study 
intervention but are continuing in the study.  Thereafter, only SAEs will be collected through 
Week 24 post-transplant in all participants, including those who have discontinued study 
intervention but are continuing in the study.
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8.10.4
CMV Infection or Early Discontinuation Visit
The CMV Infection Visit will be performed for all participants who will be discontinued 
from study intervention due to clinically significant CMV infection requiring either treatment 
of disease or initiation of PET.   It is very important to ensure that all procedures, as outlined 
in the SoA (Section 1.3), are performed at the CMV Infection Visit immediately prior to the 
initiation of treatment of CMV diseases or initiation of PET (i.e., on the day anti-CMV 
intervention is initiated).  Most importantly, a confirmatory plasma sample for CMV PCR 
testing at the central laboratory should be collected at this visit. 
After this visit, such participants will continue to be followed in the study and complete all 
remaining visits (including all subsequent treatment period visits) through Week 24 post-
transplant as outlined in the SoA (Section 1.3).  All specified procedures during the study 
intervention period will be completed for these participants with the exception of study 
intervention administration and study medication diary review.
The CMV Infection Visit will also be performed for all participants who require either 
treatment for disease or initiation of PET after study intervention completion, during the 
follow-up period (after Week 14 through Week 24 post-transplant).  It is very important to 
ensure that all procedures, as outlined in the SoA (Section 1.3), are performed at the CMV 
Infection Visit immediately prior to the initiation of treatment of CMV diseases or initiation 
of PET (i.e., on the day anti-CMV therapy is initiated).  Most importantly, a plasma sample 
for CMV PCR testing at the central laboratory should be collected at this visit. 
After this visit, such participants will continue to be followed in the study and complete all 
remaining visits through Week 24 post-transplant as outlined in the SoA (Section 1.3).  
Note:  It is mandatory to send a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (i.e., on the day of) initiating treatment for CMV 
disease or PET in ALL instances. In the event that the confirmatory result obtained on the 
day of PET initiation is NOT available (e.g., sample is lost or mishandled by the investigator 
site prior to shipment, or is inadequate upon receipt at the central laboratory), a subsequent 
sample must be obtained and sent to the central laboratory within 7 days after PET initiation 
(preferably within 48-72 hours). The participant will be considered to have met the primary 
efficacy endpoint if this confirmatory laboratory result is positive.  
In the event confirmatory test results from the central laboratory are not available within the 
timeframe the investigator wishes to initiate anti-CMV therapy, the investigator may use a 
positive local laboratory test result (from CMV DNA PCR or pp65 antigen only) to make the 
decision.  However, as described above, plasma samples for CMV DNA PCR testing must 
also be sent to the central laboratory.  The local laboratory result must also be reported in 
such instances.
Note on reinitiation of study intervention: There may be instances where confirmatory 
central lab test results for CMV DNA PCR obtained on the day of PET initiation may be 
negative (CMV DNA undetectable) and the investigator may wish to discontinue PET.  The 
decision to stop PET in the event of a negative (CMV not detectable) confirmatory central 
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laboratory result collected on the day of PET initiation resides with the investigator caring for 
the participant. Therefore, in the event the confirmatory CMV DNA sample at PET initiation 
is negative for CMV viremia, the Sponsor will allow for protocol-defined study intervention 
(i.e., letermovir) to be restarted at the investigator’s discretion, once PET is discontinued.  In 
such instances, study intervention should be restarted within 7 days from the date on which 
study intervention was stopped.  It is important to note that the status of the participant’s 
study intervention in IVRS should NOT be changed until the CMV DNA PCR result is 
confirmed and the investigator is certain that study intervention will be permanently 
discontinued.
The Early Discontinuation Visit will be performed for all participants who are prematurely 
discontinued up to Week 24 post-transplant from the study, not study intervention. It is very 
important to ensure that all procedures, as outlined in the SoA (Section 1.3), are performed in 
such participants at this visit prior to discontinuing the participant from the trial.  Most 
importantly, a plasma sample for CMV PCR testing at the central laboratory should be 
collected at this visit.
8.10.5
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
8.10.5.1
Discontinuation for Reasons Other Than CMV Infection 
Study Medication Discontinuation
Participants who discontinue study medication prior to the last scheduled treatment visit for 
reasons other than clinically significant CMV infection will continue to be followed in the 
study and complete all remaining study visits regardless of when cessation of study 
medication occurs.  All specified procedures will be completed for these participants through 
Week 24 post-transplant during the treatment period (with the exception of study medication 
administration and Study Medication Diary review) as outlined in the SoA (Section 1.3).
Early Study Discontinuation
The Early Discontinuation Visit will also be performed for all participants who prematurely 
discontinue the study (ie, withdraw consent) prior to the Week 24 post-transplant visit.  It is 
very important to ensure that all procedures, as outlined in the Study SoA (Sections 1.3), are 
performed for such participants at this visit prior to discontinuing from the study.  A plasma 
sample for CMV DNA PCR testing should be collected at this visit.
8.10.6
Survival Status
Updated survival status may be requested at any time, both during study conduct or after 
study completion, or after a participant discontinues from the study.  All participants or their 
contacts may be contacted for their survival status.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in an sSAP and 
referenced in the CSR for the study. Post hoc exploratory analyses will be clearly identified 
in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 3, open-label, single-arm clinical study to evaluate the efficacy 
and safety of MK-8228 (letermovir) for the prevention of clinically 
significant cytomegalovirus (CMV) infection in Chinese adult, CMV-
seropositive allogeneic hematopoietic stem cell transplant (HSCT) 
recipient. 
Treatment Assignment
All participants will be assigned to a single intervention group.
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
Primary Endpoint
Clinically significant CMV infection through Week 24 (~6 months) post-
transplant
Secondary Endpoints
Efficacy: 

Clinically significant CMV infection through Week 14 
(~100 days) post-transplant

CMV disease through Week 14 (~100 days) post-transplant and 
Week 24 (~6 months) post-transplant

Initiation of PET for documented CMV viremia through Week 14 
(~100 days) post-transplant and Week 24 (~6 months) post-
transplant

All-cause mortality through Week 14 (~100 days) post-transplant 
and Week 24 (~6 months) post-transplant
Safety: Number of participants experiencing

Adverse Events (AEs)

AEs resulting in study medication discontinuation
Statistical Methods for Key 
Efficacy Analyses
The efficacy analysis will be based on the FAS population. The proportion 
of participants with clinically significant CMV infection through Week 14 
(~100 days) post-transplant and through Week 24 (~6 months) post-
transplant will be provided. The corresponding 95% confidence interval via 
the Clopper-Pearson method will also be provided. The primary approach 
for handling missing data will be the Non-Completer =Failure (NC=F) 
approach.
Statistical Methods for Key 
Safety Analyses
The safety analysis will be based on the APaT population. Safety and 
tolerability will be assessed by clinical review of all relevant parameters 
including AEs, laboratory tests, vital signs and ECG parameters. 
Descriptive statistics will be provided for these safety parameters.
Interim Analyses
No interim analysis is planned in this study.
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Multiplicity
No multiplicity adjustment is planned in this study.
Sample Size and Power
This is an estimation study with no hypotheses to be tested. The planned 
sample size is approximately 120 participants. For the proportion of 
participants with clinically significant CMV infection through Week 24 (~6 
months) post-transplant, the study will allow estimation of this proportion 
among participants receiving letermovir with a 95% confidence interval 
with a half-width of ~10 percentage points, assuming approximately 16% 
of participants will be excluded from FAS due to detectable CMV DNA on 
Day 1 (based on the global pivotal study P001), and the underlying 
clinically significant CMV infection rate is 37.5% in the letermovir group.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a single-arm, open-label study, i.e., participants, 
investigators, and Sponsor personnel will be aware of participants treatment assignments 
after each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule for study 
intervention assignment. Allocation number will be assigned via an IRT.
9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are stated in 
Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
An initial description of efficacy endpoints is provided in Section 4.2.1.1.
The primary efficacy endpoint will be the proportion of participants with clinically 
significant CMV infection through Week 24 (~6 months) post-transplant, defined as the 
occurrence of either one of the following outcomes:
•
Onset of CMV end-organ disease
OR
•
Initiation of anti-CMV PET based on documented CMV viremia (as measured by the 
central laboratory) and the clinical condition of the participant.
CMV end-organ disease will be determined using the definitions in Appendix 8 and 
confirmed by an independent CAC. The adjudication of cases by the CAC (i.e., the final 
CAC assessment) will take precedence over the investigator’s assessment. Only the CAC-
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confirmed cases of CMV end-organ disease will be included in the CMV end-organ disease 
category. However, investigator-assessed CMV end-organ disease cases which were not 
confirmed by the CAC but in whom anti-CMV therapy was initiated (in the setting of 
documented CMV viremia at a central laboratory) will be included in the initiation of PET 
category and, therefore, qualify as having clinically significant CMV infection. 
Concordance/discordance between CAC and investigator assessment will be summarized.
Documented viremia is defined as any detectable CMV viral DNA on a confirmatory sample 
obtained immediately prior to (ie, on the day of) the initiation of treatment for CMV disease 
or PET, as measured by the Roche cobas® 6800 System in the central laboratory. If the 
confirmatory result is not available, a subsequent central laboratory result collected from a 
sample obtained within 7 days will be used. Initiation of anti-CMV therapy without 
documented CMV viremia (using the central laboratory) will not be considered as a case for 
clinically significant CMV infection. Similarly, detectable CMV viral DNA alone without 
initiation of anti-CMV therapy will not be considered as a case for clinically significant 
CMV infection.
The secondary efficacy endpoints are:
1. The proportion of participants with clinically significant CMV infection through Week 
14 (~100 days) post-transplant.
2. Proportion of participants with CMV disease through Week 14 post-transplant and Week 
24 post-transplant.
3. Proportion of participants with initiation of PET for documented CMV viremia through 
Week 14 post-transplant and Week 24 post-transplant. 
4. Proportion of participants with all-cause mortality through Week 14 post-transplant and 
Week 24 post-transplant.
9.4.2
Safety Endpoints
An initial description of safety endpoints is provided in Section 4.2.1.2.
All AEs will be collected through 14 days after last dose of study medication. Thereafter, 
only serious adverse events (SAEs) will be collected through Week 24 post-transplant.
Safety endpoints will be analyzed using a 3-tiered approach (see Section 9.6.2).
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all allocated participants who:
•
receive at least one dose of study treatment, and
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•
have no detectable CMV viral DNA (measured by the central laboratory) on Day 1 (when 
study intervention is initiated).
A supportive analysis using the PP Set will be performed for the primary and secondary 
efficacy endpoints. The PP population is a subset of the FAS population, and it excludes 
participants due to important deviations from the protocol that may substantially affect the 
results of the primary and secondary efficacy endpoints. Potential violations that may result 
in the exclusion of a participant from the PP population include:
•
failure to reasonably adhere to the dosing schedule for the study treatment
•
failure to comply with specific inclusion/exclusion criteria
•
use of a prohibited concomitant medication during the treatment period that may impact 
on the efficacy assessment
The final determination on important protocol deviations will be made prior to the final 
database lock and will be documented in a separate memo.
9.5.2
Safety Analysis Populations
Safety analysis will be conducted in the APaT population, which consists of all allocated 
participants who received at least one dose of study treatment. 
At least one laboratory, vital sign, or ECG measurement obtained subsequent to at least one 
dose of study treatment is required for inclusion in the analysis of the representative safety 
parameter. To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
For the efficacy analysis, the proportion of participants with clinically significant CMV 
infection through Week 14 (~100 days) post-transplant and through Week 24 (~6 months) 
post-transplant will be calculated. The 95% CI will be calculated based on the exact binomial 
method proposed by Clopper and Pearson (1934) [Clopper, C. J. 1934]. The same method 
will be used to analyze all binary endpoints.
The primary efficacy analysis will be performed on the FAS population. A supportive 
analysis including those participants who had detectable CMV viral DNA on Day 1 will be 
provided. The primary approach for handling missing data will be the NC=F approach (see 
below for details). Supportive analyses using PP population and different approaches for 
handling missing data will also be conducted (see Table 3).
An additional analysis for the primary endpoint will be performed to assess the proportion of 
participants with clinically significant CMV infection through Week 24 (~6 months) post-
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transplant using the nonparametric Kaplan-Meier method. The Kaplan-Meier curve will be 
plotted, and Kaplan-Meier estimate for the proportion at certain time point will be provided.
Table 3
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive Approach a
Statistical Method
Analysis 
Population
Missing Data 
Approach b
Proportion of participants 
with clinically significant 
CMV infection through 
Week 24 (~6 months) 
post-transplant
P
95% Confidence 
Interval (Clopper-
Pearson)
FAS
NC=F
S
95% Confidence 
Interval (Clopper-
Pearson)
PP
NC=F
S
95% Confidence 
Interval (Clopper-
Pearson)
FAS
DAO
Proportion of participants 
with clinically significant 
CMV infection through 
Week 14 (~100 days) 
post-transplant
P
95% Confidence 
Interval (Clopper-
Pearson)
FAS
NC=F
S
95% Confidence 
Interval (Clopper-
Pearson)
PP
NC=F
S
95% Confidence 
Interval (Clopper-
Pearson)
FAS
DAO
a.
P=Primary approach; S=Supportive approach.
b.
NC=F: Non-Completer=Failure. Non-completers refer to participants who prematurely discontinued from the study. 
DAO=Data-As-Observed.
Summary statistics and 95% confidence intervals will be provided for the following 
secondary endpoints:
•
Proportion of participants with CMV disease through Week 14 post-transplant and Week 
24 post-transplant.
•
Proportion of participants with initiation of PET for documented CMV viremia through 
Week 14 post-transplant and Week 24 post-transplant
•
Proportion of participants with all-cause mortality through Week 14 post-transplant and 
Week 24 post-transplant.
An additional analysis for above secondary endpoints will be performed for the proportion 
using the nonparametric Kaplan-Meier method. The Kaplan-Meier curve will be plotted, and 
Kaplan-Meier estimate for the proportion at certain time point will be provided.
Missing Data Handling
The primary approach for handling missing data will be the Non-Completer = Failure 
(NC=F) approach to be consistent with the pivotal study (P001). Non-completers refer to 
participants who prematurely discontinued from the study and had a missing efficacy 
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outcome at the time point of interest (e.g., Week 24 post-transplant). These participants will 
be considered as failure. A participant who discontinued study medication but remained in 
the study follow-up will be not considered as a non-completer.
A secondary approach for handling missing data is the DAO. With this approach, any 
participant with missing value for a particular endpoint will be excluded from the analysis.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The proportion of participants with AEs in the broad categories of any AE, a drug-related 
AE, a serious AE, an AE which is both drug-related and serious, and who discontinued study 
medication due to an AE will be provided along with the corresponding 95% CIs. In 
addition, deaths will be summarized in the same manner. The 95% CIs for the safety 
parameters will be calculated using the Clopper-Pearson method [Clopper, C. J. 1934]. 
The primary safety analysis will summarize the safety data for participants through 14 days 
following cessation of the treatment period. Safety analyses will be performed on the APaT 
population. Below Table 4 provides the analysis strategy for safety parameters.
Table 4
Analysis Strategy for Safety Parameters
Safety Endpoint
95% CI
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Deaths
X
X
Specific AEs, SOCs or PDLCs (incidence ≥3 participants)
X
X
Specific AEs, SOCs or PDLCs (incidence <3 participants)
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
95% CIs will be calculated using the Clopper-Pearson method.
Abbreviations: AE = Adverse event; ECG = electrocardiogram; SOC = System Organ Class; PDLC = Pre-Defined Limit of 
Change; X = results will be provided.
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided in table format.
Missing safety laboratory, ECGs, or vital signs will be handled using the Data-as-Observed 
approach, that is, any missing value will be excluded from the analysis. The only exception is 
when a Baseline/Day 1 result is missing; this is be replaced with the latest pre-treatment 
result, if available.
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9.6.3
Summaries of Baseline Characteristics and Demographics
Baseline characteristics for all allocated and treated participants will be summarized using 
descriptive statistics. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and allocated, and the 
primary reasons for screen failure and discontinuation will be provided. Demographic 
variables (e.g., age, gender, and high and low risk), indication for HSCT, prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical 
tables.
9.7
Interim Analyses
No interim analysis is planned for this study.
9.8
Multiplicity
There will be no multiplicity adjustments in the analysis of this study.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analysis
This is an estimation study with no hypotheses to be tested. This study will allocate 
approximately 120 participants to receive letermovir and will allow estimation of the 
proportion of participants with clinically significant CMV infection through Week 24 (~6 
months) post-transplant among participants receiving letermovir with a 95% confidence 
interval with a half-width of ~10 percentage points. This is based on the follow assumptions: 
1) an approximately 16% of participants will be excluded from FAS due to detectable CMV 
DNA on Day 1 (based on the global pivotal study P001), then the evaluable number of 
participants in the FAS population will consist of 100 participants in total; 2) the underlying 
clinically significant CMV infection rate is 37.5% in the letermovir group. The primary 
efficacy objective will be assessed based on the proportion of participants with clinically 
significant CMV infection through Week 24 (~6 months) post-transplant. The expected rate 
of participants with clinically significant CMV infection through Week 24 (~6 months) post-
transplant is 17.5% based on P001 and assuming letermovir is expected to be similarly active 
in Chinese participants as in P001. Since the primary approach for handling missing data will 
be NC=F approach, 20% was added to the expected incidence of clinically significant CMV 
infection through Week 24 (~6 months) post-transplant based on P001. The calculation is 
based on exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 
1934] with 100 participants in letermovir expected to be included in the analysis and is 
carried out using RStudio V1.1.453. Table 5 summarizes estimates of the half-width of the 
confidence interval for letermovir group under various assumptions. The upper bound of the 
95% confidence interval is less than 60.6% which is the rate of clinically significant CMV 
infection through Week 24 post-transplant in the placebo group in P001.
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Table 5
Two-Sided 95% Confidence Intervals for the Proportion of Participants with 
Clinically Significant CMV Infection through Week 24 (~6 Months) Post-Transplant 
(FAS Population)
Number of Failures a (%)
Two-Sided 95% Confidence Interval b
N=100
32 (32.0)
(23.0, 42.1)
36 (36.0)
(26.6, 46.2)
40 (40.0)
(30.3, 50.3)
44 (44.0)
(34.1, 54.3)
48 (48.0)
(37.9, 58.2)
a Based on Non-Completer = Failure approach.
b Based on the two-sided exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
9.9.2
Sample Size and Power for Safety Analysis
This study will allocate 120 participants to receive letermovir. As this will be an estimation 
study, the sample size used in this study is not based on statistical considerations.
The probability of observing at least one of a particular AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population. If the underlying incidence of a particular AE is 1% (1 of every 100 
participants receiving the drug), there is a 70% chance of observing at least one of that 
particular AE among 120 participants. If no AE of that particular type is observed among the 
120 participants, this study will provide 95% confidence that the underlying percentage of 
participants with that particular AE is <3.0% (one in every 33 participants). 
Table 6 gives the estimate of and the upper bound of the two-sided 95% Clopper-Pearson 
exact confidence interval for the underlying percentage of participants with an AE given 
various hypothetical observed number of participants with the AE. These calculations are 
based on the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 
1934].
Table 6
Estimate of Incidence of AEs and Upper Bound of 95% CI Based on 
Hypothetical Numbers of Participants with AEs
Sample Size
Hypothetical Number of Participants 
with an AE (Estimate of Incidence, %)
Upper Bound of 95% CI a for the 
Underlying Percentage of Participants with 
an AE (%)
N = 120
0 (0.0)
3.0
1 (0.8)
4.6
4 (3.3)
8.3
10 (8.3)
14.8
a. Based on the two-sided exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
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9.10
Subgroup Analyses
To assess the consistency of the response across various subgroups, the proportion of 
participants with clinically significant CMV infection through Week 24 (~6 months) post-
transplant and associated 95% CIs will be calculated within each category of the following 
classification variables:
•
Gender (Male, Female)
•
Age (≤65, >65)
•
High and low risk
•
Haploidentical donor (Yes, No)
•
CsA use (Yes, No)
The consistency of the response will be assessed descriptively via summary statistics by 
category for the classification variables listed above. Other clinically relevant variables may 
be identified for which additional subgroup analyses may be performed.
9.11
Compliance (Medication Adherence)
Drug accountability data for letermovir will be collected during the study. A day within the 
study will be considered an “On-Therapy” day if the participant takes at least one dose. For a 
participant who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from treatment allocation to the last scheduled day for 
treatment administration for that participant. For a participant who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from treatment allocation to the date of the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance for the APaT population.
In addition, percent of participants on CsA and duration of CsA use will be reported.
9.12
Extent of Exposure
The Extent of Exposure to study intervention will be evaluated by summary statistics (N, 
mean, and range) for the “Number of Days on Therapy”.
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, 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 (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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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
Committees Structure
10.1.4.1
Clinical Adjudication Committee (CAC)
A CAC will evaluate the following events for the purposes of confirming them according to 
the criteria in Section 9, as well as evaluating the presence of confounding factors.
1. CMV disease, as defined in Appendix 8: This role is important to standardize the
evaluation (ie, adjudication) of all suspected cases of CMV disease occurring during the 
trial.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
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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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 7 will be performed by the local lab except that CMV DNA 
PCR testing will be performed by the central lab.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Nonfasting Glucose 
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis
1. Specific gravity
2. Glucose, protein, blood
3. Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
1. Coagulation:  INRa
2. Serum β human chorionic gonadotropin (β-hCG) pregnancy test (for WOCBP)
3. Urine β-hCG pregnancy test (for WOCBP)b
4. Serology:  HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
(HCV) antibodyc
5. HCV RNA PCR:  to be done only in participants who test positive for HCV antibody 
6. CMV Serology (IgG) Testing
7. CMV DNA PCR
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Laboratory 
Assessments
Parameters
NOTES:
a.
For screening, values from the participant’s chart for required chemistry, hematology, coagulation, and urinalysis 
tests are acceptable. The following tests are to be performed within 5 days prior to allocation and results must be 
available prior to allocation: coagulation (INR), serum AST, ALT, and total bilirubin; creatinine clearance. If not 
available, this testing may be performed locally per SOC.
b.
Performed locally; serum pregnancy test must be performed to confirm a positive urine test result.
c.
Documented negative HIV results within 90 days prior to allocation is acceptable. HBV/HCV to be done if not 
documented within the previous 90 days. If hepatitis C virus antibody is positive, RNA PCR results should be 
provided.
The investigator (or medically qualified designee) must document their review of each 
laboratory report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
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.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
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diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
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.
10.3.5
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.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
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.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (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 STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION 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 study intervention or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE
and document this in the medical notes.
•
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 their 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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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not Applicable.
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10.5
Appendix 5: Contraceptive Guidance
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 intervention, 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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 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 non-hormonal 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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10.5.2
Contraceptive Requirements
Female participants of childbearing potential are eligible to participate if they agree to start 
contraception when initiating sexual activity and they agree to use 1 of the contraception 
methods described in Table 8 consistently and correctly during the protocol-defined time 
frame in Section 5.1.
Table 8
Contraceptive Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen- only contraceptive implantc,d

IUSc,e

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
o
Oral
o
Intravaginal
o
Transdermal
o
Injectable

Progestogen-only hormonal contraceptionc,d
o
Oral
o
Injectable
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods).
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c Male condoms must be used in addition to female participant hormonal contraception.
d If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to those which inhibit 
ovulation. 
e IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
LAM.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.5.3
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of study medication, additional pregnancy testing will be performed at 
monthly intervals during the treatment period, for participants who complete the treatment 
period, at the CMV disease/early discontinuation visit, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not Applicable.
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10.7
Appendix 7: Country-specific Requirements
Not Applicable.
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10.8
Appendix 8: Definition of CMV Disease in Hematopoietic Stem Cell Transplant 
(HSCT) Recipients
CMV 
Disease 
Type
Probable
Proven
Notes
Pneumonia
Signs and/or symptoms 
of pneumonia
AND
Detection of CMV by 
viral isolation, rapid 
culture of BAL fluid, or 
the quantitation of CMV 
DNA in BAL fluid
Signs and/or symptoms of 
pulmonary disease
AND
Detection of CMV in lung 
tissue by virus isolation, 
rapid culture, 
histopathology, 
immunohistochemistry, or 
DNA hybridization 
techniques

PCR may be too 
sensitive, so detection of 
CMV by PCR alone is 
insufficient for the 
diagnosis of CMV 
pneumonia.

Superinfection or 
coinfection with other 
pathogens may occur 
and should be noted 
when present.
GI Disease
Symptoms of upper 
and/or lower GI disease
AND
Evidence of CMV in 
tissue but without the 
requirement for 
macroscopic mucosal 
lesions
Symptoms of upper and/or 
lower GI disease
AND
Macroscopic mucosal 
lesions
AND
Detection of CMV in GI 
tissue by histopathology, 
virus isolation, rapid 
culture, 
immunohistochemistry, or 
DNA hybridization

Detection of CMV by 
PCR alone is insufficient 
for the diagnosis of 
CMV GI disease.
Hepatitis
N/A
Abnormal liver function 
tests
AND
CMV documented in tissue 
by histopathology, 
immunohistochemistry, 
virus isolation, rapid 
culture, or DNA 
hybridization techniques
AND
Absence of other 
documented cause of 
hepatitis

Detection of CMV by 
PCR alone is insufficient 
as it may represent 
transient DNAemia. 
Hence, PCR is 
insufficient to diagnose 
CMV hepatitis.

Documentation of CMV 
in liver biopsy specimen 
(ie, by culture, 
histopathology, 
immunohistochemical 
analysis or in situ 
hybridization) is needed.

Coinfection with other 
pathogens like HCV may 
be present without 
excluding the diagnosis 
of CMV hepatitis.
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CMV 
Disease 
Type
Probable
Proven
Notes
Encephalitis/ 
ventriculitis
CNS symptoms
AND
Abnormal imaging 
results or evidence of
encephalitis on 
electroencephalography
AND
Detection of CMV in 
CSF without visible 
contamination of blood
CNS symptoms
AND
Detection of CMV in CNS 
tissue by virus isolation, 
rapid culture, 
immunohistochemistry, in 
situ hybridization, or 
(preferably) quantitative 
PCR
N/A
Retinitis
N/A
Lesions typical of CMV 
retinitis confirmed by an 
ophthalmologist.
N/A
Nephritis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or 
in situ hybridization in a 
kidney allograft biopsy 
specimen obtained from a 
patient with renal 
dysfunction
AND
Identification of histologic 
features of CMV infection

Detection of CMV in 
urine by PCR or culture 
is insufficient for the 
diagnosis of CMV 
nephritis.
Cystitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or 
in situ hybridization in a 
bladder biopsy specimen 
obtained from a patient 
with cystitis
AND
Identification of 
conventional histologic 
features of CMV infection

Detection of CMV in 
urine by PCR or culture 
is insufficient for the 
diagnosis of CMV 
cystitis.
Myocarditis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or 
in situ hybridization in a 
heart biopsy specimen 
obtained from a patient 
with myocarditis
AND
Identification of 
conventional histologic 
features of CMV infection
N/A
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CMV 
Disease 
Type
Probable
Proven
Notes
Pancreatitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or 
in situ hybridization in a 
pancreatic biopsy specimen 
obtained from a patient 
with pancreatitis
AND
Identification of 
conventional histologic 
features of CMV infection
N/A
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BAL = bronchoalveolar lavage; 
CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; DNA = deoxyribonucleic acid; 
GI = gastrointestinal; HCV = hepatitis C virus; N/A = not applicable; PCR = polymerase chain reaction; ULN = 
upper limit of normal
[Ljungman, P., et al 2016]
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10.9
Appendix 9: Child-Pugh Classification for Severity of Liver Disease
Scoring by Anomaly
Signs or symptom 
1 point 
2 points 
3 points 
Hepatic encephalopathya
absent 
Grade 1 or Grade 2 
Grade 3 or Grade 4 
Ascites 
absent 
mild
moderate 
Bilirubin
<2 mg/dL
2 – 3 mg/dL
>3 mg/dL 
Albumin (g/dL) 
>3.5 g/dL
2.8 – 3.5 g/dL
<2.8 g/dL
INRb
<1.7 
1.7 – 2.3 
>2.3 
a
Hepatic encephalopathy grading: 
Grade 1:  Altered mood/confusion
Grade 2:  Inappropriate behavior, impending stupor, somnolence
Grade 3:  Markedly confused, stuporous but arousable
Grade 4:  Comatose/unresponsive
b
For participants with no known medical history of hepatic impairment or signs or symptoms attributable to hepatic 
impairment and on anticoagulation therapy within 10 days (inclusive) preceding the INR measurement, the 
corresponding INR value should be scored as 1 point for calculating the Child Pugh score for inclusion/exclusion 
and study discontinuation criteria.
INR = international normalized ratio
Child-Pugh Score Interpretation
5 – 6 points
Child-Pugh stage A (mild hepatic insufficiency)
7 – 9 points
Child-Pugh stage B (moderate hepatic insufficiencyc)
≥10 points
Child-Pugh stage C (severe hepatic insufficiency)
c
If hypoalbuminemia is the only abnormality noted, the participant will need to have a score of ≥7 to qualify for 
moderate hepatic insufficiency for this study.
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BUN
blood urea nitrogen
CAC
Clinical Adjudication Committee
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
CMV
cytomegalovirus
CrCl
creatinine clearance
CRF
Case Report Form 
CsA
cyclosporin A
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CYP
Cytochrome P450
D+
CMV-seropositive donor
DAO
Data-As-Observed
DEHP
diethylhexyl phthalate
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
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Abbreviation
Expanded Term
EMA
European Medicines Agency
EU
European Union
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FSH
follicle stimulating hormone 
FSR
First site ready
G-CSF
Granulocyte colony-stimulating factor
GCP
Good Clinical Practice 
GCV
ganciclovir
GI
gastrointestinal
GVHD
graft-versus-host disease
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV-Ab
hepatitis C virus antibody
HIV
human immunodeficiency virus
HIV-Ab
human immunodeficiency virus antibody
HLA
human leukocyte antigen
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HRT
hormone replacement therapy
HSCT
hematopoietic stem cell transplant
HSV
Herpes simplex virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
Institutional Review Board
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Abbreviation
Expanded Term
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
LLoQ
lower limit of quantification
MCV
mean corpuscular volume
MCH
Mean corpuscular hemoglobin
MedDRA
Medical Dictionary for Regulatory Activities
NC=F
Non-Completer=Failure
NIMP
Non-Investigational Medicinal Product
NTR
narrow therapeutic range
OF
observed failure
PCR
polymerase chain reaction
PES
polyethersulfone
PET
pre-emptive therapy
PK
pharmacokinetic
PO
orally
QD
once daily
RBC
red blood cell
RNA
ribonucleic acid
R+
CMV-seropositive recipient
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SMD
Study medication diary
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
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Abbreviation
Expanded Term
US
United States
VGCV
valganciclovir
VZV
Varicella zoster virus
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
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