Clinical trial NCT04129398
Conditions: Cytomegalovirus Infection Cytomegalovirus Disease
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-12-27; Completion date: 2022-10-06
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study aims to evaluate the safety, efficacy and pharmacokinetics (PK) of Letermovir (LET) administered as prevention of cytomegalovirus (CMV) infection and disease in adult Japanese kidney transplant recipients.

Detailed description:

Arms: arm 1: Letermovir oral or intravenous (IV) formulation will be administered once daily for up to 28 weeks, beginning up to 7 days post-transplant. The dose will be 240 mg once daily for participants receiving concomitant cyclosporin A (CsA) and 480 mg once daily for participants not receiving CsA. IV infusion will be administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.
Interventions: intervention 1: Letermovir tablet intervention 2: Letermovir IV
Intervention descriptions: intervention 1: A single 240 mg tablet or two 240 mg tablets letermovir administered orally, once daily for 28 weeks intervention 2: IV solution of 240 mg (one vial) or 480 mg (2 vials) letermovir in 250 mL infused over 60 minutes, once daily for 28 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT04129398
Document Date:            01-Feb-2022
A Phase 3, Open-Label, Single-Arm Clinical Study 
to Evaluate the Safety, Efficacy and 
Pharmacokinetics of MK-8228 (Letermovir) for the 
Prevention of Human Cytomegalovirus (CMV) 
Infection and Disease in Adult Japanese Kidney 
Transplant


PRODUCT: MK-8228
1
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3, Open-Label, Single-Arm Clinical Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of MK-8228 (Letermovir) for the Prevention of Human 
Cytomegalovirus (CMV) Infection and Disease in Adult Japanese Kidney Transplant 
Recipients
Protocol Number: 042-03
Compound Number: MK-8228
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
Not Applicable
EudraCT
Not Applicable
Approval Date: 01 February 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 03
01-FEB-2022
The primary purpose of this protocol amendment is to clarify that the 
first database lock will be executed when all results of letermovir 
plasma concentrations become available.
Amendment 02
26-MAY-2020
The primary purpose of this protocol amendment is to add everolimus 
as a prohibited medication (when LET is co-administered with CsA) 
and as a medication to be administered with caution when co-
administered with LET in Sections 6.5.1 and 6.5.2, respectively.
Amendment 01
11-DEC-2019
The primary purpose of this protocol amendment is to revise the 
description of sterile in-line filters to be used during administration of 
intravenous formulation of LET to align with current Japan Prescribing 
Information for letermovir.
Original Protocol (Version 00)
24-JUN-2019
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [03]
Overall Rationale for the Amendments:
The primary purpose of this protocol amendment is to clarify that the first database lock will be executed when all results of 
letermovir plasma concentrations become available.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA)
Study therapy Administration/Dispensing
(X) added to Study therapy 
Administration/Dispensing on Week 1.
To align with the actual procedure.
2.1 Study Rationale
Underlined text deleted;
Currently, there are … and 2) CMV pre-emptive 
therapy (PET), ie, active surveillance for CMV 
infection, typically by CMV deoxyribonucleic
acid (DNA) level monitoring (which is available 
but not reimbursed in Japan) or the CMV pp65 
antigen testing (which is widely available as 
standard of care [SOC] in Japan) and initiation 
of anti-CMV treatment upon detection of CMV 
viremia.
The test has now been approved and reimbursed 
in Japan.
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Section # and Name
Description of Change 
Brief Rationale 
9.2 Responsibility for Analyses/In-house 
Blinding
Underlined text added;
This trial is being conducted as an open-label 
study, ie, subjects, investigators, and SPONSOR 
personnel will be aware of subject treatment 
assignments after each subject is enrolled and 
treatment is assigned. First database lock will be 
executed when all results of letermovir plasma 
concentrations become available for population PK 
and exposure-safety analyses to submit data to 
regulatory agencies. The results of the population 
PK and exposure-safety analyses will be reported 
in a Modeling and Simulation report. Final 
database lock will be executed at the end of the 
study for safety and efficacy analyses. Additional 
database lock(s) may be conducted if needed.
To clarify that the first database lock will be 
executed when all results of letermovir plasma 
concentrations are available. By doing so, the 
availability of the PK data for analysis would be 
accelerated by approximately 6 months. These 
data will be included in the Population PK and 
exposure-safety analyses. 
1.1 Synopsis
Estimated Duration of Study and Duration 
of Participation
1.3 Schedule of Activities (SoA)
Footnote d
4.4 Beginning and End of Study 
Definition
5.1 Inclusion Criteria (inclusion criterion 
#6)
8.1.1 Informed Consent
8.1.1.1 General Informed Consent
Updated wording of informed consent 
procedures/interactions.
written
original: “written/signed informed consent” 
revised: “documented informed consent”
legal representative
original: “participant/legal representative” 
revised: “participant or their legally 
acceptable representative”
contact
original: Revised text from “study-related 
telephone-call or visit” 
revised: “study-related contact”
To align with updated informed consent text, as 
described in the Sponsor’s core protocol template.
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Section # and Name
Description of Change 
Brief Rationale 
8.1.1.2 Consent and Collection of 
Specimens for Future Biomedical 
Research
8.1.3 Participant Identification Card
8.4.1 Time Period and Frequency for 
Collecting AE, SAE, and Other 
Reportable Safety Event Information
8.8 Future Biomedical Research Sample 
Collection
8.9 Planned Genetic Analysis Sample 
Collection
10.1.8 Data Quality Assurance
Throughout
Minor editorial and grammatical revisions.
To improve accuracy and clarity, and to ensure 
consistency of language across the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.3
Ongoing Clinical Studies.............................................................................32
2.3
Benefit/Risk Assessment......................................................................................32
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................32
4
STUDY DESIGN............................................................................................................34
4.1
Overall Design......................................................................................................34
4.2
Scientific Rationale for Study Design.................................................................36
4.2.1
Rationale for Endpoints ...............................................................................36
4.2.1.1
Safety Endpoints................................................................................36
4.2.1.2
Efficacy Endpoints.............................................................................36
4.2.1.2.1
CMV Based Assessments ........................................................38
4.2.1.2.2
New Onset Diabetes Mellitus After Transplant (NODAT) .....39
4.2.1.3
Pharmacokinetic Endpoints ...............................................................40
4.2.1.4
Planned Exploratory Biomarker Research.........................................41
4.2.1.4.1
Planned Genetic Analysis ........................................................41
4.2.1.5
Future Biomedical Research..............................................................42
4.3
Justification for Dose...........................................................................................42
4.3.1
Starting Dose for This Study........................................................................42
4.3.2
Rationale for Dose Interval and Study Design ............................................44
4.4
Beginning and End of Study Definition .............................................................44
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................45
5.1
Inclusion Criteria.................................................................................................45
5.2
Exclusion Criteria................................................................................................47
5.3
Lifestyle Considerations......................................................................................50
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5.3.1
Meals and Dietary Restrictions....................................................................50
5.4
Screen Failures.....................................................................................................50
5.5
Participant Replacement Strategy......................................................................50
6
STUDY INTERVENTION............................................................................................51
6.1
Study Intervention(s) Administered...................................................................51
6.1.1
Medical Devices...........................................................................................53
6.2
Preparation/Handling/Storage/Accountability .................................................53
6.2.1
Dose Preparation..........................................................................................53
6.2.2
Handling, Storage, and Accountability........................................................53
6.3
Measures to Minimize Bias: Randomization and Blinding..............................54
6.3.1
Intervention Assignment..............................................................................54
6.3.2
Stratification.................................................................................................54
6.3.3
Blinding........................................................................................................54
6.4
Study Intervention Compliance..........................................................................54
6.5
Concomitant Therapy..........................................................................................54
6.5.1
Prohibited Medication..................................................................................55
6.5.2
Medications/Therapies to be Administered with Caution ...........................56
6.5.3
Rescue Medications and Supportive Care ...................................................58
6.6
Dose Modification (Escalation/Titration/Other)...............................................58
6.7
Intervention After the End of the Study............................................................58
6.8
Clinical Supplies Disclosure................................................................................58
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................58
7.1
Discontinuation of Study Intervention...............................................................58
7.2
Participant Withdrawal From the Study...........................................................60
7.3
Lost to Follow-up .................................................................................................61
8
STUDY ASSESSMENTS AND PROCEDURES........................................................61
8.1
Administrative and General Procedures ...........................................................62
8.1.1
Informed Consent.........................................................................................62
8.1.1.1
General Informed Consent.................................................................62
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................63
8.1.2
Inclusion/Exclusion Criteria ........................................................................63
8.1.3
Participant Identification Card.....................................................................63
8.1.4
Medical History ...........................................................................................63
8.1.5
Prior and Concomitant Medications Review...............................................63
8.1.5.1
Prior Medications...............................................................................63
8.1.5.2
Concomitant Medications..................................................................64
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8.1.6
Kidney Transplant/Dialysis Details Review................................................64
8.1.7
Assignment of Screening Number...............................................................64
8.1.8
Assignment of Treatment/Randomization Number.....................................64
8.1.9
Study Intervention Administration ..............................................................64
8.1.9.1
Timing of Dose Administration.........................................................65
8.1.9.2
Dose Modifications when LET is Co-administered with CsA ..........66
8.1.9.3
Study Medication Diary and Recording the Study Intervention........66
8.1.10
Discontinuation and Withdrawal .................................................................66
8.1.10.1
Withdrawal From Future Biomedical Research ................................67
8.1.11
Participant Blinding/Unblinding..................................................................67
8.1.12
Domiciling ...................................................................................................67
8.1.13
Calibration of Equipment.............................................................................67
8.2
Efficacy Assessments ...........................................................................................68
8.2.1
CMV Disease/Infection Assessment............................................................68
8.2.1.1
Assessment of CMV Disease.............................................................68
8.2.1.2
Assessment of CMV Infection...........................................................68
8.2.2
CMV Viral Resistance Testing....................................................................69
8.2.3
CMV Serology (IgG) Testing......................................................................69
8.2.4
QuantiFERON-CMV Assay ........................................................................70
8.2.5
New Onset Diabetes Mellitus After Transplant (NODAT) .........................70
8.3
Safety Assessments...............................................................................................71
8.3.1
Physical Examinations.................................................................................71
8.3.2
Vital Signs....................................................................................................71
8.3.3
Electrocardiograms ......................................................................................71
8.3.4
Clinical Safety Laboratory Assessments .....................................................72
8.3.5
Child-Pugh Score.........................................................................................72
8.3.6
Confirmation of Contraception (WOCBP only)..........................................73
8.3.7
Adverse Events Monitoring.........................................................................73
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................73
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................74
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......76
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...76
8.4.4
Regulatory Reporting Requirements for SAE .............................................76
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................76
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................77
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8.4.7
Events of Clinical Interest (ECIs)................................................................77
8.5
Treatment of Overdose........................................................................................77
8.6
Pharmacokinetics.................................................................................................78
8.6.1
Blood Collection for Plasma Letermovir.....................................................78
8.7
Pharmacodynamics..............................................................................................79
8.8
Future Biomedical Research Sample Collection...............................................80
8.9
Planned Genetic Analysis Sample Collection....................................................80
8.10
Biomarkers ...........................................................................................................80
8.11
Health Outcomes Assessment .............................................................................80
8.12
Visit Requirements...............................................................................................81
8.12.1
Screening......................................................................................................81
8.12.2
Treatment Period..........................................................................................82
8.12.2.1
Day 1 Visit.........................................................................................82
8.12.2.2
Study Intervention Administration ....................................................83
8.12.3
Follow-up Period .........................................................................................83
8.12.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................83
8.12.5
CMV Infection or Early Discontinuation Visit............................................84
8.12.5.1
CMV Infection Visit ..........................................................................84
8.12.5.2
Early Discontinuation Visit................................................................85
9
STATISTICAL ANALYSIS PLAN .............................................................................86
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses/In-house Blinding .................................................87
9.3
Hypotheses/Estimation ........................................................................................87
9.4
Analysis Endpoints...............................................................................................87
9.4.1
Safety Endpoints..........................................................................................87
9.4.2
Efficacy Endpoints.......................................................................................87
9.4.3
Exploratory endpoints..................................................................................88
9.5
Analysis Populations............................................................................................89
9.5.1
Safety Analysis Populations ........................................................................89
9.5.2
Efficacy Analysis Populations.....................................................................89
9.6
Statistical Methods...............................................................................................89
9.6.1
Statistical Methods for Safety Analyses ......................................................89
9.6.2
Statistical Methods for Efficacy Analyses...................................................90
9.6.2.1
Missing Data Handling ......................................................................90
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................90
9.6.3.1
Demographic and Baseline Characteristics .......................................90
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9.6.3.2
Pharmacokinetic Analyses.................................................................90
9.7
Interim Analyses ..................................................................................................91
9.8
Multiplicity ...........................................................................................................91
9.9
Sample Size and Power Calculations .................................................................91
9.10
Subgroup Analyses...............................................................................................91
9.11
Compliance (Medication Adherence).................................................................91
9.12
Extent of Exposure...............................................................................................91
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................92
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........92
10.1.1
Code of Conduct for Clinical Trials.............................................................92
10.1.2
Financial Disclosure.....................................................................................94
10.1.3
Data Protection.............................................................................................94
10.1.3.1
Confidentiality of Data ......................................................................95
10.1.3.2
Confidentiality of Participant Records...............................................95
10.1.3.3
Confidentiality of IRB/IEC Information............................................95
10.1.4
Committees Structure...................................................................................95
10.1.4.1
Clinical Adjudication Committee (CAC) ..........................................95
10.1.5
Publication Policy........................................................................................95
10.1.6
Compliance with Study Registration and Results Posting Requirements ...96
10.1.7
Compliance with Law, Audit, and Debarment ............................................96
10.1.8
Data Quality Assurance ...............................................................................97
10.1.9
Source Documents .......................................................................................98
10.1.10
Study and Site Closure.................................................................................98
10.2
Appendix 2: Clinical Laboratory Tests..............................................................99
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................101
10.3.1
Definition of AE ........................................................................................101
10.3.2
Definition of SAE ......................................................................................102
10.3.3
Additional Events Reported.......................................................................103
10.3.4
Recording AE and SAE .............................................................................103
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................107
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................108
10.5
Appendix 5: Contraceptive Guidance..............................................................109
10.5.1
Definitions..................................................................................................109
10.5.2
Contraception Requirements......................................................................110
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10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................111
10.7
Appendix 7: Country-specific Requirements..................................................116
10.8
Appendix 8: Definition of CMV Disease..........................................................117
10.9
Appendix 9: Child-Pugh Classification for Severity of Liver Disease ..........121
10.10 Appendix 10: Blood Volume Table ..................................................................122
10.11 Appendix 11: Abbreviations .............................................................................124
11
REFERENCES.............................................................................................................127
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LIST OF TABLES
Table 1
Trough Pharmacokinetic and Intensive Pharmacokinetic Collection........41
Table 2
Laboratory Exclusion Criteria....................................................................49
Table 3
Study Therapy – Oral (Tablet) Formulation..............................................52
Table 4
Study Therapy – Intravenous Formulation ................................................52
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................75
Table 6
Approach to Handle Missing Values.........................................................90
Table 7
Protocol-required Laboratory Assessments.............................................100
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
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PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Open-Label, Single-Arm Clinical Study to Evaluate the Safety, 
Efficacy and Pharmacokinetics of MK-8228 (Letermovir) for the Prevention of Human 
Cytomegalovirus (CMV) Infection and Disease in Adult Japanese Kidney Transplant 
Recipients
Short Title: P3 Trial of MK-8228 (Letermovir) in Adult Japanese Kidney Transplant 
Recipients
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses to be tested in this study.
In adult Japanese kidney transplant recipients who are organ donor (D) or organ recipient (R) 
seropositive (D+/R−, D+/R+ or D−/R+) for CMV:
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 
letermovir based on the proportion of 
participants with adverse events.
- Adverse events (AEs)
- Study drug discontinuations due to AEs
Secondary Objectives
Secondary Endpoints
- To evaluate the efficacy of letermovir in 
prevention of CMV disease and infection, as 
measured by the proportion of participants 
with adjudicated CMV disease or 
participants who have undergone anti-CMV 
treatment based on 1) positive results on 
CMV antigenemia (local) or 2) quantifiable 
CMV DNAemia (local) through Week 28 
and Week 52 post-transplant.
- Adjudicated CMV disease OR anti-CMV 
treatment based on 1) positive results on 
CMV antigenemia (local) or 2) quantifiable 
CMV DNAemia (local)
- To evaluate the efficacy of letermovir in 
prevention of CMV disease, as measured by 
the proportion of participants with 
adjudicated CMV disease through Week 28 
and Week 52 post-transplant. 
- Adjudicated CMV disease
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- To evaluate the efficacy of letermovir in 
prevention of CMV infection, as measured 
by the proportion of participants with 
quantifiable CMV DNAemia (central) 
through Week 28 and Week 52 post-
transplant.
- Quantifiable CMV DNAemia (central)
- To evaluate the pharmacokinetics of 
letermovir in Japanese kidney transplant 
recipients.
- Pharmacokinetic endpoints (the plasma 
concentrations of LET, PK parameters, ie, 
Oral: AUCtau, Ctrough, Cmax, Tmax, 
CLss/F; IV: AUCtau, Ctrough, Ceoi, CLss)
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Prevention of CMV disease in adult kidney transplant 
recipients
Population
adult Japanese D+/R−, D+/R+ or D−/R+ kidney transplant 
recipients
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
None
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 30 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related study-related contact.
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Number of Participants:
Approximately 20 participants (with at least 10 being D+/R−) will be allocated/enrolled.
Intervention Groups and Duration:
Intervention 
Groups
Drug
Dose
Strength
Dose 
Frequency
Route of Admin.
Use
LET (for participants 
not on CsA)
480 mg
Once daily
Orala or IVb, c
Experimental
LET (for participants 
on CsA)
240 mg
Once daily
Orala or IVb, c
Experimental
Duration: Interventions will be started within 7 days post-transplant and continue 
through Week 28
LET = letermovir; CsA = cyclosporin A; IV = intravenous
a: Two 240 mg LET tablets should be taken for the 480 mg dose and one tablet for the 240 mg dose.
b: LET IV formulation dosing volume is 250 mL and duration of infusion will be 60 minutes. LET IV 
will be provided as a sterile liquid concentrate for dilution (20 mg/mL), two vials to be used for the 
480 mg dose and one vial for the 240 mg dose. 
c: The LET IV formulation should be switched to oral study therapy (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.
Total 
Number
1 (single-arm study)
Duration of 
Participation
Each participant will participate in the study for approximately 52 weeks (for 
participants who receive a kidney from a deceased donor) or 54 weeks (for 
participants who receive a kidney from a living donor) from the time the 
participant provides documented informed consent through the final contact. 
After a screening phase of approximately 8 days for participants who receive 
a kidney from a deceased donor or up to 21 days for participants who receive 
a kidney from a living donor, each participant will be started on LET within 7 
days post-transplant and receive LET through approximately Week 28. After 
the end of treatment each participant will be followed through approximately 
Week 52.
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01-FEB-2022
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
1.2
Schema
The study design is depicted in Figure 1.
SCR = Screening; LET = Letermovir; QD = once daily; CsA = cyclosporin A
Screening of potentially eligible participants may begin as early as one day before transplantation for 
participants receiving a kidney from a deceased donor and 14 days prior to transplantation for participants 
receiving a kidney from a living donor. Screening should be completed by and including the day prior to Day 1.
* For participants who cannot tolerate swallowing and/or develop a condition that may interfere with the 
absorption of the oral formulation of LET at or after Day 1, study therapy can be initiated/switched to the IV 
formulation of LET.
Figure 1
Study Design
088PBS


PRODUCT: MK-8228
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01-FEB-2022
1.3
Schedule of Activities (SoA)
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Administrative Procedures
Informed Consent
X
Informed Consent 
for Future 
Biomedical 
Research
X
Inclusion/Exclusion 
Criteria
X
X
Recheck clinical 
status before 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
Intervention 
allocation
X
088PBS


PRODUCT: MK-8228
20
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Kidney 
Transplant/
Dialysis Details 
Review
X
Study therapy 
Administration/
Dispensing
X
(X)
X
X
X
X
X
X
X
X
X
Start of study 
treatment is Day 
1 (day of 
allocation). See 
Section 8.12.2.
Study Medication 
Reconciliation and 
Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Procedures
Full physical 
examination
X
X
X
Height
X
Weight
X
X
X
Directed physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performed only 
when clinically 
indicated
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 
8.3.2.
088PBS


PRODUCT: MK-8228
21
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
12-lead ECG
X
X
X
(X*)
Read locally. 
Screening values 
collected within 
3 months prior 
to screening may 
be used.
See Section 
8.3.3.
*Performed only 
if the Visit will 
occur at W28.
Child-Pugh Score
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 
8.3.5 and 
Appendix 9.
Participant 
Confirmation of 
Birth Control
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAE Review
X
X
Including 
infusion site 
reactions.
See Section 
8.3.7 and 8.4.
088PBS


PRODUCT: MK-8228
22
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Screening values 
from the 
participant’s 
chart within 14 
days prior to 
screening for 
required 
chemistry, 
hematology, 
coagulation, and 
urinalysis tests 
are acceptable. 
Screening test 
may be 
performed 
locally or 
centrally. 
Urinary tests can 
be waived if 
unable to 
provide urine.
See Section 
8.12.1.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation: 
PT/INR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
088PBS


PRODUCT: MK-8228
23
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Pregnancy Test 
(WOCBP only)
X
Per pre-
transplant SOC 
at the site (either 
urine or serum is 
acceptable).
Urine Pregnancy 
Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
Performed 
locally.  May use 
central or local 
serum pregnancy 
test if unable to 
provide urine.
See Section 
8.12.2 and 
Appendix 2.
HIV and Hepatitis 
B and C Screen
X
Screening values 
collected prior to 
screening 
(within 90 days 
for Hepatitis B 
and C) may be 
used.
See Section 
8.12.1.
088PBS


PRODUCT: MK-8228
24
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
CMV Procedures/Assessments
CMV Disease 
Assessment
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.
See Section 
8.2.1.1.
CMV DNA PCR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 
8.2.1.2.
CMV Serology 
(IgG)
X
Performed 
locally per SOC 
at the site if not 
previously 
documented 
(within 90 days 
prior to Day 1 in 
case of D+/R−).
QuantiFERON-
CMV Assay
X
X
X
X
X
X
See Sections
4.2.1.2.1 and 
8.2.4.
088PBS


PRODUCT: MK-8228
25
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
CMV Viral 
Resistance 
Testingc
X
X
To be performed 
only for 
participants in 
whom study 
treatment is 
stopped (if on 
study treatment) 
and CMV 
treatment is 
started due to 
CMV disease or 
infection. See 
Section 8.2.2.
Health Outcomes 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 
8.11.
Pharmacokinetics/Pharmacodynamics/Biomarkers
Blood for Genetic 
Analysisd
X
088PBS


PRODUCT: MK-8228
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PROTOCOL/AMENDMENT NO.: 042-03
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01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Trough PK and 
Week 1 Intensive 
PK
X
X*
X
X
X
X
X
X
X
X
X
X
X
Trough PK 
samples: 
Collected pre-
dose in all 
participants at 
each visit of the 
treatment period 
and at CMV 
Infection/Early 
Discon visit (if 
during treatment 
period).
*Week 1 
Intensive PK: To 
be collected on 
Study Day 6, 7, 
8, 9, or 10. See 
Sections 4.2.1.3 
and 8.6.
088PBS


PRODUCT: MK-8228
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01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
Additional 
Intensive PK for 
participants with 
dose formulation 
switch
Performed at any 
time between 6th
or more 
consecutive days 
until the 10th day 
after dose 
formulation 
switch.  See 
Sections 4.2.1.3 
and 8.6.
088PBS


PRODUCT: MK-8228
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PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Study Period
Pre-
treatment
Treatment
Follow-up
CMV 
Infection
and/or 
Early 
Discon 
Visit
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCRa
Day 
of 
Tp
D1b
W1
W2
W4
W6
W8
W10 W12 W16 W20 W24 W28 W32 W36 W40 W44 W48 W52
Study visits are 
calculated relative 
to Day 1.
If treatment 
discontinued 
early, all 
remaining visits 
should be 
completed.
Visit Window
-14d
-7d
±3d
±7d
Screening 
window is based 
on “Day of Tp”.
AE = adverse event; CMV = cytomegalovirus; D = Day, DNA = deoxyribonucleic acid; ECG = electrocardiogram; HIV = human immunodeficiency virus; IEC = independent 
ethics committee; IgG = immunoglobulin G; INR = international normalized ratio; IRB = institutional review board; OATP = organic anion-transporting polypeptide; PCR = 
polymerase chain reaction; PK = pharmacokinetic; PT = prothrombin time; SAE = serious adverse event; SCR = screening; SOC = standard of care; Tp = transplant; W = Week; 
WOCBP = women of childbearing potential
a. Screening should begin after obtaining documented consent and may begin on as early as one day before transplantation for participants receiving a kidney from a deceased 
donor and up to 14 days prior to transplantation for participants receiving a kidney from a living donor.  All screening procedures listed under Visit 1 of the Study SoA will be 
performed and must be completed by one day prior to Day 1. See Section 8.12.1 regarding details of screening procedures.
b. Start of study treatment is Day 1 (day of allocation).  Study therapy must begin within 7 days post-transplant and will continue through Week 28. Day 1 procedures/assessments 
must be performed prior to first dose of study treatment.
c. Once the CMV Infection Visit occurs, another plasma sample for CMV viral resistance testing should be collected at the next scheduled visit.  Among these participants, a final 
sample for CMV viral resistance testing will also be collected at Week 52.  
d. This sample will be drawn for SLCO1B1 (OATP1B1) and UGT1A1 genotyping and for planned analysis of the association between genetic variants in DNA and drug response. 
If the IRB/IEC does not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, 
data analysis will be limited to SLCO1B1 (OATP1B1) and UGT1A1 genes. Leftover extracted DNA will be stored for FBR if the participant (or legally acceptable representative) 
provides documented informed consent for FBR.
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PRODUCT: MK-8228
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01-FEB-2022
2
INTRODUCTION
2.1
Study Rationale
Cytomegalovirus (CMV) is an opportunistic pathogen which causes infection (ie, virus 
isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue 
specimen; Section 4.2.1.2) and disease (ie, end-organ involvement or CMV syndrome; 
Section 4.2.1.2 and Appendix 8) with substantial morbidity and mortality among solid organ 
transplant (SOT) recipients [Ljungman, P., et al 2016].  In a study describing the natural 
course of CMV disease over a 5-year period in kidney transplant recipients, the incidence of 
CMV infection among 477 kidney recipients was 63% over the first 100 days following 
transplantation [Husain, S., et al 2009] [Hartmann, A., et al 2006].  The incidence of CMV 
disease was the highest among CMV seronegative kidney recipients (R) with a transplanted 
kidney from CMV seropositive donor (D), ie,  D+/R– patients (56%), followed by D–/R+ 
and D+/R+ patient groups (20%) [Husain, S., et al 2009] [Hartmann, A., et al 2006].
The clinical effects of CMV can be divided into direct and indirect effects [Boeckh, M. 
2011].  Direct effects attributed to CMV include CMV syndrome or CMV end-organ disease 
[Humar, A., et al 2010] [Rubin, R. H. 2007].  Indirect effects of CMV may include an 
increased risk of allograft rejection [Humar, A., et al 2010] [Kranz, B., et al 2008], 
opportunistic infections (OIs), and post-transplant diabetes mellitus [Humar, A., et al 2010]
[Hjelmesaeth, J., et al 2005].  CMV infection and disease, as well as the CMV-associated 
direct and indirect clinical effects present a substantial challenge to the clinical management 
of SOT recipients. 
Currently, there are two clinical strategies for preventing CMV disease in the SOT recipient 
population: 1) CMV prophylaxis, ie, the post-transplant administration of anti-CMV 
medication such as valganciclovir (VGCV) for an extended duration (typically 200 days for 
D+/R− kidney transplant recipients; see below); and 2) CMV pre-emptive therapy (PET), ie, 
active surveillance for CMV infection, typically by CMV deoxyribonucleic acid (DNA) level 
monitoring or the CMV pp65 antigen testing (which is widely available as standard of care 
[SOC] in Japan) and initiation of anti-CMV treatment upon detection of CMV viremia.  
CMV prophylaxis is now widely used following SOT in the United States (US) and the 
European Union (EU) and has been associated with reductions in CMV disease, mortality, 
and graft rejection.  
In Japan, an addendum for the 2011 guideline for CMV management in the kidney transplant 
patient population was issued in 2015 [Japanese Society for Clinical Renal Transplantation
Guideline Work Group 2011; Addendum in 2015].  CMV prophylaxis with extended 
duration (200 days) of VGCV was recommended for high risk recipients (D+/R−patients 
who are treated for acute transplant rejection, received grafts from blood type incompatible 
donors or anti-donor antibody negative). The guideline also stated CMV prophylaxis with 
200 days of VGCV 450 ~ 900 mg/day decreases the incidence of CMV disease as well as 
acute graft rejection and is the current SOC regimen for CMV prophylaxis in SOT recipients 
outside Japan.  In 2016, VGCV was approved for the prevention of CMV disease in the SOT 
recipient population in Japan. However, VGCV is associated with myelotoxicity, which can 
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PRODUCT: MK-8228
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01-FEB-2022
be clinically relevant for SOT recipients on concomitant immunosuppressive agents (eg, 
mycophenolate mofetil) and antibacterial prophylaxis (eg, trimethoprim/ sulfamethoxazole) 
that can also cause myelosuppression [Kidney Disease: Improving Global Outcomes 
Transplant Work Group 2009] [Razonable, R. R. 2013] [Martin, S. I., et al 2013].  Moreover, 
VGCV requires dose adjustments based on renal function [Japan Prescribing Information, 
VALIXA 2018] and CMV strains resistant to VGCV have been identified [Razonable, R. R. 
2013] (Section 2.2.1).  An effective and well tolerated prophylactic anti-CMV medication for 
SOT recipients that does not cause myelosuppression, is dosed independent of renal function, 
and is active against both wild type and VGCV-resistant CMV strains, remains an unmet 
medical need.
MK-8228 (also known as letermovir; hereafter referred to as LET) belongs to a new class of 
anti-CMV agents with a novel mechanism of action with:
(1) Significant anti-CMV activity in in vitro and in vivo pre-clinical studies [Japan 
Prescribing Information, PREVYMIS 2018];
(2) A favorable clinical safety profile demonstrated in Phase 1 and 2 studies, as well as in 
the Phase 3 P001 study in hematopoietic stem cell transplant (HSCT) recipients
[Japan Prescribing Information, PREVYMIS 2018];
(3) Clinical efficacy as demonstrated in the P001 study in HSCT recipients [Marty, F. 
M., et al 2017]; and
(4) Activity against viral isolates resistant to marketed anti-CMV agents, also 
demonstrated in a case of multi-organ disease due to multi-resistant CMV [Kaul, D. 
R., et al 2011].  The activity of these agents map to the UL54 or UL97 genes, while 
LET activity maps to the UL56 (terminase) gene [Goldner, T., et al 2011].
Protocol 042 is planned to evaluate the safety, efficacy and pharmacokinetics (PK) of LET 
administered as prevention of CMV infection and disease in adult Japanese kidney transplant 
recipients.  In addition to D+/R– kidney transplant recipients who are at the highest risk of 
CMV disease, R+ (either D+/R+ or D–/R+) patients will also be enrolled as such group of 
patients are also expected to benefit from prophylaxis.  Duration of prophylaxis in R+ (either 
D+/R+ or D–/R+) kidney transplant recipients is noted in the overseas guideline [Kotton 
C.N., et al 2018]; while the general recommendation of prophylaxis for this group of patients 
is 3 months, an extended duration (between 3 and 6 months) of prophylaxis for the patients 
whose risk for CMV may be increased (eg, those on recent antilymphocyte therapy, 
desensitization) is suggested to be effective.  Therefore, in this study, R+ patients may be 
enrolled if the investigator considers the patient would benefit from 200 days of prophylaxis, 
and all patients will be given 200 days of prophylaxis. Study treatment will be initiated 
within 7 days post-transplant and continue through Week 28.  After approximately 28 weeks 
of study therapy, participants will be followed through Week 52 post-transplant (ie, 
approximately 12 months) to assess for late onset CMV infection and disease.  The study 
visits are calculated relative to Day 1 and the reported data will be assessed relative to the 
day of transplant for efficacy analysis.
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Details regarding specific benefits and risks for participants participating in this clinical study 
may be found in the accompanying Investigator’s Brochure (IB) and Informed Consent 
documents.
2.2
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on LET.
2.2.1
Pharmaceutical and Therapeutic Background
VGCV has been approved for the prevention of CMV disease in SOT recipients at high risk
in and outside of Japan.  The results of the IMPACT study demonstrated that VGCV 
prophylaxis of 28 weeks (ie, 200 days) is more effective than 14 weeks (ie, 100 days) in 
reducing the incidence of CMV disease in non-Japanese D+/R−kidney transplant recipients 
[Humar, A., et al 2010].
However, VGCV is also associated with myelotoxicity as described in the VGCV label 
[Japan Prescribing Information, VALIXA 2018].  Moreover, antiviral drug resistance
[Razonable, R. R. 2013], most commonly to VGCV and ganciclovir (GCV, approved only 
for treatment use in Japan), among CMV clinical isolates has emerged following widespread 
use of these drugs for CMV prophylaxis and PET.  Drug resistance is usually seen after 
treatment duration with antiviral agents of weeks to months [Beam, E., et al 2012].  The 
majority of resistance mutations to VGCV and GCV are associated with mutations in the 
UL97 encoded viral protein kinase [Lurain, N. S. and Chou, S. 2010].  Resistance to VGCV 
and GCV also occurs via mutations in the viral DNA polymerase gene (UL54), often in the 
presence of UL97 mutations [Boivin, G., et al 2012].
LET is a novel inhibitor of the CMV terminase (UL56/UL89), an enzyme that plays an 
important role in the cleavage of newly synthesized concatenated CMV DNA into individual 
unit-length viral genomes that are subsequently inserted into CMV procapsids to generate 
infectious CMV virions [Goldner, T., et al 2011]. LET has demonstrated potent, selective, 
and reversible inhibition of CMV activity in preclinical studies in vitro and efficacy against 
the virus in vivo [Lischka, P., et al 2010] [Goldner, T., et al 2011]. As there is no human 
homologue for the DNA terminase, there is a limited potential for mechanism-based toxicity.
LET has been shown to be generally well tolerated in 31 Phase 1 studies, 2 Phase 2 studies, 
and a pivotal Phase 3 study, P001, in HSCT recipients.  In P001, in which CMV seropositive 
allogeneic HSCT recipients including Japanese participants received LET or placebo from 
the early post-transplant period (within 4 weeks post-transplant) through Week 14 post-
transplant and were followed for an additional 34 weeks, LET was superior to placebo in the 
prevention of clinically significant CMV infection (defined as onset of CMV end-organ 
disease OR initiation of anti-CMV PET based on documented CMV DNAemia as measured 
by the central laboratory and the clinical condition of the participant) through Week 24 post-
transplant [Marty, F. M., et al 2017].  LET prophylaxis also resulted in lower all-cause 
mortality relative to placebo through Week 24 post-transplant and Week 48 post-transplant in 
HSCT recipients.
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Based on its mechanism of action that is distinct from other available anti-CMV agents, 
patients who are given LET for prophylaxis and experience CMV infection or disease, ie, a 
clinical and/or virological CMV “breakthrough” event, are still expected to retain available 
treatment options using existing anti-CMV medications.  This study will evaluate the safety, 
efficacy and pharmacokinetic of LET in the prevention of CMV infection and disease in 
adult Japanese D+/R−kidney transplant recipients.
2.2.2
Preclinical and Clinical Studies
Details of preclinical studies and completed clinical studies conducted with LET can be 
found in the accompanying IB.
2.2.3
Ongoing Clinical Studies
Currently, there is one ongoing clinical study involving LET for adult SOT patients (P002; a 
Phase 3 randomized, multi-site, double-blind active comparator trial to evaluate the efficacy 
and safety of LET versus VGCV in adult kidney transplant recipients).  Adult CMV D+/R−
kidney transplant recipients (n=600) will be randomized 1:1 to receive either LET or VGCV
starting within 7 days post-transplant and continuing through Week 28.  Efficacy as 
measured by the proportion of participants with adjudicated CMV disease (see Section 
4.2.1.2.1) through Week 52 post-transplant as well as safety in kidney transplant recipients 
will be evaluated.  There are no P002 sites in Japan.  Details of P002 study can be found in 
the accompanying IB.  Two more clinical studies involving LET for HSCT patients are 
ongoing/being planned.  1) P040; a Phase 3 randomized, double-blind, placebo-controlled 
clinical trial to evaluate the safety and efficacy of LET prophylaxis when extended from 100 
days to 200 days post-transplant in CMV R+ of an allogenic HSCT, and 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.  
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.
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.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this study.
In adult Japanese kidney transplant recipients who are organ donor (D) or organ recipient (R) 
seropositive (D+/R−, D+/R+ or D−/R+) for CMV:
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Objectives
Endpoints
Primary
◦
To evaluate the safety and tolerability of 
letermovir based on the proportion of 
participants with adverse events.
◦
Adverse events (AEs)
◦
Study drug discontinuations due to AEs
Secondary
◦
To evaluate the efficacy of letermovir in 
prevention of CMV disease and 
infection, as measured by the proportion 
of participants with adjudicated CMV 
disease or participants who have 
undergone anti-CMV treatment based on 
1) positive results on CMV antigenemia 
(local) or 2) quantifiable CMV 
DNAemia (local) through Week 28 and 
Week 52 post-transplant.
◦
Adjudicated CMV disease OR anti-
CMV treatment based on 1) positive 
results on CMV antigenemia (local) or 
2) quantifiable CMV DNAemia (local)
◦
To evaluate the efficacy of letermovir in 
prevention of CMV disease, as measured 
by the proportion of participants with 
adjudicated CMV disease through Week 
28 and Week 52 post-transplant. 
◦
Adjudicated CMV disease
◦
To evaluate the efficacy of letermovir in 
prevention of CMV infection, as 
measured by the proportion of 
participants with quantifiable CMV 
DNAemia (central) through Week 28 and 
Week 52 post-transplant.
◦
Quantifiable CMV DNAemia (central)
◦
To evaluate the pharmacokinetics of 
letermovir in Japanese kidney transplant 
recipients.
◦
Pharmacokinetic endpoints (the plasma 
concentrations of LET, PK parameters, 
ie, Oral: AUCtau, Ctrough, Cmax, Tmax, 
CLss/F; IV: AUCtau, Ctrough, Ceoi, CLss)
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Objectives
Endpoints
Tertiary/Exploratory
◦
To evaluate the proportion of patients 
experiencing allograft dysfunction and/or 
rejection through Week 28 and Week 52 
post-transplant.
◦
Allograft dysfunction or rejection
◦
To evaluate the incidence of new onset 
diabetes mellitus after transplant 
(NODAT) through Week 28 and Week 
52 post-transplant.
◦
NODAT
◦
To evaluate health outcomes through 
Week 28 and Week 52 post-transplant.
◦
Health outcomes (incidence of all-cause 
mortality, re-hospitalizations, 
opportunistic infections)
◦
To evaluate the antiviral resistance to 
letermovir in prophylaxis failures 
through Week 52 post-transplant.
◦
Antiviral resistance
◦
To explore the relationship between 
genetic variation and response to the 
prophylactic intervention administered, 
and mechanisms of disease.
a.
Variation across the human genome may
be analyzed for association with clinical 
data collected in this study.
b.
Variation in the SLCO1B1 (OATP1B1) 
and UGT1A1 genes will also specifically 
be evaluated.
◦
Genetic analysis
4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, single-arm, multi-site, open-label study to evaluate the safety, 
efficacy and pharmacokinetics of letermovir for the prevention of CMV infection and disease
in adult Japanese kidney transplant recipients.
This study will be conducted in conformance with Good Clinical Practices (GCP). The 
definition of CMV disease is provided in Section 4.2.1.2.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
Approximately 20 Japanese D+ and/or R+ kidney transplant recipients will be enrolled to
receive LET within 7 days post-transplant.  Of the 20 participants in total, at least 10 D+/R− 
kidney transplant recipients, who have the highest risk of developing CMV disease, will be 
enrolled.  R+ (either D+/R+ or D–/R+) kidney transplant recipients, who are at intermediate 
risk of CMV disease, will be allowed to be enrolled at the investigators’ discretion if the 
investigator considers the patient would benefit from 200 days of prophylaxis.
From Day 1 (day of allocation) through Week 28, all participants will receive:

LET 480 mg once daily (QD) given orally (two 240 mg tablets), or, if the participant 
is receiving concomitant cyclosporin A (CsA), LET 240 mg (one 240 mg tablet) QD 
given orally.
The above assumes:

Participants can tolerate swallowing and/or does not develop a condition that may
interfere with the absorption of the oral formulation.
If participants are unable to tolerate swallowing and/or have a condition (eg, vomiting, 
diarrhea, or a malabsorptive condition) that may interfere with the absorption of the oral 
formulation at or after Day 1, then such participants can be initiated/switched to the IV 
formulation of LET. Participants not on concomitant CsA will receive 480 mg IV LET QD, 
while participants on concomitant CsA will receive 240 mg IV LET QD.
The LET IV formulation should be switched to oral study therapy (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.
After completion of study therapy at Week 28, participants will continue to be followed for
safety, efficacy, and diagnosis of CMV disease, and complete all remaining visits through
Week 52. Participants who discontinue study medication early (ie, prior to Week 28) will
complete all remaining treatment-period visits through Week 28, as well as all remaining
visits through Week 52 as outlined in the SoA (Section 1.3) with the exception of study 
therapy administration, PK assessments, and study medication diary review. All scheduled 
study visits will be completed regardless of when cessation of study treatment occurs.
An independent Clinical Adjudication Committee (CAC) will be established for this study to 
adjudicate all potential CMV disease cases, as identified by site investigators or as otherwise 
described in the CAC charter (see Section 4.2.1.2.1 and Appendix 8).
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4.2
Scientific Rationale for Study Design
Since the number of kidney transplants in Japan is extremely limited (around 1700 cases 
annually) [Japanese Society for Clinical Renal Transplantation, 2018], the P042 study is
conducted as a nonrandomized, single-arm, multi-site, open-label study for a total of 20 
D+/R−, D+/R+ or D−/R+ participants (with at least 10 being D+/R−) based on feasibility of 
enrollment.
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
The safety and tolerability of LET will be assessed by a clinical evaluation of AEs and 
inspection of other study parameters including vital signs, physical examination, 12 lead 
electrocardiograms (ECGs), and standard laboratory safety tests at appropriate timepoints, as 
specified in the SoA. AEs are evaluated and recorded according to Section 8.4.  Participants 
may be asked to return for unscheduled visits in order to perform additional safety 
monitoring.
4.2.1.2
Efficacy Endpoints
The efficacy endpoints of the study (secondary endpoints) are:  

Adjudicated CMV disease or initiation of anti-CMV treatment based on 1) positive 
results on CMV antigenemia (local) or 2) quantifiable CMV DNAemia (local)
through Week 28 and Week 52 post-transplant.

Adjudicated CMV disease through Week 28 and Week 52 post-transplant.

Quantifiable CMV DNAemia (central) through Week 28 and Week 52 post-
transplant.
Following CMV prophylaxis with 200 days of VGCV in the non-Japanese D+/R−kidney 
transplant recipient population, the incidence rates of CMV disease and CMV DNAemia 
through Week 52 post-transplant have been described [Humar, A., et al 2010].  Currently, 
there is no universally accepted threshold of CMV DNA levels for therapy or treatment 
endpoints in the SOT recipient population [Kotton, C.N., et al, 2018].  
For the Japanese D+/R−kidney transplant recipient population, 200 days of VGCV for CMV 
prophylaxis is recommended [Japanese Society for Clinical Renal Transplantation Guideline 
Work Group 2011; Addendum in 2015].  However, SOC for CMV management in the 
kidney transplant recipient population in Japan is anticipated to vary depending on sites 
and/or investigators. In many sites, kidney transplant recipients may not be started on VGCV 
prophylaxis following transplant and/or started on anti-CMV treatment at the time of onset of 
CMV disease.  Instead, such kidney transplant recipients in Japan are serially monitored by 
the pp65 CMV antigen assay for post-transplant CMV infection regardless of whether 
prophylaxis or PET strategy is utilized for CMV management, and started on anti-CMV 
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treatment when CMV infection is detected. As for R+ kidney transplant recipient population, 
PET is recommended for the clinical strategy for preventing CMV disease in the Japanese 
guideline [Japanese Society for Clinical Renal Transplantation Guideline Work Group 2011; 
Addendum in 2015].
During the P042 study, the Sponsor anticipates that: 1) serial monitoring for CMV infection 
may occur as SOC in Japan during and after LET prophylaxis, ie, during study treatment and 
follow-up periods; and 2) detection of CMV infection at any time during the study may lead 
to cessation of LET prophylaxis (if during study treatment period) and initiation of anti-CMV
treatment.  Therefore, for the P042 study population, the incidence of CMV disease is 
expected to be lower than what was previously reported for the IMPACT study population
(routine CMV monitoring was prohibited during study period in the IMPACT study unless as 
part of the management of an established CMV infection), ie, the kidney transplant recipients 
in the P042 study population with CMV infection are expected to be started on anti-CMV 
treatment prior to the clinical progression of CMV infection to CMV disease.  Therefore, in 
addition to the clinical efficacy endpoints of the proportion of adjudicated CMV disease and 
the proportion of patients with quantifiable DNAemia (central) applied in the IMPACT study
[Humar, A., et al 2010], the proportion of participants with adjudicated CMV disease or 
participants who have received anti-CMV treatment based on positive results on CMV 
antigenemia (local) or 2) quantifiable CMV DNAemia (local) will also be analyzed.  
For this study, CMV infection, CMV disease, CMV end-organ disease, and CMV syndrome 
are as defined by the Disease Definitions Working Group of the CMV Drug Development 
Forum in 2016 [Ljungman, P., et al 2016].
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or nucleic 
acid in any body fluid or tissue specimen.
CMV disease consists of the two following clinical definitions:  1) CMV end-organ disease; 
and 2) “probable CMV syndrome” (which will be termed “CMV syndrome” throughout this 
protocol).

CMV end-organ disease (full definition in Appendix 8) may be further described by:
o
The specific type of end-organ disease (eg, pneumonia, gastrointestinal disease, 
or hepatitis); and
o
By categorization based on appropriate clinical signs/symptoms with 
detection/documentation of CMV by:

Proven CMV end-organ disease

Probable CMV end-organ disease

CMV syndrome (full list of criteria and clinical definition in Appendix 8) requires 
detection of CMV in blood by virus isolation, rapid culture, antigenemia, or nucleic 
acid testing with at least two of the criteria, as outlined in Appendix 8.
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4.2.1.2.1
CMV Based Assessments
CMV DNA Measurements (performed by the central laboratory)
“Quantifiable CMV DNAemia (central)” is included as a secondary endpoint in this study.  
In this study, CMV DNAemia (viral load) will be measured on plasma samples using the 
Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which will be performed 
by the central laboratory.  The lower limit of quantification (LLOQ) for this assay is 
137 IU/mL which is approximately 151 copies/mL (using a conversion factor of 
1.1 copies/IU as per the assay package insert).
The CMV DNA levels in IU/mL will be reported as one of the following:

<137 NOT DETECTED

<137 DETECTED NOT QUANTIFIABLE

A numeric value 

>910,000,000
“Quantifiable CMV DNAemia (central)” is defined as any case with a numeric value or 
reported as “>910,000,000” and does not include reporting of polymerase chain reaction
(PCR) results as “<137 not detected” or “<137 detected, not quantifiable”.  Additional details 
on CMV DNA PCR testing are described in Section 8.2.1.2.
CMV DNA Measurements and CMV antigenemia (performed locally)
In addition to central CMV DNA PCR testing at the timepoints indicated in the Study SoA 
(see Section 1.3), local CMV DNA PCR and/or CMV antigenemia testing may be conducted 
at the investigators’ discretion per institutional standards (Section 4.2.1.2).  Local CMV test 
results will be used to determine “anti-CMV treatment based on 1) positive results on CMV 
antigenemia (local) or 2) quantifiable CMV DNAemia (local)” which is a component of a 
secondary endpoint in this study.  
“Anti-CMV treatment based on 1) positive results on CMV antigenemia (local) or 2) 
quantifiable CMV DNAemia (local)” is defined as initiation of approved anti-CMV agents
based on at least one positive cell on CMV antigenemia and/or numeric value (not including 
the result of “Detected but not quantifiable”) of CMV DNA PCR assay performed locally.  
Additional details on local CMV DNA PCR testing and CMV antigenemia are described in 
Section 8.2.1.2.
CMV Disease Assessments
In addition, all potential cases of CMV disease, as identified by site investigators or as 
otherwise described in the CAC charter, will be confirmed by an independent CAC.  The 
CAC will review any available data (as documented in the CAC charter) for the participant, 
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including but not limited to clinical, laboratory, radiographic, and/or histopathological data, 
as well as the investigators’ assessments from all potential cases of CMV disease as 
identified by site investigators throughout the study.  The adjudication of cases by the CAC 
will take precedence over the investigator’s assessment.  Only cases that are adjudicated by 
the CAC as a “yes” to CMV disease (“adjudicated CMV disease”) will be included in the 
efficacy endpoints.
Adjudication of CMV disease cases by an established CAC will standardize the CMV 
disease diagnosis for the secondary efficacy endpoints.
QuantiFERON-CMV Measurements
The development of CMV-specific T cell responses, which is the predominant adaptive 
immune response that confers protection against CMV [Manuel, O., et al 2013] [Abate, D., et 
al 2013] [Cantisan, S., et al 2013] [Fernandez-Ruiz, M., et al 2014], will be measured using 
the QuantiFERON-CMV assay at the timepoints indicated in the Study SoA (see Section 
1.3).  At each of these timepoints, the proportion of participants with positive QuantiFERON-
CMV assay results will be correlated with the incidence of adjudicated CMV disease and/or 
participants who have undergone anti-CMV treatment based on 1) positive results on CMV 
antigenemia (local) or 2) quantifiable CMV DNAemia (local) through 52 weeks post-
transplant and assessed as an exploratory endpoint.
The proportion of SOT patients (including kidney transplant recipients) who develop CMV-
specific T cell responses following 3 to 6 months of VGCV prophylaxis has previously been 
reported [Manuel, O., et al 2013] [Abate, D., et al 2013] [Cantisan, S., et al 2013] 
[Fernandez-Ruiz, M., et al 2014] while the incidence of such immune response following 
LET prophylaxis in this patient population has not been previously studied.  The Week 40 
(ie, 3 months post prophylaxis) and Week 52 (ie, 6 months post prophylaxis) timepoints for 
this study are previously used in the VGCV prophylaxis reports.  Moreover, there is 
preclinical evidence to suggest that treatment with LET is accompanied by the cytoplasmic 
accumulation of large amounts of subviral, noninfectious particles termed dense bodies 
(DBs) within CMV-infected cells [Goldner, T., et al 2011].  Since DBs are immunogenic and 
prime lymphocytes and neutralizing antibodies in mice, it may be speculated that the release 
of non-infectious, immunogenic DB during LET prophylaxis may facilitate antiviral immune 
response following immunosuppression in kidney transplant recipients and as measured by 
the QuantiFERON-CMV assay [Becke, S., et al 2010] [Goldner, T., et al 2011].  The anti-
CMV response at Week 12 and Week 28 timepoints will determine whether such responses 
may be elicited during LET administration.  The central laboratory based QuantiFERON-
CMV assay results will not be shared with the respective site investigators.
4.2.1.2.2
New Onset Diabetes Mellitus After Transplant (NODAT)
NODAT is a standard clinical event to be monitored following kidney transplant and the 
incidence of NODAT is also included in the IMPACT study [Humar, A., et al 2010].  An 
increased risk of NODAT is considered one of the indirect effects resulting from CMV 
infection, along with others such as allograft rejection and opportunistic infections
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(Section 2.1).  As preventing CMV infection may then result in decreased incidence of 
NODAT, this will be evaluated as an efficacy endpoint.  
Diabetes mellitus is defined according to the World Health Organization (WHO) and 
American Diabetes Association (ADA) as follows [Kidney Disease: Improving Global 
Outcomes Transplant Work Group 2009]: 
1. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L).  Fasting is defined as no caloric intake 
for at least 8 hours.*
OR
2. Symptoms of hyperglycemia and a casual plasma glucose ≥200 mg/dL (11.1 mmol/L).  
Casual is defined as any time of day without regard to time since last meal.  The classic 
symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss.
OR
3. Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance 
test.  The test should be performed as described by the WHO, using a glucose load 
containing the equivalent of 75 g anhydrous glucose dissolved in water.*
*In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat 
testing on a different day.
NODAT is diabetes mellitus defined by the WHO and ADA that develops for the first time 
after kidney transplantation [Kidney Disease: Improving Global Outcomes Transplant Work 
Group 2009].  The incidence of NODAT is highest in the first 3 months after transplantation.  
The cumulative incidence of NODAT by the end of the first year has generally been found to 
be 10% - 30% in adult kidney transplant recipients receiving CsA or tacrolimus plus 
corticosteroids [Kidney Disease: Improving Global Outcomes Transplant Work Group 2009].
4.2.1.3
Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples will be collected from all participants as described in the SoA
(Section 1.3).  The intensive and trough PK data will be used to characterize the PK of LET 
in Japanese kidney transplant recipients.  Intensive PK data will be analyzed by non-
compartment analysis and descriptive statistics of PK parameters (as shown in below) will be 
provided by treatment:

Oral: AUCtau, Ctrough, Cmax, Tmax, CLss/F

IV: AUCtau, Ctrough, Ceoi, CLss
Table 1 summarizes the requirements of trough PK and intensive PK collection during the 
study.
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Table 1
Trough Pharmacokinetic and Intensive Pharmacokinetic Collection
Trough PK –
Pre-dose at Each Visit 
of Treatment Period
Week 1 
Intensive 
PK 
Additional 
Intensive PK
All participants
X
X
Participants with dose formulation switch
X
IV = intravenous; PK = pharmacokinetics; PO = Orally
If Week 1 intensive PK is performed after PO therapy and the dose formulation is then switched from 
PO to IV, ALL participants who receive 6 or more consecutive days of IV therapy will have intensive 
PK.
If Week 1 intensive PK is performed after IV therapy and the dose formulation is then switched from 
IV to PO, participants who receive 6 or more consecutive days of PO therapy will have intensive PK 
if required sample collection is feasible.
No more than twice will intensive PK sampling be performed during the entire study for a single 
participant, regardless of how many times the dose formulation is switched during the study.
Details of PK sample collection is in Section 8.6.1.
4.2.1.4
Planned Exploratory Biomarker Research
4.2.1.4.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
In addition to studying variation across the human genome, variants in the SLCO1B1 
(OATP1B1) and UGT1A1 genes will specifically be investigated for PK variability, as well 
as efficacy and safety.
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4.2.1.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
This clinical study will evaluate:
•
LET
o
Oral/IV 480 mg QD, if given without concomitant CsA, or 
o
Oral/IV 240 mg QD, if given concomitantly with CsA
Rationale for Dose of LET
LET 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.
LET has been safe and well tolerated in 31 Phase 1 studies in which participants received 
oral LET single doses ranging from 5 mg to 720 mg and multiple doses ranging from 40 mg 
QD to 720 mg twice daily (BID), or received IV LET 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), LET 240 mg QD, during an 84-day treatment period, was well tolerated with 
a safety profile similar to placebo.
In the Phase 2b dose-ranging study (P020) conducted in HSCT recipients, a dose response 
was observed.  LET doses of 60 mg, 120 mg, or 240 mg, or placebo, were given once daily in 
131 total participants.  One primary endpoint, the incidence of overall failure of CMV 
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prophylaxis, was significantly reduced in the primary efficacy analyses with both the 120 mg 
and 240 mg doses of LET (32%, p=0.014 and 29%, p=0.007, respectively) when compared to 
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 LET when compared to placebo.  LET was generally well-tolerated 
at all three doses in P020.
Phase 1 studies demonstrated that co-dosing with CsA increases LET exposure.  Further 
analyses using the Phase 2b study (P020) data indicated that exposure with the 240 mg QD 
dose of LET 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 LET 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 LET 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 Japanese participants [Marty, F. M., et al 
2017].  Treatment with LET 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 LET compared to placebo.  LET 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 LET group compared to the placebo group.  All-cause mortality was 
substantially lower in the LET group compared to the placebo group through Week 24 and 
Week 48 post-transplant.  LET 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 P042 study, the doses of LET that were previously used in the Phase 3 evaluation in 
HSCT recipients including Japanese participants will be used.  Since the target of LET is the 
CMV viral terminase complex, considering the mechanism of action, the LET doses shown 
to be effective in the HSCT recipient population is anticipated to be effective in the SOT 
recipient population.
The IV formulation of LET contains the excipient hydroxypropyl betadex. Following 
precautions are noted in the LET label; “there is a possibility that worsening of renal function 
and, etc. by accumulation of the excipient hydroxypropyl--cyclodextrin in the IV Infusion 
may occur in patients with renal impairment, the duration of use with the IV Infusion should 
be kept to a minimum. Oral administration should be selected for patients for whom oral 
administration is possible.”  Also, the effect of renal impairment on LET PK was evaluated in 
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participants with moderate (estimated glomerular filtration rate [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; Study P006) [Kropeit, D., et al 2017].  Based on the P006 
study results, no dose adjustment is recommended for participants with moderate or severe 
renal impairment as is in the LET label [Japan Prescribing Information, PREVYMIS 2018]. For 
this study in renal transplant participants, the LET dose for IV formulation is selected as 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 at or after Day 1.  Use of the IV 
formulation should generally be limited to 4 weeks or less in duration per participant.
4.3.2
Rationale for Dose Interval and Study Design
CMV prophylaxis has been associated with reductions in CMV disease, mortality, and graft 
rejection in high-risk patients [Humar, A., et al 2010] [Hodson, E. M., et al 2013] [Kalil, A. 
C., et al 2005] [Lowance, D., et al 1999].  The clinical benefit of CMV prophylaxis for 200 
days (ie, 28 weeks) instead of 100 days (ie, 14 weeks) to decrease the incidence of CMV 
disease has been shown in the IMPACT study comparing VGCV prophylaxis for 200 days 
versus 100 days in kidney transplant recipients [Humar, A., et al 2010].  In this study, the 
incidence of CMV disease by 12 months post-transplant was 16.1% in the 200-day group 
compared to 36.8% in the 100-day group (p<0.0001).  The relative and absolute risk 
reduction observed with prolonged prophylaxis (ie, 6 months) was 56% and 21%, 
respectively, which corresponds to a number needed to treat approximately 5 in order to 
prevent each case of CMV disease up to 12 months post-transplant [Humar, A., et al 2010].  
Prolongation of prophylaxis to 6 months or longer has been proposed as a potential strategy 
to decrease the incidence of CMV disease in SOT recipients [Humar, A., et al 2010] [Doyle, 
A. M., et al 2006] [Valentine, V. G., et al 2008] [Schnitzler, M. A., et al 2003]; for this study, 
a post-transplant prophylaxis duration of approximately 28 weeks will be used as was done in 
the IMPACT study conducted in D+/R− kidney transplant recipients [Humar, A., et al 2010]. 
Duration of prophylaxis in R+ (either D+/R+ or D–/R+) kidney transplant recipients is noted 
in the oversea guideline [Kotton, C.N., et al 2018]; between 3 and 6 months of prophylaxis 
for the patients whose risk for CMV may be increased (eg, those on recent antilymphocyte 
therapy, desensitization) may be effective.  Therefore, for this study, R+ kidney transplant 
recipients will be allowed to be enrolled at the investigators’ discretion if the investigator 
considers the patient would benefit from 200 days of prophylaxis, and the safety and efficacy 
of 200 days dosing will be assessed in all participants.  Participants will be followed through 
Week 52 to evaluate the incidence of late onset CMV disease after the conclusion of study 
medication.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male/Female Japanese participants with receipt of a kidney transplant of at least 18 years of 
age will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Meet either of the following recipient and/or donor CMV Immunoglobulin G (IgG)
serostatus:
a) Have a documented negative serostatus for CMV (ie, recipient CMV IgG
seronegative [R−]) within 90 days prior to allocation.  AND anticipate receiving an 
allograft kidney from a CMV IgG seropositive (D+) donor at the time of screening 
AND have received an allograft kidney from a documented D+ donor at the time of 
allocation.
Note: A donor who is seropositive solely based on having received a CMV-
seropositive transfusion immediately prior to organ donation is not considered to be a 
seropositive donor in this study.
b) Have a documented positive serostatus for CMV (ie, recipient CMV IgG seropositive 
[R+]) AND the investigator considers the patient would benefit from 200 days of 
prophylaxis.
Note: Either D+ or D– is allowed for donor serostatus (D+/R+ or D–/R+).
2. Anticipate receiving a primary or secondary allograft kidney at the time of screening 
AND have received a primary or secondary allograft kidney at the time of allocation.
3. Be within 0 (ie, day of transplantation) to 7 days (inclusive) post-kidney transplant at the 
time of allocation.
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Demographics
4. Participant is a Japanese male or female from 18 years to any years of age inclusive, at 
the time of signing the informed consent.
Note: Participant under 20 years of age should be provided written informed consent by 
legally acceptable representative.
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
o
Is not a woman of childbearing potential (WOCBP) 
OR
o
Is a WOCBP and using 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.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) 
within 72 hours before the first dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the main study without participating in FBR.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Received a previous solid organ transplant or HSCT.
Note: Participants who have received a prior primary allograft kidney may be enrolled, 
provided that all other inclusion/exclusion criteria are met.
2. Is a multi-organ transplant recipient (eg, kidney-pancreas).
Note: Double kidney transplant recipients (ie, transplant of two kidneys from the same 
donor to the same recipient simultaneously) will be excluded.
3. Has a history of CMV disease or suspected CMV disease within 6 months prior to
allocation.
4. Positive results on CMV DNA PCR assay and/or CMV antigen test (if either/both tests 
are performed as local SOC) at any time between the completion of the transplant surgery 
and time of allocation.
Note: Positive result on CMV DNA PCR is defined as with numeric value of CMV DNA.  
Positive result on CMV antigenemia is defined as with at least one positive cell.
5. Has suspected or known hypersensitivity to active or inactive ingredients of LET
formulations.
6. Is on dialysis or plasmapheresis at the time of allocation.
Note: For the purposes of this protocol, dialysis includes hemofiltration. Participant who: 
(1) has had dialysis or plasmapheresis within 7 days (inclusive) post-transplant but is not 
on dialysis or plasmapheresis at the time of allocation; and (2) is expected to remain off
dialysis or plasmapheresis may be enrolled, provided that all other inclusion/exclusion 
criteria are met.
7. Has post-transplant renal function of creatinine clearance (CrCl) ≤10 mL/min at
allocation (measured locally). For this exclusion criterion, CrCl will be calculated using 
the Cockcroft-Gault equation using the most recently obtained and available serum 
creatinine value collected within 3 calendar days prior to and including the day of 
allocation and after the conclusion of any clinically warranted (at the discretion of the 
investigator) post-transplant dialysis or plasmapheresis.
Note: Participants who meet this exclusion criterion at screening may, at the discretion of 
the investigator, have one repeat testing done within 3 days prior to allocation. If the 
repeat value meets this exclusion criterion again, such participants may NOT continue in 
the screening/allocation process. Only the laboratory test with specific out-of-range value 
(and not the entire laboratory panel) should be repeated.
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CrCl (Males) = (weight in kg) (140 – age)
(72) (creatinine in mg/dL)
CrCl (Females) = 0.85 × male value (ie, the value obtained with formula above)
8. Has Child-Pugh Class C severe hepatic insufficiency (Appendix 9) at screening.
Note: 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.
9. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at 
screening.
Note: Moderate hepatic insufficiency is defined as Child-Pugh Class B (see Note for 
exclusion criteria 8 above and Appendix 9); moderate-to-severe renal insufficiency is 
defined as CrCl <50 mL/min, as calculated by the Cockcroft-Gault equation (as above), 
respectively.
10. Has any uncontrolled infection on the day of allocation.
11. Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) 
test at any time prior to allocation, or for hepatitis C virus antibody (HCV-Ab) and with 
detectable HCV RNA within 90 days prior to allocation or hepatitis B surface antigen 
(HBsAg) within 90 days prior to allocation.
12. Requires mechanical ventilation, or is hemodynamically unstable, at the time of
allocation.
13. Has a history of malignancy ≤5 years prior to signing informed consent except for
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or
carcinoma in situ; or is under evaluation for other active or suspected malignancy.
14. 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 the participant’s 
participation for the full duration of the study, or put the participant 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.
15. Has exclusionary laboratory value at the screening visit, as listed in Table 2.
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Table 2
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Value
Hemoglobin
<8 g/dL
Platelets
<25,000 cells/µL
Total bilirubin
>2.5 x ULN
AST
>5 x ULN
ALT
>5 x ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
Prior/Concomitant Therapy
16. Has received within 30 days prior to allocation or plans to receive during the study any of 
the following anti-CMV IgG antibody treatment or anti-CMV drug therapy including:
a. CMV immune globulin
b. Any investigational CMV antiviral agent/biologic therapy.
17. Has received any dose of LET prior to allocation.
18. Has received within 7 days prior to allocation or plans to receive during the study any of 
the following anti-CMV drug therapy including:
a. GCV
b. VGCV
c. Foscarnet
d. Acyclovir (at doses >3200 mg PO per day or >25 mg/kg IV per day)
e. Valacyclovir (at doses >3000 mg PO per day)
f. Famciclovir (at doses >1500 mg PO per day)
19. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has
had a recent history (within the last year) of drug or alcohol abuse or dependence.
20. Is taking or plans to take any of the prohibited medications listed in the protocol (see
Section 6.5.1).
Prior/Concurrent Clinical Study Experience
21. 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 
(excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. 
Participants previously treated with an investigational monoclonal antibody will be 
eligible to participate after a 150-day washout period.
Note: Investigational regimens involving combinations of approved agents are not
permitted. Other non-interventional or other observational studies are allowed.
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22. Has previously participated in this study or any other study involving LET.
23. 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 the 
course of this study.
Other Exclusions
24. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the 
time of consent through at least 28 days following cessation of study therapy.
25. Is expecting to donate eggs starting from the time of consent through at least 28 days 
following cessation of study therapy.
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
The oral formulation of LET 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 non-study 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 (eg, participants who are taking CsA concomitantly with LET must avoid 
consumption of grapefruit and grapefruit juice).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study 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 intervention(s) to be used in this study are outlined in Table 3 (PO) and Table 4
(IV).
In this study, approximately 20 participants will be enrolled to receive LET once a day from 
the day of enrollment (Day 1, within 7 days post-transplant) through 28 weeks (~200 days) 
post-transplant.  Participants without concomitant CsA use will be dosed 480 mg (two 240 
mg tablets) once daily and participants with concomitant CsA use will be dosed 240 mg (one 
240 mg tablet) once daily. 
For participants who cannot tolerate swallowing and/or develop a condition that may 
interfere with the absorption of the oral formulation at or after Day 1, study therapy can be 
initiated/switched to the IV formulation. Simultaneous use of IV and oral study therapy is 
not allowed.  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 IV formulation should be switched to oral study therapy (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 3
Study Therapy – Oral (Tablet) Formulation
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
IMP/ 
NIMP
Sourcing
LET (for participants 
on CsA)
240 mg
Once daily
Oral
QD from Day 1 to Week 28 
Experimental
IMP
Sponsor
LET (for participants 
not on CsA)
480 mg (two 
240-mg tablets)
Once daily
Oral
QD from Day 1 to Week 28 
Experimental
IMP
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. 
LET = letermovir; CsA = Cyclosporin A; QD = Once daily
Table 4
Study Therapy – Intravenous Formulation
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
IMP/ 
NIMP
Sourcing
LET (for participants 
on CsA) 
240 mg
Once daily
IV
QD from Day 1 to Week 28 b
Experimental
IMP
Sponsor
LET (for participants 
not on CsA) 
480 mg
Once daily
IV
QD from Day 1 to Week 28 b
Experimental
IMP
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. 
LET = letermovir; CsA = Cyclosporin A; IV = intravenous; QD = Once daily
a: LET IV formulation dosing volume is 250 mL and duration of infusion will be 60 minutes. LET 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. 
b: The IV formulation should be switched to oral study therapy (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.
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All supplies indicated in Table 3 and Table 4 will be provided per the ‘Sourcing’ row 
depending upon local country operational requirements.  Every attempt should be made to 
source these supplies from a single lot/batch number. The trial site is responsible for 
recording the lot number, manufacturer, and expiry date for any locally purchased product as 
per local guidelines unless otherwise instructed by the Sponsor.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.1.1
Medical Devices
There are no medical devices to be used in this study.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
Intervention allocation will be stratified according to the following factors:
1. CMV seropositivity subgroups (D+/R– and R+).
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.
Compliance will be calculated by the Sponsor based on the drug accountability documented 
by the site staff and monitored by the Sponsor/designee.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the time periods specified by this protocol. If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
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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Since this list 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 
when appropriate.
6.5.1
Prohibited Medication
Letermovir is a substrate of OATP1B1/3, a time-dependent inhibitor of CYP3A, and inhibits 
breast cancer resistance protein (BCRP) and OATP1B1/3. Furthermore, letermovir may 
induce CYP2C9 and CYP2C19.  Medications/therapies that are prohibited are outlined as 
follows. 
The following medications/therapies are prohibited during treatment period and all of follow-
up period. 

Antiviral drugs or therapies for prevention/treatment of CMV, including but not limited 
to:
-
letermovir that is not part of study intervention
-
ganciclovir
-
valganciclovir
-
foscarnet
-
acyclovir (at doses >3200 mg PO per day or >25 mg/kg IV per day) 
-
valacyclovir (at doses >3000 mg PO per day) 
-
famciclovir (at doses >1500 mg PO per day)
-
any investigational CMV antiviral agent/biologic therapy, including CMV vaccines 
or CMV hyper-immune globulin
Note: these agents may be used for other indications while participants are on study 
therapy and all of follow-up period [eg, foscarnet for the treatment of human herpes 
virus 6 (HHV 6) or acyclovir for treatment of disseminated zoster]
The following medications/therapies are prohibited during the dosing period and for 14 days 
after the dosing period:

Investigational Agents:  Unapproved investigational agents or investigational regimens 
involving combinations of approved agents are not permitted.
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
CYP3A substrates with narrow therapeutic range (NTR), including but not limited to:
-
Pimozide: Concomitant administration of LET may result in increased 
concentrations of pimozide due to inhibition of CYP3A by LET, which may lead to 
QT prolongation and ventricular arrhythmia.
-
Ergot alkaloids: Concomitant administration of LET may result in increased 
concentration of ergot alkaloids (eg, ergotamine and dihydroergotamine) due to 
inhibition of CYP3A by LET, which may lead to ergotism.

HMG-CoA reductase inhibitors (statins):
-
Simvastatin and pitavastatin: Concomitant administration of LET may result in 
increased simvastatin or pitavastatin concentrations, which may lead to myopathy.

Enzyme and Transporter Inducers:
-
Strong inducers, such as rifampicin, phenytoin, carbamazepine, St John’s wort 
(Hypericum perforatum), rifabutin and phenobarbital: Concomitant administration 
with LET may result in decreased concentration of LET, which may lead to 
decreased efficacy.
-
Moderate inducers, such as modafinil and bosentan: Concomitant administration 
with LET may result in decreased concentration of LET, which may lead to 
decreased efficacy.

Everolimus when LET is co-administered with CsA: Co-administration of everolimus 
with LET and CsA may result in significantly increased everolimus concentrations due 
to CYP3A inhibition (Note: see Section 6.5.2 for co-administration of LET with 
everolimus).
It should be noted that the magnitude of CYP3A- and OATP1B1/3-mediated drug 
interactions on co-administered drugs may be different when LET is co-administered with 
CsA. Please also consult current prescribing information for CsA and other co-administered 
medications.
6.5.2
Medications/Therapies to be Administered with Caution
The following medications/therapies are allowed when coadministered with LET, but should 
be used with clinical monitoring for AEs related to these agents and/or drug level monitoring 
of these agents.

CYP3A substrates:
o
Co-administration of LET with drugs that are CYP3A substrates may result in 
clinically relevant increases in the plasma concentrations of co-administered 
CYP3A substrates (eg, fentanyl, quinidine and midazolam).  Therefore, frequent 
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monitoring for adverse reactions related to these agents is recommended during 
co-administration.  
o
Substrates of CYP3A with NTR (examples given below; please also consult 
current prescribing information for monitoring and dosing these products with 
inhibitors of CYP3A); dose adjustment of CYP3A substrates with NTR may be 
needed.

CsA:  Co administration of LET with CsA increases CsA 
concentrations.  Frequent monitoring of CsA whole blood 
concentrations should be performed during and at discontinuation of 
LET and the dose of CsA adjusted as appropriate. 

Sirolimus:  Co-administration of LET with sirolimus increases 
concentrations of sirolimus.  Frequent monitoring of sirolimus whole 
blood concentrations should be performed during and at discontinuation 
of LET and the dose of sirolimus adjusted as appropriate.

Tacrolimus:  Co-administration of LET with tacrolimus increases 
tacrolimus concentrations.  Frequent monitoring of tacrolimus whole 
blood concentrations should be performed during and at discontinuation 
of LET and the dose of tacrolimus adjusted as appropriate.

Everolimus: Co-administration of LET with everolimus may increase 
everolimus concentrations. Frequent monitoring of everolimus blood 
concentrations should be performed during and at discontinuation of 
LET and the dose of everolimus adjusted accordingly. The 
administration of everolimus when LET is co-administered with CsA 
is prohibited (see Section 6.5.1).

Substrates of OATP1B1/3 and/or CYP3A:
o
Statins:

Atorvastatin: Co-administration of LET with atorvastatin increases 
concentrations of atorvastatin. Monitoring for statin-associated adverse 
reactions (eg, myopathy) is recommended during co-administration.  

Fluvastatin, rosuvastatin or pravastatin: Co-administration of LET with 
these drugs increases concentrations of these drugs.  Monitoring for 
statin-associated adverse reactions (eg, myopathy) is recommended 
during co-administration. 

Substrates of CYP2C9 and CYP2C19:
o
Voriconazole:  Co-administration of LET with voriconazole decreases the 
plasma concentrations of voriconazole likely due to induction of CYP2C9 
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and/or 2C19.  If concomitant administration is necessary, close monitoring for 
reduced effectiveness of voriconazole is recommended.
o
Warfarin:  LET may decrease the plasma concentrations of CYP2C9 and/or 
CYP2C19 substrates (eg, warfarin).  Frequent monitoring of INR should be 
performed while warfarin is co-administered with LET.
6.5.3
Rescue Medications and Supportive Care
In the event of CMV disease (suspected or confirmed by the investigator) during the study 
therapy period (ie, prior to completion or early discontinuation of study therapy) or a clinical 
decision by the investigator to initiate anti-CMV treatment based on positive results on 
locally performed CMV DNA PCR or CMV antigenemia, study therapy will be discontinued 
(See Section 8.12.5) and the participant may be treated according to the local SOC (outside 
the context of the study). In this setting, any of the prohibited anti-CMV medications (as 
outlined in Section 6.5.1) may be used.
6.6
Dose Modification (Escalation/Titration/Other)
Please see Section 4.3.1 for LET dose to be used with or without co-administered CsA and 
Section 8.1.9.2 for information regarding dose modifications if CsA is initiated or 
discontinued during study therapy treatment period.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.4.
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Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.12.5.
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 has confirmed or suspected CMV disease and/or CMV infection that 
requires anti-CMV treatment as determined by the investigator (Section 4.2.1.2).
•
The participant has a confirmed positive pregnancy test.
•
An investigator feels it is in the best interest of the participant to discontinue.
•
An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
lab value that is greater than or equal to 3 × upper limit of normal (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 one of the following: 
-
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).
Note: 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.
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The participant may be discontinued from study intervention for any of the following reasons
but continue to be monitored in the study:
•
Any AE/SAE assessed by the investigator as 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, placed the participant at unnecessary risk 
from continued administration of study intervention.
Participants who interrupt (see Section 8.12.5.1) or discontinue study therapy prior to Week 
28 because they are confirmed or suspected of developing CMV disease or CMV infection 
that require anti-CMV treatment must complete a CMV Infection Visit (Sections 1.3 [SoA]
and 8.12.5.1). A CMV Infection Visit may be performed at any time when one or more 
criteria for the CMV Infection Visit (Section 8.12.5.1) is fulfilled.  If the investigator decides 
to conduct a CMV Infection Visit at a scheduled study visit, then the procedures for a CMV 
Infection Visit (if the participant is still on study therapy) should also be performed at the 
regular study visit. It is very important to ensure that all procedures, as outlined in the Study 
SoA (Section 1.3), are performed at the CMV Infection Visit immediately prior to the
initiation of treatment of CMV infection/disease. Most importantly, a confirmatory plasma 
sample for CMV DNA PCR testing, a plasma sample for CMV viral resistance testing (note: 
once the CMV Infection Visit occurs, another plasma sample for CMV viral resistance 
testing should be collected at the next scheduled visit; see Section 8.2.2), and blood sample 
for CMV-specific T cell responses using the QuantiFERON-CMV assay should be collected 
at this visit and sent to the central laboratory. Thereafter, the participant should be treated
according to the local SOC (outside the context of the study). These participants will
complete all remaining treatment-period scheduled visits through Week 28, as well as all
remaining scheduled visits through Week 52, as outlined in the SoA (Section 1.3). All
scheduled study visits will be completed regardless of when cessation of study treatment
occurs. All specified procedures through Week 28 will be completed for these participants
with the exception of study therapy administration, PK assessments, and study medication
diary review.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
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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, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If 
the participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA. 
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
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•
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained from 
the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 329.5 mL (See Appendix 10).  When a participant repeats CMV Infection 
Visit and/or Early Discontinuation Visit, the amount of blood may exceed the maximum 
amount.
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 each their legally 
acceptable representative) prior to participating in a clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant 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 
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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.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
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 on Day 1 
(allocation).
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/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at screening.
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, and record prior medication taken by the participant 
within 30 days before first dose of study medication.
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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 administered for treatment of CMV disease or for 
initiation of anti-CMV treatment and all drug/biologic therapies used to prevent/treat acute 
and/or chronic rejection should be recorded at every visit through Week 52.  During the 
follow-up period through Week 52, concomitant medication review and collection is limited 
to the above and all antimicrobials (antibacterials, antifungals, antiparasite agents, and 
antivirals), oral hypoglycemic agents, insulin, granulocyte colony-stimulating factor (G-
CSF), and immunosuppressant agents.
8.1.6
Kidney Transplant/Dialysis Details Review
All relevant data about the kidney transplant will be collected on Day 1 (at allocation).  This 
includes details regarding the donor and recipient CMV IgG serostatus, transplant type 
(donation from deceased or living donor [living related or living unrelated as determined by 
the site]), the ex-vivo time, the date and the duration of the transplant surgery, and any anti 
lymphocyte therapy prior to transplant.
Details regarding each dialysis or plasmapheresis session occurring between transplant and 
end of study will be collected.
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 prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
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/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
The first dose of study treatment will be administered at the trial site on Day 1 after 
allocation.  Subsequent oral dosing will be performed by the participant.  
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, 
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or a malabsorptive condition), a LET IV formulation is available for those participants. The 
LET IV formulation dosing volume will be 250 mL and the duration of infusion will be 60 
minutes.  The infusion will be administered through a sterile in-line filter. Refer to the 
Pharmacy Manual for details on the filters that may be used. 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 8.12.5.1).  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 at approximately the same time each day for the 
duration of the study (ie, once daily for LET).  Tablets are to be swallowed whole (ie, no 
crushing or chewing is allowed).  Study intervention may be taken 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 of study medication, the missed dose should be taken as soon as 
possible during the same day.  If more than 18 hours have gone by after the regular dosing 
time, then the missed 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.
Participants with post-allocation CrCl ≤10 mL/min or who require dialysis or plasmapheresis 
after allocation will have their study medication interrupted, but could resume medication 
once CrCl increases to >10 mL/min and dialysis or plasmapheresis is no longer required 
provided they had not missed >7 consecutive days of study medication.
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8.1.9.2
Dose Modifications when LET is Co-administered with CsA
Participants who are not on CsA will receive LET 480 mg QD given orally (two 240 mg 
tablets).  Participants who are receiving concomitant CsA will receive oral formulation of 
LET 240 mg QD.  Participants requiring IV formulation of LET who are not on CsA will 
receive 480 mg QD of IV LET.  Participants requiring the IV formulation of LET who are on 
concomitant CsA will receive 240 mg QD of IV LET (Section 6.1).
If CsA is initiated after starting study intervention at an oral dose of LET 480 mg QD, the 
next dose of oral LET (administered up to 24 hours later) should be adjusted to 240 mg QD. 
If CsA is initiated after starting study intervention at an IV dose of LET 480 mg QD, the dose 
of IV LET (next administered up to 24 hours later and with continued need for IV 
formulation of LET) should be adjusted to 240 mg QD. 
If CsA is discontinued during the study intervention period for more than 3 consecutive days, 
the dose of LET (next administered up to 24 hours later) should be increased from 240 mg to 
480 mg QD.  
8.1.9.3
Study Medication Diary and Recording the Study Intervention
For participants receiving oral tablets, 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 subject’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 prior to 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 8.12.4.
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation Visit should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4 and visit requirements as 
outlined in Section 1.3 (SoA).
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the principal investigator for the main study. If medical records for the 
main study are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@msd.com). Subsequently, the participant's consent 
for FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator 
confirming the withdrawal. It is the responsibility of the investigator to inform the participant 
of completion of withdrawal. Any analyses in progress at the time of request for withdrawal 
or already performed prior to the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.12
Domiciling
For participants who will undergo intensive PK sampling, the investigator should make 
arrangements such that all PK sampling at specified timepoints (ie, up to the last scheduled 
timepoint of 24 hours post-dose) will be performed as scheduled.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
8.2.1
CMV Disease/Infection Assessment
8.2.1.1
Assessment of CMV Disease
CMV disease will be assessed at every visit from screening through Week 52.  Diagnostic 
criteria for the evaluation of CMV disease are outlined in Appendix 8.  If CMV Disease is 
suspected and anti-CMV therapy is started, site should perform the CMV Infection Visit 
instead of the scheduled visit assessments (see Sections 1.3 [SoA] and 8.12.5.1)  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.
8.2.1.2
Assessment of CMV Infection
Protocol-specified CMV DNA PCR assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
Protocol-specified CMV DNA PCR samples will be drawn at prespecified clinical visits:  at 
allocation, Week 2, and Week 4; thereafter, samples must be collected on a monthly basis up 
to Week 52 and sent to the central laboratory, as indicated in the Study SoA (Section 1.3).
The central laboratory CMV DNA PCR results will not be provided to the investigator.
Central laboratory based CMV DNA levels will be retrospectively analyzed at the end of the 
study.  
Locally performed CMV DNA PCR assay or CMV antigenemia assay
In this study, the monitoring of CMV DNA levels or CMV antigenemia for the clinical 
management of participants may be performed locally at the discretion of the site investigator 
and/or clinical management team.  When the local CMV DNA or antigenemia testing is 
conducted, every effort should be made to draw samples on the same day as the central 
testing.  The protocol-specified CMV DNA PCR assay sample should be collected per 
protocol even if the local CMV DNA PCR or CMV antigenemia sample is drawn at the same 
visit. When a CMV DNA level and/or antigenemia is measured locally, it is mandatory that 
the results of locally performed CMV DNA PCR assay or antigenemia is entered to the CRF.  
There is no protocol-specified threshold for stopping CMV prophylaxis (if applicable) and 
initiating anti-CMV treatment.
If a clinical decision is made by the investigator to start anti-CMV treatment based on 
positive results on locally performed CMV DNA PCR or CMV antigenemia, a CMV 
Infection Visit will be completed prior to initiating anti-CMV treatment. 
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Note:  It is mandatory to collect a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (ie, on the day of) initiating anti-CMV 
treatment.  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 initiation of 
anti-CMV treatment (preferably within 48-72 hours).
Locally performed CMV DNA PCR assay or CMV antigenemia assay results will be 
retrospectively analyzed at the end of the study.  
8.2.2
CMV Viral Resistance Testing
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
CMV viral resistance can contribute to clinical failure, ie, development of CMV 
infection/disease, during LET prophylaxis.  LET resistance mutations in the CMV UL56, 
UL89 and UL51 genes (which encode subunits of the CMV DNA terminase complex) have 
been identified in in vitro viral cultures and UL56 mutations have been detected in 
participants who received LET and experienced virologic breakthrough.
To better understand the impact of genotypic variants on the susceptibility of CMV to LET, 
CMV viral resistance testing will be performed using plasma derived from blood collected at 
the CMV Infection Visit (and the following visit if applicable) from participants if any of the 
following occurs:  (1) any discontinuation of study treatment in response to suspected or 
confirmed CMV disease; (2) any discontinuation of study treatment and initiation of anti-
CMV treatment; or (3) initiation of anti-CMV treatment during the follow-up period (see 
Section 1.3).  Once the CMV Infection Visit occurs, another plasma sample for CMV viral 
resistance testing should be collected at the next scheduled visit.  Among these participants, a 
final sample for CMV viral resistance testing will also be collected at Week 52.  Plasma 
samples may also be evaluated for the presence of known VGCV resistance mutations or 
other newly identified CMV mutations associated with LET resistance. 
Analysis of genotypic variant will entail a variety of techniques that may include population 
sequencing and/or next generation sequencing.  Additionally, phenotyping by marker transfer 
and investigational assays may be employed to distinguish LET resistance mutations from 
variants that have no impact on susceptibility to LET.  CMV viral resistance testing may also 
be performed on leftover samples from other study-related testing.
8.2.3
CMV Serology (IgG) Testing
For each participant, the conduct of CMV serology (IgG) testing used at the site to determine 
the recipient CMV serostatus as part of pre-transplant evaluation (ie, within 90 days of 
allocation and/or as routine pre-transplant clinical management) will be as per local SOC for 
kidney transplantation recipients.  The CMV serology assay for the kidney donor is expected 
to be performed at the medical facility at which the organ is harvested from the donor and as 
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per local SOC for the assessment of the kidney donor.  Available CMV serology (IgG) 
testing data for the kidney donor and recipient will be obtained from the participant’s chart. 
8.2.4
QuantiFERON-CMV Assay
CMV-specific T-cell responses will be measured using the QuantiFERON-CMV assay 
[Becke, S., et al 2010] [Goldner, T., et al 2011] at various time points through Week 52 post-
transplant using plasma samples.  The central laboratory based QuantiFERON-CMV assay 
results will not be shared with the respective site investigators.
8.2.5
New Onset Diabetes Mellitus After Transplant (NODAT)
Participants developing NODAT (as identified by the site and also as identified by a 
confirmatory analysis) will be analyzed (Section 9).  Site determination of participants with 
NODAT will be the primary method of identifying participants with NODAT and the site 
will identify and document which of the three WHO/ADA criteria for diabetes mellitus (See 
Section 4.2.1.2.2) and an additional category - “other” as identified and annotated by the 
investigator - has been fulfilled.  Among participants identified by the site as developing 
NODAT, concomitant medications used during the study will be reviewed for use of insulin 
or an oral hypoglycemic agent between Week 4 and Week 52 to determine the method of 
NODAT management used by the site during the study [Bayer, N. D., et al 2010].
A confirmatory analysis for NODAT will be performed on the participants identified by the 
investigator as developing NODAT during the study as well as screening for cases of 
NODAT not identified by the investigator by identifying participants who fulfill one or more 
of the following:
1. Fasting blood glucose of ≥126 mg/dL (if available/specified as fasting blood glucose, 
since the protocol does not require that blood samples for chemistries be collected after 
fasting; it is expected that participants who fulfill the WHO/ADA NODAT Criterion 1, 
see Section 4.2.1.2.2, will also fulfill this confirmatory criterion).
AND/OR
2. AE of diabetes mellitus (for those who developed this AE during the AE reporting 
period).
AND/OR
3. Use of one or more hypoglycemic agents after allocation (ie, such hypoglycemic agents 
that are not listed as prior medications and newly identified as a concomitant medication 
during the study).
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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 pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 10.10
(Appendix 10).
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator as per institutional 
standard at the screening visit, Day 1 (allocation), and Week 28. 
After Day 1 (allocation), the physical examination does not need to be performed at every 
visit except for Week 28; a targeted physical examination should be performed only if a 
participant has any complaints.  The timing of physical examinations is indicated in the 
Study SoA (Section 1.3).
Height and weight will be measured and recorded per the SoA.
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:
•
Pulse rate, blood pressure, and body temperature (oral preferred; see below).
Note: Oral temperatures should be taken, but if oral is not possible, tympanic, rectal, 
or axillary temperatures may be taken.
•
Participants should be resting for at least 5 minutes prior to measurement of vital 
signs
8.3.3
Electrocardiograms
•
Single 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee as outlined in the SoA (Section 1.3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
Note: ECG will be performed if CMV Infection Visit or Early Discontinuation Visit 
will occur at Week 28.
•
Participants should be resting for at least 10 minutes prior to having ECG readings 
obtained.
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8.3.4
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 case report 
form (CRF). The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the 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.
8.3.5
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 local (or central) 
laboratory parameters (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 central or local laboratory parameters (total bilirubin, albumin, and INR) obtained 
at the corresponding scheduled study visit, or up to four weeks 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).
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8.3.6
Confirmation of Contraception (WOCBP only)
Throughout the screening and treatment periods, precaution must be taken to avoid 
pregnancy in WOCBP.  Confirmation must be obtained and documented by site personnel 
that WOCBP are using acceptable methods of contraception (see Appendix 5).  This 
assessment must be documented in the participant's study chart at each specified visit.
8.3.7
Adverse Events Monitoring
Adverse event monitoring will include the collection of all AEs and SAEs from the time 
informed consent is signed through 14 days following the last dose of study treatment in all 
participants.  Thereafter, any SAEs related to study medication will be collected through 
Week 52.
Refer to Section 8.4 for further details.
Infusion-Site Adverse Events for Participants Administered IV Study Intervention
Safety monitoring of infusion-site AEs will be performed by the evaluation of the site of 
infusion during and at the end of IV study intervention.  Events will be entered on the AEs 
electronic case report form (eCRF).  
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, 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/randomization through 14 days following cessation 
of study intervention, all AEs, SAEs, and other reportable safety events must be reported by 
the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require 
regulatory reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (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
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
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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, events of clinical interest (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 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
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) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of 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.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints (Health Outcomes) including re-hospitalizations (including 
rehospitalizations for CMV infection/disease), all-cause mortality, NODAT, biopsy-proven 
acute renal graft rejections, graft loss, use of G-CSF and select OIs (see Section 8.11 for a 
complete list) must be collected throughout the study (ie, during both treatment and follow-
up).  From the time of allocation, through 14 days following cessation of treatment, these 
events must be reported as described in Section 8.4.1.  Efficacy endpoints (Health Outcomes) 
that occur after 14 days following cessation of treatment must continue to be assessed for 
seriousness and causality, however, they must only be reported within 24 hours as AEs if 
they are assessed as serious and there is evidence to suggest a causal relationship between the 
drug and the AE. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon 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.
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8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma Letermovir
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.  PK samples should not be collected in participants after 
discontinuation of study intervention.
Blood collection for trough PK (all participants)
Plasma samples for trough PK will be collected in all participants.  A single sample per 
subject will be collected pre-dose (within 0-2 hours prior to dose) at each visit of the 
treatment period and at CMV Infection/early discontinuation visit (if during treatment 
period).
Blood collection for Week 1 intensive PK (all participants)
Plasma samples for Week 1 intensive PK will be collected at the following timepoints at any 
time between Study Day 6-10, IF the participant is treated with the same dose formulation
(IV or PO) between Day 1 and the day of Week 1 intensive PK:  
•
Pre dose (within 0-2 hours prior to dose)
•
1 hour (± 10 min) following oral administration (or within 10 min after infusion 
completion, when given IV)
•
2.5 hours following oral/start of IV administration (± 30 min)
•
5 hours following oral/start of IV administration (± 30 min)
•
8 hours following oral/start of IV administration (range of 6-10 hours)
•
24 hours following oral/ start of IV administration (range of 22-24 hours; 0-2 hours 
prior to next day’s dose)
If there is a switch in dose formulation (IV or PO) between Day 1 and the day of Week 1 
intensive PK, Week 1 intensive PK will be performed on any day starting from the 6th
consecutive days of IV or PO therapy until the 10th day after dose formulation switch (prior 
to and after the study dose on 6th -10th day after dose formulation switch).  In this case, Week 
1 intensive PK may be performed beyond Study Day 6-10.
Blood collection for additional intensive PK (participants with dose formulation switch)
Additionally, plasma samples for intensive PK will be collected for participants with dose 
formulation switch.  
<Dose formulation switch from PO to IV>
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If Week 1 intensive PK is performed after 6 or more consecutive days of PO therapy and the 
dose formulation is then switched from PO to IV, ALL participants who receives 6 or more 
consecutive days of IV dosing will have additional intensive PK.  No more than ONCE 
during the entire study, regardless of how many times the IV therapy criterion is fulfilled 
during the study.  The timing of the intensive PK collection will be on any day starting from 
the 6th consecutive day of IV therapy until the 10th day after switched to IV formulation at the 
following timepoints prior to and after start of study medication infusion:
•
Pre dose (within 0-2 hours prior to dose)
•
1 hour (ie, within 10 min after infusion completion)
•
2.5 hours following the start of IV administration (± 30 min)
•
5 hours following the start of IV administration (± 30 min)
•
8 hours following the start of IV administration (range of 6-10 hours)
•
24 hours following the start of IV administration (range of 22-24 hours; 0-2 hours 
prior to next day’s dose)
<Dose formulation switch from IV to PO >
If Week 1 intensive PK is performed after 6 or more consecutive days of IV therapy and the 
dose formulation is switched from IV to PO, participants who receives 6 or more consecutive 
days of PO dosing will have additional intensive PK, no more than ONCE during the entire 
study.  Additional intensive PK after 6 or more consecutive days of PO therapy will be 
performed if required sample collection is feasible (eg, the participant is in the hospital).  The 
timing of the intensive PK collection will be on any day starting from the 6th consecutive day 
of PO therapy until the 10th day after switched to PO formulation at the following timepoints 
prior to and after start of study medication:
•
Pre dose (within 0-2 hours prior to dose)
•
1 hour (± 10 min) following oral administration 
•
2.5 hours following oral administration (± 30 min)
•
5 hours following oral administration (± 30 min)
•
8 hours following oral administration (range of 6-10 hours)
•
24 hours following oral administration (range of 22-24 hours; 0-2 hours prior to next 
day’s dose)
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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8.8
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
•
Leftover main study plasma from CMV DNA PCR stored for future research
•
Leftover main study plasma from CMV viral resistance stored for future research
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for SLCO1B1 (OATP1B1) and UGT1A1
genotyping and for planned analysis of the association between genetic variants in DNA and 
drug response. If the IRB/IEC does not approve of the planned analysis of the association 
between DNA variation and drug response, or if there is a local law or regulation prohibiting 
the same, data analysis will be limited to SLCO1B1 (OATP1B1) and UGT1A1. Leftover 
extracted DNA will be stored for FBR if the participant provides documented informed 
consent for FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Health Outcomes Assessment
Health Outcomes assessed for this study will include collection of re-hospitalizations 
(including re-hospitalizations for CMV infection/disease), all-cause mortality, NODAT, 
select OIs, biopsy-proven acute renal graft rejections, graft loss, and use of G-CSF.  These 
outcomes will be collected via electronic CRF as described in the SoA (Section 1.3).  Select 
OIs [Kidney Disease: Improving Global Outcomes Transplant Work Group 2009] [Trofe-
Clark, J. and Sawinski, D. 2016] are as follows:
•
Pneumocystis jirovecii pneumonia
•
BK virus infection
•
Human polyomavirus (non-BK virus) infection
•
HSV infection (including superficial, eg, oral HSV infection, and systemic HSV 
infection)
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•
VZV infection (including primary varicella zoster infection and herpes zoster [including 
uncomplicated and disseminated forms])
•
Oral candidiasis
•
Candidiasis (ie, non-oral Candida infection)
•
Mycobacterium tuberculosis infection
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Screening of potentially eligible participants may begin on as early as 1 day before 
transplantation for participants receiving a kidney from a deceased donor and up to 14 days 
prior to (including the day of transplantation [ie, prior to transplantation]) transplantation for 
participants receiving a kidney from a living donor.  All screening procedures listed under 
Visit 1 of the Study SoA (Section 1.3) will be performed and must be completed by one day 
prior to Day 1.  Participants will be allocated within 7 days post-transplant.  The informed 
consent must be obtained before any study-specific procedure is performed.  It is acceptable 
that the date of informed consent administration is earlier than the day screening procedures 
are performed.  However, once informed consent is obtained, AE reporting must be 
conducted according to Section 8.3.7.
Potential participants will be evaluated to determine if they fulfill the Inclusion/Exclusion 
entry requirements as described in Sections 5.1 and 5.2.  The investigator will discuss with 
each potential participant the nature of the study and its requirements/restrictions.  All 
screening procedures listed under Visit 1 of the Study SoA (Section 1.3) will be performed.  
Participants will be instructed about the restrictions for concomitant medications, as noted in 
Section 6.5.  WOCBP participants will be instructed that they are required to use birth 
control, as described in Appendix 5, starting from the time of consent through 28 days after 
the last dose of study intervention.  
For screening purposes, values from the participant’s chart within 14 days prior to screening 
for required chemistry, hematology, coagulation, and urinalysis tests are acceptable.  If not 
available, this testing may be performed by the central laboratory or locally per SOC (see 
Appendix 2). 
HIV antibody test results documented at any time prior to allocation of the participant will be 
acceptable; a copy of this HIV report must be available (See Exclusion Criterion 11 in 
Section 5.2).  If documentation of a previous HIV test is not available, the HIV antibody test 
must be conducted using the central or local laboratory.  Hepatitis B and hepatitis C 
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screening should only be performed if not previously documented within the last 90 days.  If 
HCV-Ab is positive, HCV RNA PCR results should be provided (or, if not available, HCV 
RNA PCR testing will be performed by the central or local laboratory).
On the day of allocation, eligibility for enrollment into the study should be confirmed.  
Presence of CMV disease in the screening period will be assessed according to Appendix 8.
Rescreening
Those participants who meet any of the laboratory exclusion criteria in Table 2 and/or Child-
Pugh classification in Exclusion Criterion 9 at screening or whose kidney transplant is 
delayed may be rescreened for study eligibility.  To reconfirm the participant’s eligibility, all 
pre-study evaluations should be repeated, after approval from the Sponsor.
8.12.2
Treatment Period
Study intervention will begin within 7 days post-transplant and will continue through Week 
28.  The Day 1 Visit (as shown in the Study SoA, Section 1.3) will be the day the participant 
is allocated and study intervention is initiated (ie, Day 1).
Study visits in the treatment period will occur at Week 1, every two weeks from Week 2 
through Week 12, and every 4 weeks from Week 16 through Week 28 (Section 1.3).  At 
these scheduled visits, the investigator will perform an assessment of CMV disease, and 
participants’ blood samples will be collected at scheduled timepoints (see Study SoA, 
Section 1.3) for CMV DNA PCR testing by the central laboratory in order to detect CMV 
DNAemia.  The central laboratory CMV DNA PCR results will not be provided to the 
investigator but will be analyzed at the end of the study.  Safety will also be evaluated while 
participants are on study intervention.  Note that serum creatinine screening intervals should 
occur according to the local SOC (outside the context of the study) as part of a participant’s 
SOC post-kidney transplantation.
8.12.2.1
Day 1 Visit
Day 1 procedures/assessments listed in the Study SoA (Section 1.3) must be performed prior 
to initiation of study intervention.
For WOCBP participants, a urine pregnancy test will be performed at the site prior to the 
initiation of study intervention.  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.  A 
serum pregnancy test (within 72 hours before the first dose of study intervention) may be 
performed on Day 1 for those WOCBP participants who are anuric and/or unable to provide 
urine. 
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8.12.2.2
Study Intervention Administration
Within 7 days post transplant, following completion of the Day 1 procedures/assessments 
and confirmation of eligibility (including availability of results from samples for CrCl and 
liver function tests), the participant will be allocated.  Sites should not allocate the participant 
for study intervention administration until the participant has met all eligibility criteria for the 
study and is ready to receive the first dose of LET on Day 1.  The site pharmacist or study 
coordinator will select appropriate bottle(s) or vial(s) of study intervention to be 
administered.
The first dose of study intervention will be administered at the trial site with monitoring by 
investigative site personnel at the Day 1 Visit (note: after pre-dose PK sample collection on 
Day 1).  Thereafter, at each scheduled visit during treatment period, participants will visit the 
trial site before taking the study intervention.  The dose of study intervention will be 
administered appropriately at the trial site under the control of investigative site personnel.
For participants who cannot swallow and/or have 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.  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 (See Section 8.1.9).
After Day 1, study intervention will continue through Week 28, with the primary intent of 
preventing CMV disease/infection.
The participant will be instructed in the use of the Study Medication Diary to record the 
number of tablets of study intervention taken during the study treatment period.  IV study 
intervention will be recorded by the site pharmacist or study personnel in the CRF.
8.12.3
Follow-up Period
After completion of study therapy at Week 28, participants will continue to be followed for 
efficacy and safety assessment, and complete all remaining visits through Week 52.  
Information will continue to be collected for (1) re-hospitalizations (including re-
hospitalizations for CMV infection/disease), (2) all-cause mortality, (3) NODAT, (4) select 
OIs, (5) biopsy-proven acute renal graft rejections and graft loss, and (6) use of G-CSF.
During the follow-up period, samples for CMV DNA PCR should be sent to the central 
laboratory as per the Study SoA (Section 1.3).
8.12.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study medication early (ie, prior to Week 28) due to any reason
will complete all remaining treatment period visits through Week 28 as well as all remaining 
follow-up visits through Week 52 as outlined in the SoA (Section 1.3).  All scheduled study 
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visits will be completed regardless of when cessation of study treatment occurs.  All 
specified procedures will be completed for these participants during the treatment period 
(with the exception of study intervention administration, PK assessments, and study 
medication diary review) and in the follow-up period as outlined in the SoA (Section 1.3).
8.12.5
CMV Infection or Early Discontinuation Visit
8.12.5.1
CMV Infection Visit
The CMV Infection Visit will be performed if any of the following occurs: (1) any 
discontinuation of study treatment in response to suspected or confirmed CMV disease; 
(2) any discontinuation of study treatment and initiation of CMV treatment (excluding 
initiation of CMV prophylaxis following discontinuation of study treatment for non-CMV 
adverse events); or (3) initiation of CMV treatment during the follow-up period (see Section 
1.3 [SoA]).  
During study treatment period
If CMV disease is suspected or confirmed by the investigator or a clinical decision is made 
by the investigator to stop study treatment and start anti-CMV treatment based on positive 
results on locally performed CMV DNA PCR or CMV antigenemia 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 and a CMV viral 
resistance sample; see Section 1.3) will be completed prior to initiating anti-CMV treatment
as an SOC for CMV disease/infection, which may be started at the investigator’s discretion.  
These participants will complete all remaining treatment-period visits through Week 28 as 
well as all remaining visits through Week 52 as outlined in the Section 1.3 (SoA).  All 
specified procedures through Week 28 will be completed for these participants with the 
exception of study intervention administration, PK assessments, 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 
SOC treatment for CMV Disease/Infection for up to 7 days (inclusive) before the 
participant is permanently discontinued from study treatment (but remains in the 
study).  If within the 7 day interval, CMV Disease/Infection 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 SOC treatment for CMV Disease 
and resume study treatment.
During follow-up period
If CMV disease is suspected or confirmed by the investigator or a clinical decision is made 
by the investigator to start anti-CMV treatment based on positive results on locally 
performed CMV DNA PCR or CMV antigenemia during the post-treatment follow-up period 
(ie, after completion or early discontinuation of study intervention):  CMV Infection Visit 
(including collection of CMV DNA PCR and a CMV viral resistance sample; see Section 
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1.3) will be completed prior to initiating anti-CMV treatment as an SOC for CMV 
disease/infection, which may be started at the investigator’s discretion.  Participants may be 
started on SOC therapy for CMV disease/infection at the investigator’s discretion and will 
complete all remaining follow-up visits (through Week 52).  See Section 1.3 (SoA) for 
procedures performed at the CMV Infection Visit.
Note:  It is mandatory to collect a confirmatory plasma sample for CMV DNA PCR testing at 
the central laboratory immediately prior to (ie, on the day of) initiating treatment for CMV 
disease/infection in ALL instances.  In the event that the confirmatory result obtained on the 
day of initiation of anti-CMV treatment 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 treatment for CMV disease/infection (preferably within 48-72 hours; Section 
8.2.1).
During the course of the study, a participant may undergo ≥1 CMV Infection Visit at the 
discretion of the investigator.
8.12.5.2
Early Discontinuation Visit
Early Discontinuation Visit will be performed when the participants discontinue study 
intervention or prematurely discontinue the study.
Study Intervention Discontinuation (During study treatment period)
Participants who discontinue study therapy prior to the last scheduled treatment visit for 
reasons other than CMV disease/infection should have an Early Discontinuation Visit and 
then complete all remaining treatment-period visits through Week 28, as well as all 
remaining visits through Week 52, as outlined in the SoA (Section 1.3).  All specified 
procedures through Week 28 will be completed for these participants with the exception of 
study therapy administration, PK assessments, and study medication diary review.  All 
scheduled study visits will be completed regardless of when cessation of study treatment 
occurs.
Early Study Discontinuation (During study treatment period or follow-up period)
The Early Discontinuation Visit will also be performed for all participants who prematurely 
discontinue the study prior to Week 52.  It is very important to ensure that all procedures, as 
outlined in the Study SoA (Section 1.3), are performed in such participants at this visit prior 
to discontinuing the participant from the study.  Most importantly, a plasma sample for CMV 
DNA PCR testing at the central laboratory should be collected at this visit.
During the course of the study, a participant may undergo Early Discontinuation Visit twice 
(ie, Study Intervention Discontinuation and Early Study Discontinuation).
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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, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.  
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan (SAP) 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 Safety, Efficacy and Pharmacokinetics of MK-8228 
(Letermovir) for the Prevention of Human Cytomegalovirus 
(CMV) Infection and Disease in Adult Japanese Kidney 
Transplant Recipients
Treatment Assignment
All participants will be allocated to LET treatment group.
Analysis Populations
Efficacy: Full Analysis Set (FAS) population.  
Safety: All Participants as Treated (APaT) population
Primary Endpoint

Adverse events (AEs)

Discontinuing study treatment due to AEs
Statistical Methods for 
Key Safety Analyses
The Safety analysis will be based on the APaT population. AEs 
will be summarized by the number and percentage of the 
subjects who experienced respective events. Change from 
baseline in laboratory tests, vital signs and ECG will be 
summarized by descriptive statistics.
Statistical Methods for 
Key Efficacy Analyses
The efficacy analysis will be based on the FAS population. The 
following proportion and 95% confidence interval (CI) will be 
provided by timepoint.

Adjudicated CMV disease or anti-CMV treatment based on 
1) positive results on CMV antigenemia (local) or 2) 
quantifiable CMV DNAemia (local)

Adjudicated CMV disease

Quantifiable CMV DNAemia (central)
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Interim Analyses
No interim analysis is planned in this trial.
Multiplicity
No multiplicity adjustment is planned in this trial.
Sample Size and Power The planned sample size is 20 participants with at least 10 being
D+/R−.
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 trial is being conducted as an open-label study, ie, subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned. First database lock will be executed when all results of 
letermovir plasma concentrations become available for population PK and exposure-safety 
analyses to submit data to regulatory agencies. The results of population PK and exposure-
safety analyses will be reported in a Modeling and Simulation report. Final database lock will 
be executed at the end of the study for safety and efficacy analyses. Additional database 
lock(s) may be conducted if needed.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Safety and efficacy endpoints that will be evaluated are listed below.
9.4.1
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs and ECG.
9.4.2
Efficacy Endpoints
1. Adjudicated CMV disease or anti-CMV treatment based on 1) positive results on 
CMV antigenemia (local) or 2) quantifiable CMV DNAemia (local) through Week 28 
and Week 52 post-transplant.
Adjudicated CMV disease is defined as the presence of either CMV end-organ 
disease or CMV syndrome and will be confirmed by an independent CAC.  Only 
CAC-confirmed (“adjudicated”) cases will be included in number of participants who 
met the endpoint.  Investigator-assessed cases which are not confirmed by the CAC 
will not be included.  Concordance/discordance between CAC and investigator 
assessment will be summarized.
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Anti-CMV treatment based on 1) positive results on CMV antigenemia (local) or 2) 
quantifiable CMV DNAemia (local) is defined as initiation of approved anti-CMV
agents (GCV, VGCV and/or foscarnet) based on at least one positive cell on CMV 
antigenemia and/or numeric value (not including the result of “Detected but not 
quantifiable”) of CMV DNA PCR assay performed locally. CMV DNA test and/or 
CMV antigenemia results obtained from an investigator site-specific laboratory will 
be used to determine CMV infection.  
2. Adjudicated CMV disease through Week 28 and Week 52 post-transplant.
3. Quantifiable CMV DNAemia (central) through Week 28 and Week 52 post-
transplant.
Quantifiable CMV DNAemia (central) is defined as any case with a numeric value or 
>910,000,000 (not including reporting of PCR results as “detected, not quantifiable”) 
using the Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which 
will be performed by the central laboratory.  CMV DNA test results obtained from an 
investigator site-specific laboratory will not be used to determine quantifiable CMV 
DNAemia (central).  Quantifiable CMV DNAemia may be considered as a subset of 
CMV infection, which is defined as virus isolation or detection of viral proteins 
(antigens) or nucleic acid in any body fluid or tissue specimen. 
9.4.3
Exploratory endpoints
1. Allograft dysfunction and/or rejection through 28 weeks post-transplant and 52 weeks 
post-transplant
a.
A ≥20% decline in post-transplant eGFR (using Modification of Diet in Renal 
Disease [MDRD] formula) from 4 weeks post-transplant (baseline) through 28 
weeks post-transplant and 52 weeks post-transplant
b. A biopsy-proven acute renal graft rejection through 28 weeks post-transplant and 
52 weeks post-transplant
c.
Graft loss through 28 weeks post-transplant and 52 weeks post-transplant
2. NODAT through 28 weeks post-transplant and 52 weeks post-transplant
Of the participants identified by the investigator as developing NODAT during the 
study, the study team will perform a confirmatory analysis of NODAT.
3. Selected health outcomes (in addition to NODAT, see above) as follows:
a.
All-cause mortality through 28 weeks post-transplant and 52 weeks post-
transplant
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b. All re-hospitalizations (following initial hospital discharge) and re-
hospitalizations for CMV infection/disease through 28 weeks post-transplant and 
52 weeks post-transplant
c.
Select OIs through 28 weeks post-transplant and 52 weeks post-transplant 
d. More than one use of any G-CSF within any consecutive 30-day period beginning 
on Day 1 of treatment through the end of the treatment period.
4. Antiviral resistance to LET in prophylaxis failures through 52 weeks post-transplant
5. CMV-specific T cell responses (positive, indeterminate, or negative) as measured by 
the release of γ-interferon using the QuantiFERON-CMV assay.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study.  The APaT 
population consists of all subjects 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 each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
9.5.2
Efficacy Analysis Populations
The FAS population will serve as the population for the analysis of efficacy data in this 
study. The FAS population consists of all subjects who:

received at least one dose of study treatment

D+/R−, D+/R+ or D−/R+

No detectable CMV DNA (measured by central laboratory) on Day 1
9.6
Statistical Methods
9.6.1
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 through the end of the treatment period. Drug-
related SAEs which are collected throughout the study will also be assessed through Week 52.
AEs, study drug discontinuation due to AEs and other safety events will be summarized 
using the number and percentage of the subjects who experienced respective events. Change 
from baseline in laboratory tests, vital signs and ECG at respective timepoints will be 
summarized using descriptive statistics.  Baseline is defined as the last available 
measurement prior to enrollment.
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9.6.2
Statistical Methods for Efficacy Analyses
For all binary efficacy endpoints, the proportion and corresponding 95% CI will be provided 
by timepoint.  The calculation is based on the exact binomial method proposed by Clopper 
and Pearson (1934). Continuous efficacy measurement will be summarized descriptively.
The results will be provided by all participants, D+/R−and R+. Methods related to 
exploratory objectives will be described in the sSAP.
9.6.2.1
Missing Data Handling
There are two types of missing values:

Intermittent missing values due to a missed or skipped visit.  This applies only to 
those endpoints evaluated prior to 52 weeks post-transplant.  Participants who had 
missing information at the end of the trial are monotone missing.

Monotone (non-intermittent) missing due to premature discontinuation from the study 
for any reason.
Table 6 provides an approach to handle of missing values.
Table 6
Approach to Handle Missing Values
Approach
Intermittent Missing
Monotone Missing 
Observed 
Failure
Excluded
No failure
NC = F
Failure
Failure
F = Failure; NC = Non Completer
The primary missing data approach will be Observed Failure (OF) approach. NC = F 
approach will be used for supportive analyses.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The number and percentage of participants screened and allocated, and the primary reasons 
for screening failure, and discontinuation will be displayed.  Demographic variables (eg, age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical 
tables.
9.6.3.2
Pharmacokinetic Analyses
The PK data obtained from this study will be used to characterize the PK of LET in Japanese 
kidney transplant recipients. Intensive PK data will be analyzed by non-compartment 
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analysis. Descriptive statistics (number of participants, arithmetic mean, standard deviation, 
coefficient of variance, geometric mean, geometric coefficient of variance, minimum, median 
and maximum) of PK parameters (see Section 4.2.1.3) will be provided. Population PK 
analysis will be conducted, if needed. The prospective details of this population PK analysis 
will be specified in a separate Modeling and Simulation analysis plan.
9.7
Interim Analyses
No interim analysis is planned for the study.
9.8
Multiplicity
No adjustment for multiplicity is planned for the study.
9.9
Sample Size and Power Calculations
A total of 20 participants will be enrolled in the treatment period. The sample size was 
derived based on feasibility of enrollment, in consideration of the limited number of D+/R−
and R+ kidney transplants conducted in Japan.  
If a specific AE is not observed in any of the 20 participants, then the true incidence of that 
event is 11% or less with 90% confidence.
9.10
Subgroup Analyses
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by CMV seropositivity subgroups D+/R−and R+.
9.11
Compliance (Medication Adherence)
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 allocation to the last scheduled 
day for treatment administration for that participant.  For a participant who discontinued from 
the study medication, the “Number of Days Should be on Therapy” is the total number of 
days from allocation to the date of the last dose of study medication. Percent compliance for 
each participant will be calculated using the following formula:
(Number of Days on Therapy / Number of Days Should be on Therapy) x 100.
Summary statistics will be provided on percent compliance for the FAS population. 
9.12
Extent of Exposure
The extent of exposure of study treatment will be evaluated by summary statistics 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 Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data. 
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Clinical Adjudication Committee (CAC)
A Clinical Adjudication Committee (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 
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multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
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, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 will be performed by the central laboratory unless otherwise 
specified within the protocol.

Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is also obtained.  Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered 
into the CRF.

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.

Pregnancy testing 
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined necessary 
by the investigator, to establish the absence of pregnancy at any time during the 
subject's participation in the study.
-
A serum pregnancy test may be performed for those WOCBP participants who are 
anuric and/or unable to provide urine.
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Table 7
Protocol-required Laboratory Assessments
Hematologya
Chemistrya
Urinalysisa
Other
RBC count
Albumin
Blood
HBsAgb
Hematocrit
Alkaline phosphatase
Glucose
HCV-Abb
Hemoglobin
ALT
Protein
Hepatitis C RNA PCRb 
Platelet count
AST
Specific gravity 
HIV antibodyb
WBC count with 
differential:
Bicarbonate
Microscopic examination, 
if abnormal results are 
noted
CMV IgG Antibody
Neutrophils
Calcium
Lymphocytes
Chloride
CMV DNA PCRc
Monocytes
Creatinine
QuantiFERON-CMV Assay
Eosinophils
Glucose
CMV viral resistance testingd
Basophils
Phosphorus
Potassium
Coagulation:  PT/INRa
Sodium
Total Bilirubin  
Urine hCGe
Direct Bilirubin
Serum β hCGe
Indirect Bilirubin
Total protein
Blood Urea Nitrogen
ALT = alanine aminotransferase; AST = aspartate aminotransferase; hCG = human chorionic gonadotropin; CMV = 
cytomegalovirus; HBsAg = Hepatitis B surface antigen; HCV-Ab = Hepatitis C virus antibody; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; INR = International normalized ratio; PCR = polymerase chain 
reaction; PT = prothrombin time; RBC = red blood cell; RNA = ribonucleic acid; SOC = standard of care; WBC = white 
blood cell
a. For screening, values from the participant’s chart within 14 days prior to screening for required chemistry, hematology, 
coagulation, and urinalysis tests are acceptable.  If not available, this testing may be performed by the central laboratory 
or locally per SOC.
b. Hepatitis B, C testing only performed if results not previously documented within 90 days of Day 1.  If HCV-Ab is 
positive, HCV RNA PCR results should be provided (or, if not available, HCV RNA PCR testing will be performed by 
the central or local laboratory).  HIV antibody test results documented at any time prior to allocation of the participant 
will be acceptable; a copy of this HIV report must be available.  If documentation of a previous HIV test is not available, 
the HIV antibody test must be conducted using the central or local laboratory.
c. Protocol-specified CMV DNA PCR testing will be performed by the central laboratory using the Roche COBAS®
AmpliPrep/COBAS TaqMan® (CAP/CTM) System.
d. CMV viral resistance testing to be performed only for participants if any of the following occurs: (1) any discontinuation 
of study treatment in response to suspected or confirmed CMV disease; (2) any discontinuation of study treatment and 
initiation of anti-CMV treatment; or (3) initiation of anti-CMV treatment during the follow-up period.
e. May use local or central laboratory serum pregnancy test if unable to provide urine.
The investigator must document their review of each laboratory safety report.
The central laboratory based CMV DNA PCR and QuantiFERON-CMV assay results will 
not be shared with the respective site investigators.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

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 Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This 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.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the Sponsor’s 
product such as: reliable history, acceptable compliance assessment (pill count, diary, 
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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 Sponsor’s product? 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 Sponsor’s product 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 Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.
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
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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 follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Female Participants
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.

Intrauterine hormone-releasing system (IUS)c,d

Intrauterine device (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 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 contraception
-
Oral

Progestogen-only hormonal contraception
-
Oral
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.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

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)e
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 If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
implants are limited to those which inhibit ovulation
d IUS is a progestin releasing IUD.
e
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but 
not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@msd.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/ 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Definition of CMV Disease
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.

Detection of fungal 
copathogens like 
Aspergillus spp. + 
"halo" sign (radiology) 
indicates fungal, rather 
than CMV pneumonia.a

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.
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CMV 
Disease Type
Probable
Proven
Notes
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.
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.
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CMV 
Disease Type
Probable
Proven
Notes
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
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
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CMV 
Disease Type
Probable
Proven
Notes
CMV 
syndrome
Two or more of the 
following:
1) Fever 38C for at least 
2 days 
2) New or increased 
malaise or new or 
increased fatigueb
3) Leukopenia or 
neutropenia on two 
separate measurements at 
least 24 hours apartc
4) 5% atypical 
lymphocytes
5) Thrombocytopeniad
6) Elevation of ALT or 
AST to 2 × ULN
AND
Evidence of CMV in blood 
by viral isolation, rapid 
culture, antigenemia, or 
nucleic acid testing
N/A
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; PCR = polymerase chain reaction; ULN = upper limit of normal.
a.
The presence of co-pathogens, such as Aspergillus species together with typical radiologic signs of Aspergillus 
pneumonia, would indicate fungal pneumonia, although a role of CMV cannot be conclusively excluded if the criteria 
for CMV disease are otherwise met. It is therefore recommended that studies report separately cases where CMV 
disease is found with or without co-pathogens with details given on the co-pathogens [Ljungman, P., et al 2016].
b.
New or increased malaise (Toxicity Grade 2):  uneasiness or lack of well-being; limiting instrumental Activities of 
Daily Living. New or increased fatigue (Toxicity Grade 3):  fatigue not relieved by rest, limiting self-care Activities of 
Daily Living Toxicity grade according to National Cancer Institute:  Common Terminology Criteria for Adverse 
Events, Version 4.0
c.
Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) 
count of <3500 cells/μL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/μL, or a 
WBC decrease of >20%, if the WBC count prior to the development of clinical symptoms was <4000 cells/μL. The 
corresponding neutrophil counts are <1500 cells/μL or a decrease of >20% if the neutrophil count before the onset of 
symptoms was <1500 cells/μL [Ljungman, P., et al 2016].
d.
Thrombocytopenia defined as a platelet count of <100 000 cells/μL if the platelet count prior to the development of 
clinical symptoms was ≥115 000 cells/μL or a decrease of >20% if the platelet count prior to the development of 
clinical symptoms was <115 000 cells/μL [Ljungman, P., et al 2016]. 
[Ljungman, P., et al 2016] [National Cancer Institute 2009]
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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 
>3.5 g/dL
2.8 – 3.5 g/dL
<2.8 g/dL
INRb
<1.7 
1.7 – 2.3 
>2.3 
INR = international normalized ratio
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.
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: Blood Volume Table
Study Period
Pre-
Treatment
Treatment
Follow-up
CMV Infection 
and/or Early 
Discon Visit
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCR
D1
W1
W2
W4
W6
W8
W10
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Blood Parameter
Approximate Blood Volume (mL)
Hematologya
2
2
2
2
2
2
2
2
2
2
2
2
Chemistrya
7
7
7
7
7
7
7
7
7
7
7
7
Coagulationa
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
1.8
Serum pregnancy Test 
(WOCBP only, if unable 
to provide urine)
2
2
2
2
2
2
2
2
2
2
2
HIV and Hepatitis B and 
C Screenb
11
Blood for Genetic 
Analysis
8.5
CMV DNA PCRc
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
QuantiFERON-CMV 
Assay
3
3
3
3
3
3
CMV Viral Resistance 
Testingd
5
5e
Trough PK and Week 1 
Intensive PK
3
18
3
3
3
3
3
3
3
3
3
3
3
Additional Intensive PK 
for participants with dose 
formulation switch
----------18 (performed at most once during the study; this volume is 
NOT included in the Expected Total volume)-----------
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Study Period
Pre-
Treatment
Treatment
Follow-up
CMV Infection 
and/or Early 
Discon Visit
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Visit Name
SCR
D1
W1
W2
W4
W6
W8
W10
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W52
Expected Total (mL)
35.3
18.8 28.8
7.8
18.8
4.8
18.8
4.8
21.8
18.8
18.8
18.8
21.8
15.8
3
6
3
3
11
31.8
CMV = cytomegalovirus; D = Day; DNA = deoxyribonucleic acid; HCV = hepatitis C virus; HIV = human immunodeficiency virus; PCR = polymerase chain reaction; PK = 
pharmacokinetic; RNA = ribonucleic acid; SCR = screening; SOC = standard of care; W = Week
a.
For screening, values from the participant’s chart within 14 days prior to screening for required chemistry, hematology, and coagulation tests are acceptable.  If not available, 
this testing may be performed by the central laboratory or locally per SOC.
b.
Hepatitis B, C testing only performed if results not previously documented within 90 days of Day 1.  If hepatitis C virus antibody is positive, HCV RNA PCR results should 
be provided (or, if not available, HCV RNA PCR testing will be performed by the central or local laboratory).  HIV antibody test results documented at any time prior to 
allocation of the participant will be acceptable; a copy of this HIV report must be available.  If documentation of a previous HIV test is not available, the HIV antibody test
must be conducted using the central or local laboratory.
c.
Protocol-specified CMV DNA testing will be performed by the central laboratory using the Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) System.
d.
To be performed only for participants who discontinue study treatment due to CMV disease or in whom anti-CMV treatment is started.
e.
A repeat sample should be collected at the next scheduled visit after the CMV Infection Visit.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
American Diabetes Association
AE
Adverse event 
ALT
Alanine aminotransferase
APaT
All Participants as Treated
AST
Aspartate aminotransferase
AUCtau
Area under the concentration-time curve to the end of the dosing period
β-hCG
β-human chorionic gonadotropin
BAL
Bronchoalveolar lavage
BCRP
Breast cancer resistance protein
BID
Twice daily
CAC
Clinical Adjudication Committee
Ceoi
Concentration at the end of infusion
CI
Confidence interval
CLss
Clearance at steady state
CLss/F
Apparent clearance at steady state
Cmax
Maximum concentration
CMV
Cytomegalovirus
CNS
Central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CrCl
Creatinine clearance
CRF
Case Report Form 
CsA
Cyclosporin A
CSR
Clinical Study Report
CSF
Cerebrospinal fluid
CTFG
Clinical Trial Facilitation Group 
Ctrough
Trough concentration
CYP
Cytochrome P450
D
Doner
DB
Dense body
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid 
DNAemia
Detection of DNA in samples of plasma, whole blood, and isolated peripheral blood 
leukocytes or in buffy-coat specimens
ECG
Electrocardiogram 
ECI
Event of clinical interest
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
G-CSF
Granulocyte colony-stimulating factor
GCV
Ganciclovir
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HCV-Ab
Hepatitis C virus antibody
088PBS


PRODUCT: MK-8228
125
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Abbreviation
Expanded Term
HHV
Human herpes virus
HIV
Human immunodeficiency virus
HMG-CoA reductase
Hydroxymethylglutaryl-CoA reductase
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
IND
Investigational New Drug 
INR
International normalized ratio
IRB
Institutional Review Board 
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
KDIGO
Kidney Disease Improves Global Outcomes
LET
Letermovir
LH
Luteinizing hormone
LLOQ
Lower limit of quantification
MDRD
Modification of Diet in Renal Disease
NC = F
Non Completer = Failure
NIMP
Non-Investigational Medicinal Product
NODAT
New onset diabetes mellitus after transplant
NTR
Narrow therapeutic range
OATP
Organic anion-transporting polypeptide
OF
Observed Failure
OI
Opportunistic infection
PCR
Polymerase chain reaction
PET
Pre-emptive therapy
PK
Pharmacokinetic
PO
Orally
PT
Prothrombin time
QD
Once daily
R
Recipient
RNA
Ribonucleic acid
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SCR
Screening
SMD
Study medication diary
SoA
Schedule of activities
SOC
Standard of care
SOT
Solid organ transplant
SUSAR
Suspected unexpected serious adverse reaction
Tmax
Time to reach maximum concentration
Tp
Transplant
ULN
Upper limit of normal
VGCV
Valganciclovir
VZV
Varicella zoster virus
088PBS


PRODUCT: MK-8228
126
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
Abbreviation
Expanded Term
WBC
White blood cell
WHO
World Health Organization
WOCBP
Woman/women of childbearing potential 
088PBS


PRODUCT: MK-8228
127
PROTOCOL/AMENDMENT NO.: 042-03
MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
11
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01-FEB-2022
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MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
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088PBS


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130
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MK-8228-042-03 FINAL PROTOCOL
01-FEB-2022
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088PBS