Clinical trial NCT03443869
Conditions: CMV Disease
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-05-03; Completion date: 2022-04-05
Enrollment: 601 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of letermovir (LET) versus valganciclovir (VGCV) in preventing CMV disease in adult kidney transplant recipients. The primary hypotheses are that LET is non-inferior to VGCV; and if non-inferiority is demonstrated, that LET is superior to VGCV, in preventing CMV disease through 52 weeks post-transplant.

Detailed description:

Arms: arm 1: LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) tablet orally; placebo to VGCV tablet orally once daily; and 400 mg capsule of acyclovir (ACV) orally every 12 hours for 28 weeks arm 2: 900 mg VGCV tablet orally, once daily; placebo to LET tablet orally once daily; and placebo to ACV orally every 12 hours for 28 weeks
Interventions: intervention 1: Letermovir intervention 2: Valganciclovir intervention 3: Acyclovir (ACV) intervention 4: Placebo to ACV intervention 5: Placebo to LET intervention 6: Placebo to VGCV
Intervention descriptions: intervention 1: LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) once daily for 28 weeks intervention 2: 900 mg VGCV tablet orally, once daily for 28 weeks intervention 3: 400 mg over-encapsulated ACV tablet orally, every 12 hours for 28 weeks intervention 4: Over-encapsulated placebo tablet orally, every 12 hours for 28 weeks intervention 5: Placebo to LET tablet orally, once daily for 28 weeks intervention 6: Placebo to VGCV tablet orally, once daily for 28 weeks

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03443869 
Document Date: 
27-Aug-2019
A Phase III, Randomized, Double-Blind, Active Comparator-
Controlled Study to Evaluate the Efficacy and Safety of MK-8228 
(Letermovir) Versus Valganciclovir for the Prevention of Human 
Cytomegalovirus (CMV) Disease in Adult Kidney Transplant
Recipients


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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., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: A Phase III, Randomized, Double-Blind, Active Comparator-Controlled 
Study to Evaluate the Efficacy and Safety of MK-8228 (Letermovir) Versus Valganciclovir 
for the Prevention of Human Cytomegalovirus (CMV) Disease in Adult Kidney Transplant 
Recipients
Protocol Number: 002-05
Compound Number: MK-8228
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   104,706 (tablet IND); 118,361 (IV IND)
EudraCT NUMBER: 2017-001055-30
Approval Date:  27-August-2019
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial 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
P002-05
27-Aug-2019
To add the requirement that the intravenous (IV) formulation of letermovir 
(LET) supplied by the Sponsor to sites as study medication must be 
administered through a sterile 0.2-micron or 0.22-micron polyethersulfone 
(PES) in-line filter and using diethylhexyl phthalate (DEHP)-free IV bags 
and infusion set materials.  This requirement is being added to prevent the 
possible administration of product-related particulate matter.  The presence 
of visible product-related particulate matter is an expected characteristic of 
new clinical supplies of the IV formulation of LET.  This requirement is 
being implemented to allow for the release of new clinical supplies of IV 
LET, and as a precaution, it must be applied regardless of whether the 
clinical site considers its current clinical supply to be impacted.  In addition, 
where applicable, the matching placebo to the IV formulation of acyclovir 
must be administered through a sterile 0.2-micron or 0.22-micron PES in-
line filter and using DEHP-free IV bags and infusion set materials, in order 
to maintain the blind for IV study medications.
P002-04
11-Feb-2019
To add strong and moderate inducers of transporters (eg, P-glycoprotein [P-
gp]) and/or enzymes (eg, uridine diphosphate glucuronosyltransferase 
[UGT]) to the list of prohibited medications due to the potential for co-
administration to result in a decrease in letermovir plasma concentrations.
P002-03
29-May-2018
To permit potential participants to be consented and screened up to 5 days 
(inclusive) after transplant surgery instead of requiring the completion of all 
screening procedures prior to transplant. Extending the screening to the 
post-transplant period will facilitate the screening and enrollment of 
deceased donor transplant recipients who are typically under time 
constraints immediately prior to the transplant surgery and also will provide 
additional time for the investigator to obtain the required screening 
laboratory results after the transplant surgery.
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Document
Date of Issue
Overall Rationale
P002-02
21-Feb-2018
To add two laboratory exclusion criteria for consistency with the 
valganciclovir (VGCV) product circular information.
P002-01
07-Dec-2017
To add a letermovir (LET) 240 mg dose group when administered 
intravenously (IV) without cyclosporine (CsA). LET has previously been
evaluated in a Phase 3 trial in hematopoietic stem cell transplant (HSCT) 
recipients at doses of 240 mg PO or IV when administered with CsA, and 
480 mg PO or IV when administered without CsA. All doses were generally 
well-tolerated and efficacious; however, LET exposures (steady state 
median AUC) in HSCT recipients with the 480 mg IV dose (without CsA) 
were higher than in the other three dose groups. Population pharmacokinetic 
(PK) simulations using data from the Phase 3 trial in HSCT recipients 
suggest that a 240 mg IV dose (without CsA) will provide exposures 
comparable to exposures obtained following administration of a 480 mg PO 
dose (without CsA). Therefore, an additional dose group of 240 mg IV 
(without CsA) is being added to the current protocol to evaluate the PK, 
efficacy, and safety of this dose in transplant recipients. Participants who 
receive IV LET (without CsA) will be randomized 1:1 to receive either a 
480 mg or 240 mg dose.
P002-00
21-Sep-2017
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 05
Overall Rationale for the Amendment:
To add the requirement that the intravenous (IV) formulation of letermovir (LET) supplied by the Sponsor to sites as study medication
must be administered through a sterile 0.2-micron or 0.22-micron polyethersulfone (PES) in-line filter and using diethylhexyl 
phthalate (DEHP)-free IV bags and infusion set materials.  This requirement is being added to prevent the possible administration of 
product-related particulate matter.  The presence of visible product-related particulate matter is an expected characteristic of new 
clinical supplies of the IV formulation of LET.  This requirement is being implemented to allow for the release of new clinical 
supplies of IV LET, and as a precaution, it must be applied regardless of whether the clinical site considers its current clinical supply 
to be impacted.  In addition, where applicable, the matching placebo to the IV formulation of acyclovir must be administered through 
a sterile 0.2-micron or 0.22-micron PES in-line filter and using DEHP-free IV bags and infusion set materials, in order to maintain the 
blind for IV study medications.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
7.4, Blinding
7.5.1, Dose Preparation
9.1.9, Treatment 
Administration
Added information regarding the requirement 
that the IV formulation of letermovir (LET) 
and, where applicable, matching placebo to IV 
acyclovir, must be administered through a 
sterile 0.2-micron or 0.22-micron 
polyethersulfone (PES) in-line filter and using 
diethylhexyl phthalate (DEHP)-free IV bags 
and infusion set materials.  
To align with the overall rationale for the amendment 
as detailed in the beginning of the document.
7.1, Treatments 
Administered
Removed option for IV acyclovir or matching 
placebo to IV acyclovir to be prepared with 
To maintain the blind for IV study medications.
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Section # and Name
Description of Change
Brief Rationale
7.4, Blinding
7.5.1, Dose Preparation
125-mL bags and clarified that IV acyclovir or 
matching placebo to IV acyclovir must be 
prepared with 250-mL bags.
2, Schedule of Activities
9.5.3, Vital Signs
Removed note/text requiring vital signs to be 
measured in a semi-recumbent position and 
following resting in a semi-recumbent 
position.
Removal of unnecessary operational restraint.
6.2, Exclusion Criteria
Added “for the purposes of this protocol, 
dialysis includes hemofiltration” to Note in
Exclusion Criterion 5.
Acknowledgment that dialysis, for the purposes of this 
protocol, includes hemofiltration.
6.2, Exclusion Criteria
7.6, Treatment 
Compliance
9.1.6, Kidney 
Transplant/Dialysis 
Details Review
9.1.9.1, Timing of Dose 
Administration
10.6.3.1, Demographic 
and Baseline 
Characteristics
Added “plasmapheresis” to text.
Since there are insufficient data in patients on 
plasmapheresis to make letermovir dosing 
recommendations, all applicable aspects of the 
protocol involving hemodialysis, eg, exclusion 
criteria, study medication dosing recommendations, 
and data collection, will also apply to plasmapheresis.
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Section # and Name
Description of Change
Brief Rationale
7.7, Concomitant 
Therapy
Broadened prohibition of imipenem-cilastatin
beyond coadministration with VGCV/GCV.
Clarification that imipenem-cilastatin is a prohibited 
concomitant medication.
9.5.8.2, CMV DNA PCR 
Testing
Removed text “…based on clinical suspicion 
of CMV disease…”.
Clarification to permit sites to locally monitor CMV 
DNA levels whenever clinically indicated, regardless 
of whether CMV disease is suspected.
9.11.4.1, Discontinuation 
Due to CMV Disease
Visit
Changed title of section from “Discontinuation 
Due to CMV Disease” to “CMV Disease 
Visit”
Added text to clarify that one of the CMV 
Disease Visit criteria (any discontinuation of 
study treatment and initiation of CMV 
treatment) excludes initiation of CMV 
prophylaxis following discontinuation of study 
treatment for non-CMV adverse events.
To harmonize the title of the section with its contents 
describing the criteria and procedures for the CMV 
Disease Visit.
To provide investigators and sites with additional 
clarification on protocol-specified criteria for 
performing a CMV Disease Visit, since the initiation 
of CMV prophylaxis following discontinuation of 
study treatment for non-CMV adverse events is not 
consistent with clinical management of confirmed or 
suspected CMV disease.
10.6.1.3 Missing Data 
Handling
Removed treatment related discontinuation = 
failure (TRD=F) sensitivity analysis from text 
and from Table 13
To align with subject disposition eCRF available 
choices for end of study.  This analysis cannot be 
performed because the choice of discontinuation from
study due to adverse event is no longer available.  
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1.
Synopsis.......................................................................................................................16
2.
Schedule of Activities (SoA)......................................................................................19
3.
Introduction................................................................................................................26
Study Rationale .......................................................................................................26
Background..............................................................................................................27
Pharmaceutical and Therapeutic Background .....................................................28
Benefit/Risk Assessment.........................................................................................29
4.
Objectives/Hypotheses and Endpoints.....................................................................29
5.
Study Design...............................................................................................................32
Overall Design .........................................................................................................32
Study Diagram .....................................................................................................34
Number of Participants ..........................................................................................35
Beginning and End of Study Definition ................................................................35
Clinical Criteria for Early Study Termination .....................................................35
Scientific Rationale for Study Design....................................................................35
Rationale for Endpoints .......................................................................................35
Efficacy Endpoints........................................................................................35
5.4.1.1.1
CMV Based Assessments......................................................................36
5.4.1.1.2
New Onset Diabetes Mellitus After Transplant (NODAT)...................37
5.4.1.1.3
Rationale for Non-Inferiority Margin....................................................39
Patient-reported Outcome Endpoints............................................................40
Safety Endpoints...........................................................................................40
Pharmacokinetic Endpoints ..........................................................................42
Planned Genetic Analysis .............................................................................44
Future Biomedical Research.........................................................................44
Rationale for the Use of Comparator (Valganciclovir and Ganciclovir).............44
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Justification for Dose ..............................................................................................45
Starting Dose for This Trial .................................................................................45
Maximum Dose/Exposure for This Trial.............................................................47
6.
Study Population........................................................................................................47
Inclusion Criteria....................................................................................................47
Exclusion Criteria ...................................................................................................49
Lifestyle Restrictions...............................................................................................52
Meals and Dietary Restrictions............................................................................52
Screen Failures ........................................................................................................53
Participant Replacement Strategy.........................................................................53
7.
Treatments..................................................................................................................53
Treatments Administered.......................................................................................53
Dose Modification (Escalation/Titration/Other)..................................................56
Method of Treatment Assignment.........................................................................59
Stratification.........................................................................................................59
Blinding....................................................................................................................60
Preparation/Handling/Storage/Accountability ....................................................64
Dose Preparation..................................................................................................64
Handling, Storage and Accountability.................................................................64
Treatment Compliance...........................................................................................65
Concomitant Therapy.............................................................................................66
Rescue Medications & Supportive Care..............................................................72
Treatment After the End of the Study ..................................................................72
Clinical Supplies Disclosure...................................................................................72
8.
Discontinuation/Withdrawal Criteria......................................................................72
Discontinuation of Study Treatment.....................................................................72
Withdrawal from the Study ...................................................................................74
Lost to Follow Up....................................................................................................75
9.
Study Assessments and Procedures..........................................................................75
Administrative and General Procedures ..............................................................76
Informed Consent.................................................................................................76
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General Informed Consent............................................................................76
Consent and Collection of Specimens for Future Biomedical 
Research........................................................................................................77
Inclusion/Exclusion Criteria ................................................................................77
Participant Identification Card.............................................................................77
Medical History ...................................................................................................77
Prior and Concomitant Medications Review .......................................................77
Prior Medications..........................................................................................77
Concomitant Medications.............................................................................77
Kidney Transplant/Dialysis Details Review........................................................78
Assignment of Screening Number.......................................................................78
Assignment of Treatment/Randomization Number.............................................78
Treatment Administration....................................................................................78
Timing of Dose Administration....................................................................79
Withdrawal/Discontinuation................................................................................79
Withdrawal From Future Biomedical Research ...........................................79
Participant Blinding/Unblinding..........................................................................80
Domiciling ...........................................................................................................80
Calibration of Equipment.....................................................................................81
Efficacy Assessments...............................................................................................81
CMV Disease Assessment ...................................................................................81
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events.......................................................................................................................82
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ..................................................................82
Method of Detecting AE, SAE and Other Reportable Safety Events..................84
Follow-up of AE, SAE and Other Reportable Safety Event Information............84
Regulatory Reporting Requirements for SAE .....................................................85
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................85
Pregnancy and Exposure During Breastfeeding ..................................................85
Events of Clinical Interest (ECI)..........................................................................86
Treatment of Overdose...........................................................................................86
Safety........................................................................................................................86
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Physical Examinations.........................................................................................86
Weight and Height Assessment ...........................................................................87
Vital Signs............................................................................................................87
12-Lead Electrocardiogram..................................................................................87
Child-Pugh Score.................................................................................................87
Birth Control Confirmation..................................................................................88
Adverse Events Monitoring .................................................................................88
Clinical Safety Laboratory Assessments..............................................................88
Laboratory Safety Evaluations......................................................................88
CMV DNA PCR Testing ..............................................................................89
CMV Viral Resistance Testing.....................................................................90
CMV UL55 (gB) Genotypic Testing ............................................................90
CMV Serology (IgG) Testing.......................................................................91
Pharmacokinetics....................................................................................................91
Blood Collection for Plasma Letermovir.............................................................91
Pharmacodynamics.................................................................................................92
Future Biomedical Research Sample Collection..................................................92
Biomarkers ..............................................................................................................92
Planned Genetic Analysis Sample Collection......................................................92
Health Outcomes and Quality of Life Assessments .............................................92
Health Outcomes Assessment..............................................................................92
Quality of Life Assessments ................................................................................93
Visit Requirements..................................................................................................94
Screening..............................................................................................................94
Treatment Period..................................................................................................95
Day 1 Visit....................................................................................................95
Study Therapy Administration......................................................................96
Follow-up Period .................................................................................................97
CMV Disease or Early Discontinuation Visit......................................................98
CMV Disease Visit .......................................................................................98
Discontinuation for Reasons Other Than CMV Disease..............................98
10.
Statistical Analysis Plan ............................................................................................99
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Statistical Analysis Plan Summary........................................................................99
Responsibility for Analyses/In-House Blinding..................................................100
Hypotheses/Estimation .........................................................................................101
Analysis Endpoints................................................................................................101
Efficacy Endpoints.............................................................................................101
Safety Endpoints ................................................................................................102
Exploratory Endpoints .......................................................................................102
Analysis Populations.............................................................................................104
Efficacy Analysis Populations ...........................................................................104
Safety Analysis Populations ..............................................................................104
Statistical Methods................................................................................................105
Statistical Methods for Efficacy Analyses .........................................................105
Primary Efficacy Analysis ..........................................................................105
Secondary Efficacy Analyses .....................................................................106
Missing Data Handling ...............................................................................106
Statistical Methods for Safety Analyses ............................................................107
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.............................................................................................................109
Demographic and Baseline Characteristics ................................................109
Pharmacokinetic Analyses..........................................................................109
Interim Analyses ...................................................................................................110
Multiplicity ............................................................................................................110
Sample Size and Power Calculations ..................................................................110
Sample Size and Power for Efficacy Analyses..................................................110
Sample Size and Power for Safety Analyses .....................................................110
Subgroup Analyses................................................................................................111
Compliance (Medication Adherence)..................................................................112
Extent of Exposure................................................................................................112
11.
References.................................................................................................................113
12.
Appendices................................................................................................................121
Appendix 1: Abbreviations and Trademarks.....................................................121
Appendix 2: Clinical Laboratory Tests...............................................................125
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Appendix 3: Study Governance Considerations ................................................129
Merck Code of Conduct for Clinical Trials ...................................................................129
Financial Disclosure.......................................................................................................131
Data Protection...............................................................................................................131
Confidentiality of Data ..................................................................................................131
Confidentiality of Participant Records...........................................................................132
Confidentiality of IRB/IEC Information........................................................................132
Committees Structure.....................................................................................................132
Scientific Advisory Committee..................................................................................132
Executive Oversight Committee................................................................................132
Data Monitoring Committee......................................................................................132
Clinical Adjudication Committee ..............................................................................133
Publication Policy......................................................................................................133
Compliance with Trial Registration and Results Posting Requirements.......................133
Compliance with Law, Audit and Debarment ...............................................................134
Data Quality Assurance .................................................................................................135
Source Documents .........................................................................................................135
Study and Site Closure...................................................................................................136
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................137
Definition of AE ............................................................................................................137
Definition of SAE ..........................................................................................................138
Additional Events reported ............................................................................................139
Recording AE and SAE .................................................................................................139
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor................143
Appendix 5: Contraceptive Guidance and Pregnancy Testing.........................145
Contraception Requirements..........................................................................................145
Pregnancy Testing..........................................................................................................147
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................148
Appendix 7: Definition of CMV Disease.............................................................153
Appendix 8: Child-Pugh Classification for Severity of Liver Disease .............156
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LIST OF TABLES
Table 1
Percentage of Efficacy Retained with 10 percentage point Margin (n = 
300/arm)................................................................................................................40
Table 2
Population Pharmacokinetic and Intensive Pharmacokinetic Collection .............43
Table 3
Laboratory Exclusion Criteria ..............................................................................51
Table 4
Study Treatments – Oral Formulation..................................................................54
Table 5
Study Therapy – IV Formulation (For Participants Who Cannot 
Tolerate Oral Formulation at and/or After Randomization).................................55
Table 6
VGCV Dosage Recommendations for Adult Participants Based on 
Creatinine Clearance.............................................................................................57
Table 7
GCV (Intravenous) Dosage Recommendations for Adult Participants 
Based on Creatinine Clearance.............................................................................58
Table 8
ACV (Oral) Dosage Recommendations for Adult Participants Based on 
Creatinine Clearance.............................................................................................58
Table 9
ACV (Intravenous) Dosage Recommendations for Adult Participants 
Based on Creatinine Clearance.............................................................................59
Table 10
Blinding of Oral Formulation Related to Concomitant CsA Use for 
Participants With Normal Renal Function............................................................61
Table 11
Blinding of IV Study Medication Related to Concomitant CsA Use for 
Participants Based on Renal Function..................................................................62
Table 12
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................83
Table 13
Summary of Approaches to Handle Missing Values..........................................106
Table 14
Analysis Strategy for Key Efficacy Variables....................................................107
Table 15
Analysis Strategy for Safety Parameters ............................................................109
Table 16
Power to Show Superiority for a Variety of Hypothetical Underlying 
Incidences of Leukopenia Adverse Events (n = 300/arm) .................................111
Table 17
Protocol-Required Safety Laboratory Assessments ...........................................125
Table 18
Approximate Blood/Tissue Volumes Drawn/Collected by Study Visit 
and by Sample Types..........................................................................................127
Table 19
Highly Effective Contraceptive Methods That Have Low User 
Dependency ........................................................................................................146
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LIST OF FIGURES
Figure 1
MK-8228-002 Study Design.................................................................................34
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1. Synopsis
Protocol Title:  
A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Study to 
Evaluate the Efficacy and Safety of MK-8228 (Letermovir) Versus Valganciclovir for the 
Prevention of Human Cytomegalovirus (CMV) Disease in Adult Kidney Transplant 
Recipients
Short Title: 
LET vs VGCV for Prevention of CMV disease in Kidney Transplant Recipients
Objectives/Hypotheses and Endpoints:
In adult D+/R- (ie, CMV seropositive organ donor/CMV seronegative organ recipient) 
kidney transplant recipients:
Objective/Hypothesis
Endpoint
Primary

Objective:  To evaluate the efficacy 
of letermovir (LET) versus 
valganciclovir (VGCV), as measured 
by the proportion of participants with 
adjudicated CMV disease through 
52 weeks post-transplant.

Hypothesis (H1):  LET is 
non-inferior to VGCV in the 
prevention of CMV disease 
through 52 weeks post-
transplant.

CMV disease

Hypothesis (H2):  LET is 
superior to VGCV in the 
prevention of CMV disease 
through 52 weeks post-
transplant.  Hypothesis testing 
will be performed only if non-
inferiority is demonstrated.
Secondary

Objective:  To evaluate the efficacy 
of LET versus VGCV, as measured 
by the proportion of participants 
with adjudicated CMV disease 
through 28 weeks post-transplant.

CMV disease
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
Objective:  To evaluate the efficacy 
of LET versus VGCV, as measured 
by the time to onset of adjudicated
CMV disease through 52 weeks 
post-transplant.

Time to onset of adjudicated CMV 
disease through 52 weeks 
post-transplant

Objective:  To evaluate the safety 
and tolerability of LET versus 
VGCV.

Accumulated safety data (adverse 
events, laboratory, vital signs, etc.)
Overall Design:
Study Phase
Phase 3
Clinical Indication
Prevention of CMV disease in D+/R- kidney transplant 
recipients
Population
Adult D+/R- kidney transplant recipients
Study Type
Interventional
Type of Design
Active comparator, multi-site, randomized
Type of Control
Active control (VGCV)
Study Blinding
Double-blind
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require 
approximately 40 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related phone call or visit.
Number of Participants:
Approximately 600 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
ARM 1: LET administration as follows:
i. Oral administration of LET 480 mg once daily
(QD), or
ii. Oral administration of LET 240 mg QD if given 
concomitantly with cyclosporin A (CsA), or
iii. IV administration of LET 480 mg QD, or
iv. IV administration of LET 240 mg QD, or
v. IV administration of LET 240 mg QD if given 
concomitantly with CsA
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with VGCV matching placebo (for oral administration), 
and acyclovir (ACV) 400 mg orally or 250 mg/m2
intravenously starting within 7 days post-transplant and 
continuing through Week 28; the dose of ACV will be 
modified based on creatinine clearance.
Note: For IV administration of LET, participants on 
concomitant CsA will receive 240 mg IV LET QD, while 
participants not on concomitant CsA will be randomized 
1:1 to receive either 240 mg IV LET QD or 480 mg IV 
LET QD.
ARM 2:  Oral VGCV 900 mg QD or intravenous 
administration of ganciclovir (GCV) 5 mg/kg QD with 
LET matching placebo (for oral administration), and 
ACV matching placebo (for both oral and intravenous 
[IV] administration) starting within 7 days post-transplant 
and continuing through Week 28; the dose of VGCV and 
GCV will be modified based on creatinine clearance.
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 signs the Informed Consent 
Form (ICF) through the final contact.  The screening 
duration will be approximately 6 days for participants 
who receive a kidney from a deceased donor or up to 
19 days for participants who receive a kidney from a 
living donor. Participants will then be randomized within 
7 days post-transplant and receive assigned treatment 
through approximately Week 28.  After the end of 
treatment, each participant will be followed through 
approximately Week 52.
A list of abbreviations used in this document can be found in Appendix 1. Study governance 
considerations are outlined in Appendix 3.
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2. Schedule of Activities (SoA)
Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
Administrative Procedures
Informed Consent
X
Informed Consent 
for FBR
X
Intensive PK 
Consent
X
For participants of non-Asian descent 
eligible for optional intensive PK
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
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
Treatment 
Allocation/
Randomization
X
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Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
Administration/
Dispensing:
LET+Placebo to 
VGCV+ACV
or
VGCV+Placebo to 
LET+Placebo to 
ACV 
X
X
X
X
X
X
X
X
X
X
IV formulation (ie, IV LET, IV GCV, 
and IV ACV) available for participants 
unable to tolerate swallowing and/or 
have a condition that may interfere 
with the absorption of oral 
formulation.  Contact IVRS/IWRS at 
all dispensing visits for assignment of 
study therapy (see Section 9.11.2.2).
Kidney 
Transplant/Dialysis
Details Review
X
Study Medication 
Reconciliation and 
Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant will be trained in the use of 
Study Medication Diary on Day 1.
Efficacy Procedures
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
Safety Procedures
Full Physical 
Examination
X
X
X
Height
X
Weight
X
X
X
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Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
Targeted 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 (heart 
rate, blood pressure, 
respiratory rate, 
body temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram
X
X
X
Read locally. Screening values 
collected within 3 months prior to 
screening may be used.
Semi-recumbent position.
Child-Pugh Score
X
X
X
X
X
X
X
X
X
X
X
X
X
See Appendix 8.
Participant 
Confirmation of 
Birth Control
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 9.5.7 (including infusion 
site reactions).
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.  If not available, testing 
may be performed by the central 
laboratory or locally as per SOC.
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
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Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
Pregnancy Test
(WOCBP only)
X
Per pre-op SOC at the site (either urine 
or serum pregnancy test)
Urine Pregnancy 
Test (WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
Performed locally; may use serum 
pregnancy test (local or central 
laboratory) if unable to provide urine
Serum Inhibin B, 
LH, FSH, 
Testosterone Levels 
in Men
X
X
X
X
Performed by the central laboratory
HIV and Hepatitis B 
and C Screen
X
See Section 9.11.1, Screening for 
details on testing.
CMV Procedures/Assessments
CMV DNA PCRc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performed by the central laboratory
CMV Serology 
(IgG)
X
Performed locally per SOC at the site
if not previously documented within 
180 days prior to Day 1.
QuantiFERON-
CMV Assay
X
X
X
X
X
X
Performed by the central laboratory
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Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
CMV Viral 
Resistance 
Testing/gB 
Genotypic Testingc, d
X
X
The CMV Disease Visit can occur at 
any time during the study. Collect 
these samples at CMV Disease Visit. 
Repeat samples should be collected at 
the next scheduled visit after the CMV 
Disease Visit.
Health Outcomes 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 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.
Quality of Life 
Assessments
X
X
X
X
X
Electronic EQ-5D and SF-36v2®
(performed prior to any other 
procedures at the visit)
PK/Biomarkers
Blood for Genetic 
Analysise
X
Population PK
X
X
X
X
X
X
X
X
X
X
X
X
X
Collected pre-dose in all participants at 
each visit of the treatment period and 
at CMV Disease/early discontinuation 
visit (if during treatment period)
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Study Period
Pre-
Treatment
Treatment
Follow-Up
CMV 
Disease
and/or Early 
Discon Visit
Notes
Visit No.
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
W
1
W
2
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
28
W
32
W
36
W
40
W
44
W
48
W
52

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”.
See Footnote a for screening window.
Intensive PK at 
Week 1f
(For participants of 
Asian descent AND 
participants of non-
Asian descent who 
consent to the 
intensive PK study)
X
To be collected on Study Day 6, 7, 8, 
9, or 10.
Intensive PKf
(For all participants 
receiving IV 
treatment for >5 
consecutive days)
-------------------------X--------------------------
Performed on the 6th day of IV 
administration
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ACV = acyclovir; AE = adverse event; β-hCG = β-human chorionic gonadotropin; CMV = cytomegalovirus; D = Day, DNA= deoxyribonucleic acid; FBR = Future Biomedical Research; 
EQ = EuroQol; FSH = follicle-stimulating hormone; G-CSF = granulocyte colony-stimulating factor; gB = glycoprotein B; GCV = ganciclovir; HIV = human immunodeficiency virus; 
IEC = Independent Ethics Committee; IgG = immunoglobulin G; INR = international normalized ratio; IRB = Institutional Review Board; IV = intravenous; IVRS = interactive voice 
response system; IWRS = integrated web response system; LET = letermovir; LH = luteinizing hormone; NODAT = new onset diabetes mellitus after transplant; OI = opportunistic 
infections; PCR = polymerase chain reaction; PK = pharmacokinetic; PT = prothrombin time; SAE = serious adverse event; SCR = screening; SF-36v2® = 36-Item Short Form Health 
Survey Version 2.0; SOC = standard of care; Tp = transplant; VGCV = valganciclovir; W = Week; WOCBP = women of childbearing potential
a.
Screening should begin after obtaining documented consent and may begin on the day of transplantation (ie, prior to transplantation) or as early as one 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 2) will be performed and must be completed by Day 5 post-transplant 
(inclusive).  See Section 9.11.1 regarding details of screening procedures.
b. Start of study treatment is Day 1 (day of randomization).  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.
Leftover main study plasma will be stored for FBR if the participant consents to FBR.
d. To be performed only for participants who discontinue study treatment due to suspected or confirmed CMV disease or in whom study treatment is stopped (if on study treatment) and 
CMV treatment is started.
e.
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 signs FBR consent.
f.
Each participant will participate in the intensive PK substudy no more than twice during the study.
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3. Introduction
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 5.4.1.1) and disease (ie, end-organ involvement or CMV syndrome; 
Section 5.4.1.1 and Appendix 7) 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 disease 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 nearly 3-fold higher among CMV seronegative (R-) kidney recipients with a 
transplanted kidney from CMV seropositive (D+) donor, ie, D+/R– patients (56%) compared 
to the incidence among D–/R+ and D+/R+ patient groups (20%; p <0.001) [Husain, S., et al 
2009] [Hartmann, A., et al 2006].
CMV prophylaxis is now widely used following SOT and has been associated with 
reductions in CMV disease, mortality, and graft rejection in high-risk patients [Humar, A., et 
al 2010].  Although ganciclovir (GCV) and valganciclovir (VGCV) are used for CMV 
prophylaxis during the post-SOT period, both GCV and VGCV are associated with 
myelosuppression and CMV strains resistant to GCV and VGCV have been identified
[Razonable, R. R. 2013].  Although intravenous (IV) GCV is dosed based on weight, oral 
VGCV is prescribed in fixed doses.  GCV is renally cleared, so changes in renal function 
may lead to over exposure and increased risk of toxicity.
There is an unmet medical need for new agents which do not cause myelosuppression, are 
dosed independent of renal function, and are active against both wild-type and GCV-resistant 
CMV.  
MK-8228 (also known as letermovir, AIC246, AIC001; 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;
(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;
(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 002 is a pivotal study that will evaluate the efficacy and safety of LET versus 
VGCV administered as prevention of CMV disease in approximately 600 D+/R- adult kidney 
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transplant recipients.  Study treatment will be initiated within 7 days post-transplant and 
continue through Week 28.  After approximately 28 weeks of study therapy post-transplant, 
participants will be followed through Week 52 (ie, approximately 12 months post-transplant) 
to assess for late onset CMV disease and DNAemia (detection of CMV DNA in samples of 
plasma, serum, whole blood, or isolated PBLs, or in buffy-coat specimens) [Ljungman, P., et 
al 2016].
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.
Background
Refer to the IB/approved labeling for detailed background information on LET.
CMV continues to be the single major pathogen affecting the outcome of SOT [Eid, A. J. and 
Razonable, R. R. 2010].  Rates of CMV infection or disease vary depending on baseline 
CMV-specific immunity (ie, donor and recipient CMV immunoglobulin G [IgG]
seropositivity), the overall state of post-SOT immunosuppression, and the type of organ 
transplant [Beam, E. 2012].  CMV infection (see also Section 5.4.1.1) may be the result of 
reactivation or reinfection (in CMV-seropositive recipients) or primary infection (in a 
CMV-seronegative recipient who received a transplant from CMV-seropositive donor) 
[Beam, E. 2012].
CMV disease (consisting of CMV end-organ disease and CMV syndrome, see Section 
5.4.1.1 for further details) occurs most frequently between one and four months following 
SOT and is associated with increased morbidity, mortality as well as poor long-term 
outcomes following SOT [Beam, E. 2012].  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].
The spectrum of CMV disease manifestations from CMV syndrome (ie, CMV infection with 
≥2 prespecified clinical signs/symptoms and/or laboratory criteria) to CMV end-organ 
disease (ie, involvement of ≥1 organ system with clinical manifestations) have been 
described extensively (see Appendix 7; [Boeckh, M. 2011]).  The most common form of 
CMV end-organ disease involves the gastrointestinal tract [Beam, E. 2012] [Kute, V. B., et al 
2012].  Studies have shown that the risk of CMV disease in SOT is highest in CMV-
seronegative recipients of CMV-seropositive donors (ie, D+R-), and in patients who receive
antilymphocyte antibody therapy as pre-transplant induction or as post-transplant treatment 
for acute rejection [Humar, A., et al 2010].
There are currently two approaches to preventing CMV disease in SOT: prophylaxis with 
antivirals and pre-emptive therapy (PET), the practice of active surveillance for viral 
replication and initiating treatment with anti-CMV agents when CMV DNAemia is detected
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[Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S 2013].  Guidelines on the 
management of CMV in SOT recipients favor the use of prophylaxis over PET in the highest 
risk recipients [Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S 2013].  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].  However, VGCV is associated with myelotoxicity, which can 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. 2013].
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.  An effective 
and well-tolerated prophylactic anti-CMV medication for SOT recipients, which also has
activity against CMV strains resistant to currently available agents, remains an unmet 
medical need.
Pharmaceutical and Therapeutic Background
The current standard of care (SOC) regimen for CMV prophylaxis in SOT recipients is 
VGCV, which has been approved for the prevention of CMV disease in kidney, heart, or 
kidney-pancreas transplant recipients at high risk.  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 D+/R- kidney 
transplant recipients [Humar, A., et al 2010].
However, VGCV is also associated with myelotoxicity as described in the VGCV label [U.S. 
Prescribing Information 2017].  Moreover, antiviral drug resistance, most commonly to GCV 
and VGCV, among CMV clinical isolates has emerged following widespread use of these 
drugs for prophylaxis and PET.  Drug resistance is usually seen after treatment duration with 
antiviral agents of weeks to months [Beam, E. 2012].  The majority of resistance mutations to 
GCV and VGCV are associated with mutations in the UL97 encoded viral protein kinase 
[Lurain, N. S. and Chou, S. 2010].  Resistance to GCV and VGCV also occurs via mutations 
in the viral deoxyribonucleic acid (DNA) polymerase gene (UL54), often in the presence of 
UL97 mutations [Boivin, G., et al 2012].
LET is an anti-CMV agent with a novel mechanism of action.  LET inhibits the viral 
terminase complex (UL51/UL56/UL89), an enzyme that plays an important role in cleavage 
of concatenated viral DNA into individual unit-length 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 
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studies in vitro and efficacy against the virus in vivo [Lischka, P., et al 2010] [Goldner, T., et 
al 2011].
LET has been shown to be generally well tolerated in 28 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 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.
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 
efficacy and safety of LET versus VGCV in prevention of CMV disease in adult D+/R-
kidney transplant recipients.
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.
4. Objectives/Hypotheses and Endpoints
In adult D+/R- (ie, CMV seropositive organ donor/CMV seronegative organ recipient) 
kidney transplant recipients:
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Objective/Hypothesis
Endpoint
Primary

Objective:  To evaluate the efficacy of 
LET versus VGCV, as measured by the 
proportion of participants with 
adjudicated CMV disease through 
52 weeks post-transplant.

Hypothesis (H1):  LET is non-inferior 
to VGCV in the prevention of CMV 
disease through 52 weeks 
post-transplant.

Hypothesis (H2): LET is superior to 
VGCV in the prevention of CMV 
disease through 52 weeks 
post-transplant. Hypothesis testing 
will be performed only if 
non-inferiority is demonstrated.

CMV disease (see Section 5.4.1.1)
Secondary

Objective:  To evaluate the efficacy of 
LET versus VGCV, as measured by the 
proportion of participants with 
adjudicated CMV disease through 28 
weeks post-transplant.

CMV disease (see Section 5.4.1.1)

Objective:  To evaluate the efficacy of 
LET versus VGCV, as measured by the 
time to onset of adjudicated CMV disease 
through 52 weeks post-transplant.

Time to onset of adjudicated CMV 
disease through 52 weeks 
post-transplant

Objective:  To evaluate the safety and 
tolerability of LET versus VGCV.

Accumulated safety data (adverse 
events, laboratory, vital signs, etc.)
Exploratory

Objective:  To evaluate the proportion of 
participants with quantifiable CMV 
DNAemia in LET versus VGCV as 
measured by the central laboratory
through 28 weeks post-transplant and 52 
weeks post-transplant.

Quantifiable CMV DNAemia (see 
Section 5.4.1.1.1)

Objective:  To evaluate the proportion of 
participants who develop leukopenia and 
neutropenia in LET versus VGCV during 
the treatment phase.

Laboratory and AE indications of 
leukopenia and neutropenia (see 
Section 10.4.2)
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Objective/Hypothesis
Endpoint

Objective:  To evaluate the proportion of 
participants experiencing allograft 
dysfunction and/or rejection in LET 
versus VGCV through 28 weeks 
post-transplant and 52 weeks 
post-transplant.

Allograft dysfunction and/or rejection 
(see Section 10.4.3)

Objective:  To evaluate the incidence of 
new onset diabetes mellitus after 
transplant (NODAT) in LET versus 
VGCV through 28 weeks post-transplant 
and 52 weeks post-transplant.

NODAT (see Section 5.4.1.1.2)

Objective:  To evaluate health outcomes 
in LET versus VGCV through 28 weeks 
post-transplant and 52 weeks 
post-transplant.

Health outcomes (see Section 10.4.3)

Objective:  To evaluate the antiviral 
resistance to LET in prophylaxis failures 
through 52 weeks post-transplant.

Antiviral resistance to LET in 
prophylaxis failures (see Section 
9.5.8.3)

Objective: To explore the relationship 
between CMV glycoprotein B (gB) 
genotype and response to the treatments 
administered

See Section 9.5.8.4 for details.

Objective:  To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease.
a. Variation across the human genome 
will 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 analyses (see Section 5.4.1.5
for details)

Objective:  To evaluate patient-reported 
outcomes in LET versus VGCV through 
52 weeks post-transplant.

EuroQol (EQ)-5D and 36-Item Short 
Form Health Survey Version 2.0 
(SF-36v2®) scores

Objective:  To evaluate the 
pharmacokinetics of LET.

Pharmacokinetic endpoints (see 
Section 10.6.3.2 for details).
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5. Study Design 
Overall Design 
This is a randomized, active-controlled, multi-site, double-blind (with in-house blinding) 
study to evaluate the efficacy and safety of LET versus VGCV in the prevention of CMV 
disease in adult kidney transplant recipients with a negative CMV IgG serostatus who 
received a kidney transplant from a donor with a positive CMV IgG serostatus (D+/R–).  
This study will be conducted in conformance with Good Clinical Practices.  The definition of 
CMV disease is provided in Section 5.4.1.1.
Approximately 600 D+/R- kidney transplant recipients will be randomized in a 1:1 ratio to 
receive LET or VGCV within 7 days post-transplant.
LET Arm
From Day 1 (day of randomization) through Week 28, participants in the LET treatment arm 
will receive:

LET 480 mg once daily (QD) given orally (either as one 480 mg tablet or two 240 mg 
tablets, based on participant’s swallowing capability at the site investigator’s 
discretion), or, if the participant is receiving concomitant cyclosporin A (CsA), LET 
240 mg QD given orally.

Placebo to VGCV given orally.

Acyclovir* (ACV) 400 mg** given orally (supplied as capsule or tablet) every 12 
hours for prophylaxis against herpes simplex virus (HSV) and varicella zoster virus 
(VZV).
VGCV Arm
From Day 1 through Week 28, participants in the VGCV treatment arm will receive:

Placebo to LET given orally

VGCV 900 mg QD** (given orally as two 450 mg tablets)

Placebo to ACV given orally
The above (LET arm and VGCV arm) assumes:

Participants can tolerate swallowing and/or does not develop a condition that may 
interfere with the absorption of the oral formulation (see Section 7.1 for details 
regarding IV dosing).

That the renal function as measured by creatinine clearance (CrCl) is ≥60 mL/min 
(see Section 7.2 for details on CrCl-based dose adjustments).
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Note:  The antiviral activity of LET is specific for CMV, while VGCV has anti-CMV, as 
well as anti-HSV and anti-VZV activities.  Since patients receiving VGCV for CMV 
prophylaxis for ≥100 days typically do not receive additional agents for HSV/VZV 
prevention, ACV is provided to participants in the LET arm from Day 1 through Week 28 
(ie, ~200 days) [Pergam, S. A. 2009] [Wilck, M. B. 2013]. Therefore, participants in the 
LET and VGCV arms will receive ACV for HSV and VZV prophylaxis and matching 
placebo from Day 1 through Week 28, respectively.
* Acyclovir and Aciclovir are equivalent generic names.
**Dose adjustments of VGCV, GCV, and ACV based on CrCl are provided in Section 7.2.  
There are no dose adjustments of LET based on CrCl.
If participants in the LET treatment arm 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 randomization/Day 1, then such participants can 
receive an IV formulation of LET.  Participants on concomitant CsA will receive 240 mg IV 
LET QD, while participants not on concomitant CsA will be randomized 1:1 to receive either 
240 mg IV LET QD or 480 mg IV LET QD, as well as IV ACV (see Section 7.2 for IV ACV 
dosing).  Participants randomized to receive either 240 mg IV LET or 480 mg IV LET 
without concomitant CsA will receive 480 mg of oral formulation of LET when they are able 
to tolerate oral formulation of LET, and if unable to tolerate the oral formulation at a later 
time point in the study, will receive the same dose of IV LET (either 240 mg QD or 480 mg 
QD) to which they were randomized to receive earlier in the study.
Participants in the VGCV treatment arm who cannot tolerate swallowing and/or have a 
condition that may interfere with the absorption of the oral formulation at or after 
randomization/Day 1 will receive a comparable prophylaxis dose of IV GCV at 5 mg/kg QD,
as well as IV ACV matching placebo.
Randomized participants will be stratified by the use or non-use of highly cytolytic 
anti-lymphocyte immunotherapy during induction; such highly cytolytic anti-lymphocyte 
immunotherapy is associated with increased risk for CMV infection (Sections 3.2 and 
5.4.1.1) (see Section 7.3.1 for further details).
After completion of study therapy at Week 28, participants will continue to be followed for 
efficacy, safety, 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 Schedule of Activities (SoA) (Section 2). All 
scheduled study visits will be completed regardless of when cessation of study treatment 
occurs.
Key aspects of the proposed study are described in the remainder of Section 5 (Study 
Design), as well as Sections 6-9 (Study Population, Treatments, Discontinuation/Withdrawal 
Criteria, and Study Assessments and Procedures).
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For ongoing safety evaluations and to ensure safe study conduct, an independent unblinded 
external Data Monitoring Committee (DMC) will be established.  The DMC will not review 
CMV DNA polymerase chain reaction (PCR) results or perform any planned efficacy 
analysis but can be provided with efficacy data (upon request by the DMC) to support the 
benefit-risk assessment.  Specific details regarding the DMC will be described in the DMC 
charter (see Appendix 3 for additional details).
An independent blinded 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 5.4.1.1.1 and Appendix 3).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
Study Diagram
The study design is depicted in Figure 1.
Figure 1
MK-8228-002 Study Design
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Number of Participants
Approximately 600 participants will be randomized (see Section 10.9).
Beginning and End of Study Definition
The overall study begins when the first participant signs the informed consent form (ICF).  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criteria specified below:
Based on recommendations from the external DMC, the Executive Oversight Committee 
(EOC) determines that the extent (incidence and/or severity) of emerging adverse 
effects/clinical endpoints is such that the risk/benefit ratio to the study population as a whole 
is unacceptable.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
As stated in Section 3.2.1, the current SOC for CMV prophylaxis in D+/R- kidney transplant 
recipients is the administration of VGCV during the 200-day post-transplant period.  Several 
studies of VGCV in this patient population have been conducted; therefore, the CMV disease 
event rate is well characterized [Humar, A., et al 2010] [Paya, C., et al 2004].
Accordingly, Protocol 002 is a non-inferiority study of LET versus VGCV and the primary 
efficacy endpoint is:  

The proportion of participants with adjudicated CMV disease through 52 weeks 
post-transplant.
The key secondary efficacy endpoints of the study are:

The proportion of participants with adjudicated CMV disease through 28 weeks 
post-transplant.

Time to onset of adjudicated CMV disease through 52 weeks post-transplant.
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].
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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 7) 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:

Proven CMV end-organ disease

Probable CMV end-organ disease.

CMV syndrome (full list of criteria and clinical definition in Appendix 7) 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 7.
5.4.1.1.1 CMV Based Assessments
CMV DNA Measurements
Evidence of quantifiable CMV DNAemia is included as an exploratory analysis 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 150 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
Documented quantifiable CMV DNAemia is defined as any detected CMV with a numeric 
value and does not include reporting of PCR results as “detected, not quantifiable.”  
Additional details on CMV DNA PCR testing are described in Section 9.5.8.2.
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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, blinded CAC.  
The CAC will review any available data (as documented in the CAC charter) for the 
participant, 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 primary and secondary efficacy endpoints.
Adjudication of CMV disease cases by an established CAC will standardize the CMV 
disease diagnosis for the primary and 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 2).  
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 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.
5.4.1.1.2 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].  
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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].
Participants developing NODAT (as identified by the site and also as identified by a 
confirmatory analysis) will be analyzed (Section 10).  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 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 (Section 10) [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, 
above, will also fulfill this confirmatory criterion).
AND/OR
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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 randomization (ie, such hypoglycemic 
agents that are not listed as prior medications and newly identified as a concomitant 
medication during the study).
5.4.1.1.3 Rationale for Non-Inferiority Margin
The 10% non-inferiority margin used in this study is based on the preservation of the 
majority of efficacy (>50%) of VGCV compared to placebo in preventing CMV disease after 
renal transplantation under a number of scenarios.
From the VGCV label for 200-day treatment, the CMV disease rate at 12 months 
post-transplant in the VGCV group was 16.8% (26 out of 155), which corresponds to a 
disease-free rate of 83.2% with a 95% confidence interval (CI) of (76.4%, 88.7%). The
proportion of participants with CMV disease in a placebo group at 12 months post-transplant 
was extrapolated from Lowance, et al. [Lowance, D., et al 1999], which showed that the 
CMV disease rate was 45% at 90 days after renal transplantation (corresponding to a disease-
free rate of 55%). Since it is expected that more cases of CMV disease would occur between 
90 days and 12 months post-transplant, it is reasonable to assume the disease-free rate in a
placebo group at 12 months post-transplant is 50% or less.
Table 1 shows the percent of efficacy retained in this study using a 10 percentage point
margin for a range of disease-free rates consistent with the above assumptions for the VGCV 
and placebo groups. The percent retained was based on the lower bound of the 95% CI of 
difference in the disease-free rate (VGCV - Placebo), assuming 300 participants per group.  
For example, in the scenario where the VGCV disease-free rate = 90% and the placebo 
disease-free rate = 50%, the 95% two-sided CI for the VGCV rate (270/300) minus the 
placebo rate (150/300) is (33%, 46%) using the Miettinen and Nurminen method [Miettinen, 
O. and Nurminen, M. 1985].  A 10 percentage point non-inferiority margin would indicate 
that the lower bound for this difference in the study could be as low as 23% (33% minus 
10%); thus, the percent retained would be 23/33 = 69.7%.
This is a conservative approach since the lower bound of the 95% CI was used as the 
historical effect and a range of possible placebo rates were used in the calculations.  In the 
majority of scenarios in Table 1, more than 50% of the efficacy is retained using the 10 
percentage point margin.  Thus, a 10 percentage point margin is proposed in this study.
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Table 1
Percentage of Efficacy Retained with 10 percentage point Margin (n = 300/arm)
VGCV Disease-free Rate
Placebo Disease-free Rate
0.50
0.45
0.40
0.35
0.9
69.7%
73.7%
76.7%
79.2%
0.85
64.3%
69.7%
73.7%
76.7%
0.8
56.5%
64.3%
69.7%
73.7%
0.75
41.2%
54.5%
63.0%
68.8%
VGCV = valganciclovir
Patient-reported Outcome Endpoints
Successful kidney transplantation is often judged by the impact on morbidity and mortality, 
but these measures do not capture the full extent of the impact on patients’ life and well-
being. Patient-reported outcomes (PROs) measuring health-related quality of life (QoL) can 
fill this gap and provide a more complete evaluation of the impact of a kidney transplant 
procedure on a patients’ health [Acquadro, C., et al 2003] [Szende, A., et al 2005]. Post-
transplant complications and toxicities resulting from drugs commonly used in the transplant 
process can have a negative effect on a patients’ QoL. Patient-reported outcomes (PROs)
have been used extensively to study various immunosuppressive regimens in kidney 
transplant, particularly where use of these drugs can result in drug toxicities or other 
complications that are not life-threatening but occur frequently and are burdensome to 
patients [Cleemput, I. 2007].
The EuroQoL (EQ)-5D, a validated tool of PROs, is a general measure of QoL that has been 
used frequently in kidney transplant and plays an important role in providing utility estimates 
for economic modeling [Cleemput, I., et al 2004]. The 36-Item Short Form Health Survey 
Version 2.0 (SF-36v2®) is a generic health survey which includes 36 questions to measure 
functional health and well-being from the participant’s perspective and has been validated in 
kidney transplant patients [Barotfi, S., et al 2006].  The QoL questionnaires will be 
collected/performed at the timepoints indicated in the Study SoA (see Section 2).
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 Study SoA (Section 2).  Serum Inhibin B, luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), and testosterone levels in male participants will be 
collected to monitor testicular function.  Adverse events are evaluated and recorded 
according to Section 9.3.  Participants may be asked to return for unscheduled visits in order 
to perform additional safety monitoring.
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Leukopenia and Neutropenia
An evaluation of the safety and tolerability of LET, as assessed by review of the accumulated 
safety data, will be assessed as an endpoint in this study.  For the safety analysis, leukopenia 
and neutropenia reported as AEs during the treatment period and also using prespecified 
laboratory parameter limits (see below) will be used for analysis (Section 10).
For each episode of leukopenia or neutropenia that is reported as an AE during the treatment 
period, the corresponding laboratory values and normal ranges of total white blood cell 
(WBC) and absolute neutrophil count (ANC) will be collected (ie, local and central 
laboratory values).

If the AE of leukopenia or neutropenia was reported based on local laboratory results 
collected at the discretion of the investigator during non-study visits, such local 
laboratory results and corresponding normal range values will be collected for 
analysis.  

If the AE of leukopenia or neutropenia was reported based on central laboratory 
values of total WBC and ANC collected at a scheduled study visit, then such 
corresponding central laboratory values will be analyzed.
Sex Hormone Analysis
The rationale for analyzing sex hormone levels is as follows:

Preclinical repeat-dose toxicity studies and fertility studies of LET in male rats revealed 
non-reversible testicular degeneration and reduced male fertility indices with LET at high 
dose levels.  These findings were not observed in studies in mice (in studies up to a 
3-month duration) or monkeys (in studies up to a 9-month duration) where higher 
systemic exposures were obtained, suggesting that the testicular findings in rats may be 
specific for this species.  The relevance to humans is unknown.

In order to evaluate the potential risk for testicular toxicity associated with LET in human 
subjects, levels of serum Inhibin B, LH, FSH, and testosterone as markers of testicular 
toxicity were evaluated in male participants in the Phase 3 trial (P001) to monitor 
changes in testicular function from baseline 04XH3T.  These serum biomarkers have 
been used to monitor gonadotoxicity in subjects who received antineoplastic 
chemotherapy [Muller PY and Dieterle F 2009] and are also listed as hormones that may 
help to inform the drug’s effect on testicular function in the United States Food and Drug 
Administration (US FDA) guidance document on testicular toxicity and evaluation during 
drug development [U.S. Food and Drug Administration 2015].  The proportion of 
participants with low, normal, or high levels of serum Inhibin B, LH, FSH, and 
testosterone in male participants at Baseline and the shift from baseline at the End-of-
Treatment and Week 24 post-transplant visit was evaluated in P001 by treatment arm.  
There was no clinically relevant effect of LET on male sex hormones in a participant 
population of allogeneic HSCT recipients.
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In this study, serum Inhibin B, LH, FSH, and testosterone levels will be measured in all male 
participants.  The central laboratory based sex hormone results will not be shared with the 
respective site investigators.
Pharmacokinetic Endpoints
Pharmacokinetic (PK) samples will be collected from all participants as described in the 
Study SoA (Section 2).  The intensive and population PK data will be used to characterize 
the PK of LET in kidney transplant recipients and evaluate exposure-response relationships 
with selected efficacy and safety endpoints.
LET has a complex PK profile with non-linearity observed over the clinical dose range and 
also small differences were observed in exposures between Asians versus non-Asians (eg, 
33.2% higher in Asians versus whites). As such, PK samples from a sufficient number of 
participants will be needed to characterize PK and identify clinically relevant covariates.
Population PK will be collected in all participants pre-dose (a single sample per subject
within 0-2 hours prior to dose) at each visit of the treatment period.
Intensive PK will be collected during the study as follows:
Week 1 intensive PK:

ALL participants of Asian descent
o
Based on the proportion of participants who were of Asian descent (<10%) in 
P001 (defined as a participant who self-reports both parents as being of Asian 
heritage, ie, the parents should trace their heritage to one of the following 
countries:  Brunei, Cambodia, East Timor, Indonesia, Japan, Laos, Malaysia, 
Mongolia, Myanmar (Burma), Korea, People's Republic of China, Philippines, 
Singapore , Taiwan, Thailand, or Vietnam), intensive PK (at the Week 1 visit; 
see below and Section 2) from all Asian participants for a robust assessment 
of PK and ethnic differences will be needed for this study.  Such intensive PK 
sampling will occur regardless of the study drug formulation (IV or oral) 
administered at the Week 1 visit.
o
Week 1 intensive PK will be performed pre- and post-dose at any time 
between Study Day 6-10 (inclusive) for participants of Asian descent.

OPTIONAL for additional participants (up to ~60 participants of non-Asian descent 
or up to 10% of the non-Asian study population) who consent to Week 1 intensive PK 
regardless of study drug formulation (IV or oral) prior to or at the Week 1 visit to 
obtain additional PK data in the kidney transplant population.
o
Week 1 intensive PK will be performed pre- and post-dose at any time 
between Study Day 6-10 (inclusive) for consenting participants of non-Asian 
descent.
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Intensive PK during IV administration of study medication:

ALL participants who receive >5 consecutive days of IV therapy will have intensive 
PK on the 6th day of IV (prior to and after the 6th day dose) – no more than ONCE 
during the entire study, regardless of how many times the IV therapy criterion is 
fulfilled during the study.
o
No participant will have more than 1 intensive PK performed during the first 
2 weeks of the study.
o
If a participant qualifies for the intensive PK at the Week 1 visit (see above 
and Section 2) and also qualifies for intensive PK due to >5 consecutive days 
of IV therapy within the first two weeks of the study, then intensive PK will 
only be performed on the first qualifying event.  If the events coincide on the 
same day (eg, the Week 1 visit), the intensive PK will still only be collected at 
the Week 1 visit (see above and Section 2).
Based on the above, participants may qualify for and undergo no more than two intensive PK 
measurements during the study: at Week 1 (see above) and on the 6th day after 5 consecutive 
days of IV therapy (also see above).
Table 2 summarizes the requirements of population PK and intensive PK collection during 
the study.
Table 2
Population Pharmacokinetic and Intensive Pharmacokinetic Collection
Population PK – Pre-
dose at Each Visit of 
Treatment Period
Intensive PK at 
Week 1 Visit (Oral or 
IV Administration)
Intensive PK (IV 
Administration >5 
consecutive days)
All Participants 
(Asian and Non-
Asian)
X (Mandatory)
X (Mandatory)
Asian Participants
X (Mandatory)
Optional Consenting 
Non-Asian 
Participants
X (Optional)
All participants who receive >5 consecutive days of IV therapy will have intensive PK on the 6th day of IV (prior to and 
after the 6th day dose) – no more than ONCE during the entire study, regardless of how many times the IV therapy 
criterion is fulfilled during the study.
Participants may qualify for and undergo no more than two intensive PK measurements during the study:  at Week 1 and 
on the 6th day after 5 consecutive days of IV therapy.
IV = intravenous; PK = pharmacokinetics
Details of planned analyses of PK measurements are in Section 10.6.3.2.
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Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
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 will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses 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 be specifically investigated for PK variability, as well 
as efficacy and AEs.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (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 trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of this Future Biomedical Research sub-trial are presented in Appendix 6  –
Collection and Management of Specimens for Future Biomedical Research.
Rationale for the Use of Comparator (Valganciclovir and Ganciclovir)
In the setting of kidney transplant, the SOC for prevention of CMV disease is VGCV at an 
oral dose of 900 mg QD to be started within 10 days of transplantation until 28 weeks (ie, 
200 days) post-transplant [Humar, A., et al 2010].
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Both VGCV and GCV are approved for the prevention of CMV disease following SOT and 
are associated with myelotoxicity.  GCV has been available in both IV and oral formulations 
and was studied in heart transplant and HSCT recipients.  The oral formulation of GCV is 
associated with low oral bioavailability and high pill burden (1 g × three times a day dose) 
and is not currently available.  VGCV is a prodrug of GCV with improved bioavailability 
compared with oral GCV.  VGCV is indicated for the prevention of CMV disease in kidney, 
kidney-pancreas, and heart transplant patients, at the 900 mg QD oral dose.  Therefore, 
VGCV (and IV GCV, if intolerant of oral medications) has been chosen as the comparator 
for this study.
Justification for Dose 
Starting Dose for This Trial
This clinical study will evaluate:

LET
– Oral 480 mg QD, if given without concomitant CsA, or 
– Oral 240 mg QD, if given concomitantly with CsA, or 
– IV 480 mg QD, if given without concomitant CsA, or 
– IV 240 mg QD, if given without concomitant CsA, or 
– IV 240 mg QD, if given concomitantly with CsA
versus 

VGCV oral 900 mg QD (see Section 7.2 for comparable IV dose of GCV).
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 28 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 240 mg QD to 480 mg QD.  In the Phase 2b study
(Protocol 020 (P020), AIC246-01-II-02), LET 240 mg QD, during an 84-day treatment 
period, was well tolerated with a safety profile similar to placebo.
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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 
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 
approximately 3-fold.  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 [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.
LET has previously been evaluated in a Phase 3 trial in HSCT recipients at doses of 240 mg 
PO or IV when administered with CsA, and 480 mg PO or IV when administered without 
CsA.  All doses were generally well-tolerated and efficacious; however, LET exposures 
(steady state median AUC) in HSCT recipients with the 480 mg IV dose (without CsA) were 
higher than in the other three dose groups.  Population PK simulations using data from the 
Phase 3 trial in HSCT recipients suggest that a 240 mg IV dose (without CsA) will provide 
exposures comparable to exposures obtained following administration of a 480 mg PO dose 
(without CsA).  Therefore, an additional dose group of 240 mg IV (without CsA) was added 
to the current protocol to evaluate the PK, efficacy, and safety of this dose in transplant 
recipients.  Participants who receive IV LET (without CsA) will be randomized 1:1 to 
receive either a 480 mg or 240 mg dose.
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Rationale for Dose of VGCV and GCV
In the setting of kidney transplant, the SOC for prevention of CMV disease is VGCV at an 
oral dose of 900 mg QD to be started within 10 days of transplantation until 28 weeks 
(ie, 200 days) post-transplant [Humar, A., et al 2010].
If participants in the VGCV arm cannot tolerate oral medications, IV GCV 5 mg/kg QD will 
be administered [U.S. Prescribing Information 2017].
See Section 5.4.2 for further details.
Maximum Dose/Exposure for This Trial
Rationale for Treatment Duration
CMV prophylaxis is now widely used in the transplant setting and 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 
results of the recent IMPACT study (Section 3.2) confirm that the incidence of CMV disease 
at 12 months post-transplant can be significantly reduced if a 6-month prophylaxis course is 
implemented instead of a 3-month course.  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 [Humar, A., et al 
2010].  Participants will be followed through Week 52 to evaluate the incidence of late-onset 
CMV disease after the conclusion of study medication.
6. Study Population
Male/Female participants of at least 18 years of age with receipt of a kidney transplant will 
be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have a documented negative serostatus for CMV (ie, recipient CMV IgG 
seronegative [R-]) within 180 days prior to randomization.
2. Anticipate receiving a primary or secondary allograft kidney from a CMV IgG 
seropositive (D+) donor at the time of screening AND have received a primary or 
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secondary allograft kidney from a documented D+ donor at the time of 
randomization.
a.
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.
3. Be within 0 (ie, day of transplantation) to 7 days (inclusive) post-kidney transplant at 
the time of randomization.
Demographics
4. Be ≥18 years of age on day of signing informed consent.
Male Participants
5. A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 90 days after the last dose of 
study treatment and refrain from donating sperm during this period.
Note:  A male participant who has a pregnant partner at enrollment will not be 
included in the study.
Female Participants
6. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP), as defined in Appendix 5
OR
b. A WOCBP who agrees to follow the contraception guidance in Appendix 5 
during the treatment period and for at least 90 days after the last dose of study 
treatment.
Informed Consent
7. Understand the study procedures, alternative treatment available, and risks involved 
with the study, and he/she voluntarily agrees to participate by giving written informed 
consent and is willing to adhere to dose and visit schedules.  Participant may also 
provide consent for Future Biomedical Research.  However, the participant may 
participate in the main study without participating in Future Biomedical Research.
Other
8. Be able to read, understand, and complete questionnaires and diaries.
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Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
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 
randomization.
4. Has suspected or known hypersensitivity to active or inactive ingredients of LET
formulations, VGCV, GCV, and/or ACV formulations.
5. Is on dialysis or plasmapheresis at the time of randomization.
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 randomization; and (2) is 
expected to remain off dialysis or plasmapheresis may be enrolled, provided that all 
other inclusion/exclusion criteria are met.
6. Has post-transplant renal function of CrCl ≤10 mL/min at randomization (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 randomization 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 
randomization.  If the repeat value meets this exclusion criterion again, such 
participants may NOT continue in the screening/randomization 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)
7. Has Child-Pugh Class C severe hepatic insufficiency (Appendix 8) at screening.
8. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency
at screening.
Note:  Moderate hepatic insufficiency is defined as Child-Pugh Class B 
(Appendix 8); moderate-to-severe renal insufficiency is defined as CrCl <50 mL/min,
as calculated by the Cockcroft-Gault equation (as above), respectively.
9. Has any uncontrolled infection on the day of randomization.
10. Has documented positive results for human immunodeficiency virus antibody 
(HIV-Ab) test at any time prior to randomization, or for hepatitis C virus antibody 
(HCV-Ab) and with detectable HCV ribonucleic acid (RNA) within 90 days prior to 
randomization or hepatitis B surface antigen (HBsAg) within 90 days prior to 
randomization.
11. Requires mechanical ventilation, or is hemodynamically unstable, at the time of 
randomization.
12. 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.
13. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the 
time of consent through at least 90 days following cessation of study therapy.
14. Is expecting to donate eggs or sperm starting from the time of consent through at least 
90 days following cessation of study therapy.
15. 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.
16. Has exclusionary laboratory value at screening, as listed in Table 3.
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Table 3
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Value
CMV serology (IgG)
Positive
Hemoglobin
<8 g/dL
Platelets
<25,000 cells/µL
Absolute neutrophil count
<1,000 cells/µL
Total bilirubin
>2.5 × ULN
ALT
>5 × ULN
AST
>5 × ULN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; 
IgG = immunoglobulin G; ULN = upper limit of normal
Prior/Concomitant Therapy
17. Has received within 30 days prior to randomization or plans to receive during the 
study any of the following anti-CMV IgG antibody treatment or anti-CMV drug 
therapy including:
a.
Cidofovir
b.
CMV hyper-immune globulin
c.
Any investigational CMV antiviral agent/biologic therapy.
18. Has received within 7 days prior to randomization or plans to receive during the study 
any of the following anti-CMV drug therapy including:
d.
LET
e.
GCV
f.
VGCV
g.
Foscarnet
h.
ACV (at doses 3200 mg PO per day or 25 mg/kg IV per day)
i.
Valacyclovir (at doses 3 g PO per day)
j.
Famciclovir (at doses 1500 mg PO per day)
Note:  The exclusion of LET, GCV, and VGCV applies to prior use and no additional 
unblinded use of LET, GCV, or VGCV outside of the context of the study.
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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.
Note:  Participants with a history of marijuana use which is not deemed excessive by 
an investigator or does not interfere with the participant’s daily function may 
participate in the study but must be instructed to discontinue any further use of 
recreational marijuana prior to entry into study and throughout the study period.
20. Is taking or plans to take any of the prohibited medications listed in the protocol (see 
Section 7.7).
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.
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 or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
Lifestyle Restrictions
No lifestyle restrictions are required based on study procedures.
Meals and Dietary Restrictions
Study therapy should be taken with food, as described in Section 9.1.9.1.
Participants must avoid consumption of grapefruit, Seville oranges or their respective juices, 
and other quinine-containing drinks or food during the study from 2 weeks prior to study 
treatment administration until 72 hours after the final administration of study treatment.
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Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/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 adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
A participant who discontinues from the study will not be replaced.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Treatments Administered
The study treatments to be used in this trial are outlined below in Table 4 and Table 5.  In
this study, approximately 600 participants will be randomized in a 1:1 ratio as follows: 
approximately 300 participants will receive LET, placebo to VGCV, and ACV through 
Week 28 and approximately 300 participants will receive VGCV, placebo to LET, and 
placebo to ACV through Week 28.
The oral and IV formulations of LET, ACV, and VGCV (and the corresponding IV 
formulation of GCV) that will be administered in this study are outlined below in Table 4 and
Table 5, respectively.  Since VGCV tablets are recommended to be taken with food, study 
therapy in both treatment arms should be taken with food.
Participants requiring the oral 480 mg dose of LET should be initiated with one 480 mg 
tablet (LET or matching placebo).  In the event a participant is unable to swallow the 480 mg 
tablet, study therapy may be initiated with 2 × 240 mg tablets (LET or matching placebo).  
Participants who are initiated with two tablets of the 240 mg LET or matching placebo 
should continue with that regimen.  If the 480 mg tablet is not available based on 
country-specific requirements or is not available at the site for any other reason, 2 × 240 mg 
tablets should be used for the 480 mg dose.
For participants who cannot tolerate swallowing and/or develop a condition that may 
interfere with the absorption of the oral formulation at or after randomization/Day 1, study 
therapy can be initiated/switched to the IV formulation. Use of the IV formulation should 
generally be limited to 4 weeks or less in duration per participant. However, it will be left to 
the investigator’s discretion to continue IV administration beyond 4 weeks, if the benefit/risk 
ratio supports continued administration.  Simultaneous use of IV and oral study therapy is 
not allowed.  The IV formulation should be switched to oral study therapy (ie, at the next 
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planned dose) as soon as such participants are able to swallow and/or the condition 
necessitating the use of the IV formulation resolves.
For weight-based dosing of GCV and body surface area (BSA) calculations for IV ACV 
dosing, the most recently measured total body weight (kg) as part of standard of care should 
be used (additional details provided in the Pharmacy Manual).
Table 4
Study Treatments – Oral Formulation
LET
VGCV
ACV
LET (for 
Participants 
not on CsA)
LET (for 
Participants 
on CsA)
Placebo 
to LET
VGCV
Placebo 
to VGCV
ACV (for 
Participants 
in the LET 
Arm)
Placebo to 
ACV (for 
Participants 
in the 
VGCV 
Arm)
Dose
/Potency
480 mg (one 
480-mg tablet 
or two 240-mg 
tablets)
240 mg 
tablet
NA
900 mg 
(Two 450-
mg tablets)
NA
400 mg 
capsule or 
400 mg 
tablet
NA
Dose Frequency
QD
QD
QD
QD
QD
Every 12 
hours
Every 12 
hours
Route of 
Administration
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Regimen/Treatment 
Period
Through 
Week 28
Through 
Week 28
Through 
Week 28
Through 
Week 28
Through 
Week 28
Through 
Week 28
Through 
Week 28
Use
Experimental
Experimental
NA
Active 
comparator
NA
Prophylaxis 
against HSV 
and VZV
NA
Sourcing
Centrally
Centrally
Centrally
Centrally
Centrally
Centrally
Centrally
Dose of ACV and VGCV will be modified based on creatinine clearance, see Section 7.2.
ACV = acyclovir; CsA = Cyclosporin A; HSV = herpes simplex virus; LET = letermovir; NA = not applicable; QD = once 
daily; VGCV = valganciclovir; VZV = varicella zoster virus
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Table 5
Study Therapy – IV Formulation (For Participants Who Cannot Tolerate Oral 
Formulation at and/or After Randomization)
LET
GCV
ACV
LET (for 
Participants not 
on CsA)
LET (for 
Participants on 
CsA or not on 
CsA)
GCV
ACV (for 
Participants in 
the LET Arm)
Placebo to ACV 
(for Participants 
in the VGCV 
Arm)
Dose/
Potency
480 mg
240 mg
5 mg/kg
250 mg/m2
NA
Dose Frequency
QD
QD
QD
Every 12 hours
Every 12 hours
Route of 
Administration
Intravenous*
Intravenous*
Intravenous*
Intravenous*
Intravenous*
Regimen/Treatment 
Period
Through Week 
28**
Through Week 
28**
Through Week 
28**
Through Week 
28**
Through Week 
28**
Use
Experimental
Experimental
Active-
comparator
Prophylaxis 
against HSV 
and/or VZV
NA
Sourcing
Centrally 
(blinding done by 
site)
Centrally 
(blinding done by 
site)
Centrally 
(blinding done by 
site)
Centrally 
(blinding done by 
site)
Locally***
Dose of ACV and GCV will be modified based on creatinine clearance, see Section 7.2.
ACV = acyclovir; CsA = Cyclosporin A; HSV = herpes simplex virus; IV = intravenous; LET = letermovir; NA = not 
applicable; QD = once daily; VZV = varicella zoster virus  
*
The IV formulation dosing volume of LET is 250 mL and the duration of infusion will be 60 minutes.  To reduce the risk 
of unblinding, the infusion volume of GCV IV formulation will be 250 mL and dosed at 5 mg/kg body weight and 
duration of infusion will be 60 minutes. The IV formulation of ACV (or matching IV placebo) will be 250 mL and dosed 
at 250 mg/m2 body surface area (BSA) and duration of infusion will be 60 minutes.  The maximum concentration of 
ACV for IV infusion is not to exceed 7 mg/mL as specified per the product label.
**
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.
*** The type of placebo and diluent for the IV formulation of ACV are described in the Pharmacy Manual.
If the participant fulfills all inclusion criteria and does not meet any exclusion criteria for the 
study, then the participant should begin study therapy on the day of randomization, which 
will be within the first 7 days (inclusive) post-transplant.  The total duration of therapy is 
approximately 28 weeks during which any interruptions of study therapy may not exceed 
>7 consecutive days.
All placebos were created by the Sponsor to match the active product.
All supplies indicated in Table 4 and Table 5 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 
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recording the lot number, manufacturer, and expiry date for any locally purchased product as 
per local guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.9 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other) 
Both oral (tablet) and IV formulations of LET (and matching placebo) will be available. For 
additional details on IV or oral formulations of LET dosing, see Section 5.1. The distribution 
of blinded oral study therapy and blinded IV study therapy with respect to concomitant CsA 
use is described in Table 10 and Table 11, respectively. For additional details on adjustments 
to LET dosing based on the status of concomitant CsA administration (eg, interruption or 
stopping) see Section 9.11.2.2.
The IV formulation of LET contains the excipient hydroxypropyl betadex. Cyclodextrins 
can cause nephrotoxic effects in animals at systemic exposure; however, there is currently no 
evidence of these effects in humans. Hydroxypropyl betadex amounts of approximately 
250 mg/kg/day for 21 days were found to be safe in humans older than 2 years [European 
Medicines Agency 2014].  Given this tolerability information in humans and the amount of 
cyclodextrin (3600 mg) contained in the highest dose (480 mg) of the IV formulation of LET
administered in P001, nephrotoxic effects due to cyclodextrin were not expected in the trial 
population of adult HSCT recipients. Data from P001 suggest that the use of the 
cyclodextrin-containing IV formulation in this trial was not associated with renal toxicity and 
that dosing with the IV formulation is justified throughout the duration of therapy [Marty, F. 
M., et al 2017].
Based on the above, the use of IV LET is permitted in participants with renal insufficiency, 
provided CrCl is >10 mL/min.  However, for this study in renal transplant participants, the 
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 
randomization/Day 1.  Participants on IV LET should be switched to the oral formulation (ie, 
at the next planned dose) as soon as they are able to swallow and/or the condition that 
warranted the use of the IV formulation has resolved.
The effect of renal impairment on LET PK was evaluated in 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, the changes observed in 
LET exposures in participants with moderate or severe renal impairment are within the 
clinical comparability bounds and no dose adjustment is recommended for participants with 
moderate or severe renal impairment [Kropeit, D., et al 2017].
Participants will be randomized to receive LET (480 mg oral LET, or 240 mg oral LET if 
concomitantly given with CsA), or 900 mg VGCV (two 450 mg tablets) PO once daily 
provided that the participant has normal renal function (ie, CrCl of ≥60 mL/min based on
Table 6).  Dose modification of study medications due to reasons other than reduced renal 
function (eg, leukopenia and/or neutropenia) is not permitted.  If a participant initiates 
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treatment with CsA at any time during the study therapy period (ie, through Week 28), then 
the LET dose should be decreased to 240 mg QD.  If a participant discontinues CsA during 
the study therapy period for more than 3 consecutive days, then LET should be increased to 
480 mg QD.
For participants with reduced renal function, the dose of VGCV (or IV GCV) or ACV will be 
modified, based on CrCl (using Cockcroft-Gault formula) according to Table 6 (VGCV), 
Table 7 (GCV), Table 8 (oral ACV), and Table 9 (IV ACV). Dose modification of study 
medications due to reasons other than reduced renal function (eg, leukopenia and/or 
neutropenia) is not permitted.
Table 6
VGCV Dosage Recommendations for Adult Participants Based on Creatinine 
Clearance
CrCl* (mL/min)
VGCV (450 mg Tablets) Dose
≥60
900 mg (2 tablets) once daily
40 – 59
450 mg (1 tablet) once daily
25 – 39
450 mg (1 tablet) every 2 days
10 – 24
450 mg (1 tablet) twice weekly
Participants will need to maintain CrCl >10 mL/min throughout the treatment period with study medication.
*An estimated CrCl is calculated from serum creatinine by the following formula:
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)
CrCl = creatinine clearance; VGCV = valganciclovir
[U.S. Prescribing Information 2017]
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Table 7
GCV (Intravenous) Dosage Recommendations for Adult Participants Based on 
Creatinine Clearance
CrCl* (mL/min)
GCV for Injection
Maintenance Dose (mg/kg)
Dosing Interval (hours)
≥70
5
24
50 – 69
2.5
24
25 – 49
1.25
24
10 – 24
0.625
24
Participants will need to maintain CrCl >10 mL/min throughout the treatment period with study medication.
*An estimated CrCl is calculated from serum creatinine by the following formula:
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)
CrCl = creatinine clearance; GCV = ganciclovir
[U.S. Prescribing Information 2017]
Table 8
ACV (Oral) Dosage Recommendations for Adult Participants Based on 
Creatinine Clearance
CrCl* (mL/min)
ACV (400 mg Capsule or 400 mg Tablet) Dose
≥30
400 mg every 12 hours
10 and <30
400 mg once daily
Participants will need to maintain CrCl >10 mL/min throughout the treatment period with study medication.
*An estimated CrCl is calculated from serum creatinine by the following formula:
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)
ACV= acyclovir; CrCl = creatinine clearance
[Winston, D.J., et al 2012] [Zuckerman, R. A. 2013] [Gold, D. 1987]
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Table 9
ACV (Intravenous) Dosage Recommendations for Adult Participants Based on 
Creatinine Clearance
CrCl* (mL/min)
ACV Dosing Regimen†
≥30
250 mg/m2 every 12 hours
>10 and <30
250 mg/m2 once daily
Participants will need to maintain CrCl >10 mL/min throughout the treatment period with study medication.
*An estimated CrCl is calculated from serum creatinine by the following formula:
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)
ACV = acyclovir; BSA= body surface area; CrCl = creatinine clearance
[Tomblyn, M, et al 2009] [Gold, D. 1987]
†Total BSA (m2) is calculated by the following (Mosteller) formula:
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).  There are 2 study treatment arms.  
Participants will be assigned randomly in a 1:1 ratio to either the LET or VGCV treatment 
arm. Participants randomized to the LET arm and who require intravenous (IV) formulation 
of LET and who are not on concomitant CsA will undergo another randomization (1:1
centrally using IVRS/IWRS) to receive either 240mg IV LET QD or 480mg IV LET QD. See 
Sections 5.1 and 9.11.2.2 for additional details on LET dosing. 
Stratification
Treatment allocation/randomization will be stratified according to the following factors:

Use or non-use of highly cytolytic, anti-lymphocyte immunotherapy during induction
Note:  Such highly cytolytic, anti-lymphocyte immunotherapy includes the use of one or 
more of the following:  horse-derived or rabbit-derived anti-thymocyte globulin, 
alemtuzumab (CAMPATH™), or muromonab-CD3 (OKT3).  During the course of the 
study, this list may be expanded to include other anti-lymphocyte agents that are 
approved for induction therapy in kidney transplant recipients.
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Blinding 
A double-blinding technique with in-house blinding will be used.  The oral formulations will 
be packaged identically so that treatment blind/masking is maintained.  The participant, the 
investigator and Sponsor personnel or delegate(s) who are involved in the study treatment 
administration or clinical evaluation of the participants are unaware of the group 
assignments.
Placebo images to LET (both 240 mg and 480 mg), VGCV, and ACV will be implemented to 
maintain study blinding, and placebo will be indistinguishable from these respective study 
therapies.  Assuming normal renal function (Section 7.2), a participant randomized to the 
LET treatment arm will receive the following from Day 1 through Week 28:

LET (one 480 mg tablet [or 2 × 240 mg tablets] or one 240 mg tablet if given 
concomitantly with CsA per day, ie, once daily)

Placebo to VGCV (2 VGCV-matching placebo tablets per day, ie, once daily)

ACV (two 400 mg capsules or tablets per day, ie, 1 capsule or tablet every 12 
hours)
Accordingly, assuming normal renal function, a participant randomized to the VGCV 
treatment arm will receive the following from Day 1 through Week 28:
1. VGCV (two 450 mg tablets per day, ie, once daily)
2. Placebo to LET (one 480 mg LET-matching placebo tablet [or 2 × 240 mg 
LET-matching placebo tablets] or one 240 mg LET-matching placebo tablet if given 
concomitantly with CsA per day, ie, once daily)
3. Placebo to ACV (2 ACV-matching placebo capsules or tablets per day, ie, 1 capsule 
or tablet every 12 hours)
Table 10 summarizes use of oral study medication (active and placebo) for the LET and 
VGCV treatment arms by use of concomitant CsA for participants with normal renal 
function.
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Table 10
Blinding of Oral Formulation Related to Concomitant CsA Use for Participants 
With Normal Renal Function
LET Arm
VGCV Arm
With 
Concomitant
CsA

One 240 mg LET tablet

Two VGCV-matching placebo 
tablets

Two ACV 400 mg capsules or 
tablets (each capsule or tablet
given every 12 hours)

One 240 mg LET matching placebo 
tablet

Two VGCV 450 mg tablets

Two ACV-matching placebo capsules
or tablets (each capsule or tablet given 
every 12 hours)
Without
Concomitant
CsA

One 480 mg LET tablet or two 
240 mg LET tablets

Two VGCV-matching placebo 
tablets

Two ACV 400 mg capsules or 
tablets (each capsule or tablet
given every 12 hours)

One 480 mg LET-matching placebo 
tablet or two 240 mg LET-matching 
placebo tablets

Two VGCV 450 mg tablets

Two ACV-matching placebo capsules 
or tablets (each capsule or tablet given 
every 12 hours)
ACV = acyclovir; CsA = cyclosporin A; LET = letermovir; VGCV = valganciclovir
Dose of VGCV and ACV will be modified based on creatinine clearance, see Section 7.2.
IV LET, IV GCV, IV ACV (for participants in the LET arm), and IV ACV matching placebo 
(for participants in the VGCV arm) will be prepared in a blinded fashion by an unblinded 
pharmacist (or qualified study site personnel designated to prepare blinded IV study therapy).  
The Sponsor will provide opaque covers for the IV bags in order to assist with blinding IV 
study therapy.
Because this is a double-blind study, the investigator, study personnel, and participant must 
remain blinded to the IV study therapy (LET and ACV for participants in the LET arm and 
LET dose for those not on CsA [240 or 480 mg]; GCV and ACV matching placebo for 
participants in the VGCV arm). In order to maintain the blinding, the unblinded pharmacist 
(or qualified study site personnel designated to prepare blinded IV study therapy) will be 
responsible solely for the preparation of the IV study therapy.  He/she will not be involved in 
evaluating participants for efficacy or safety.  The IV study therapy will be administered by 
blinded personnel of the site.  Refer to the Pharmacy Manual for further details.
Table 11 summarizes use of IV study medication (active and placebo) for the LET and 
VGCV treatment arms by use of concomitant CsA for participants based on renal function.
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Table 11
Blinding of IV Study Medication Related to Concomitant CsA Use for 
Participants Based on Renal Function
LET Arm
VGCV Arm
With Concomitant
CsA
CrCl ≥30 mL/min:

One 250-mL IV bag containing 
240 mg LET (must be administered 
through a sterile 0.2-micron or 
0.22-micron PES in-line filter using 
IV bags and infusion set materials 
that are DEHP-free)

Two 250-mL IV bags, each 
containing ACV 250 mg/m2 × BSA
(each bag given every 12 hours)* .
CrCl >10 mL/min and <30 mL/min:

One 250-mL IV bag containing 
240 mg LET (must be administered 
through a sterile 0.2-micron or 0.22-
micron PES in-line filter using IV 
bags and infusion set materials that 
are DEHP-free)

One 250-mL IV bag containing ACV 
250 mg/m2 × BSA
CrCl ≥30 mL/min:

One 250-mL IV bag containing GCV 
(see Table 7 for GCV dosage 
recommendations based on renal 
function)

Two 250-mL IV bags:  ACV-
matching placebo (each bag given 
every 12 hours); one of the ACV-
matching placebo doses, ie, the one to 
be paired with IV GCV infusion, must 
be administered through a sterile 
0.2-micron or 0.22-micron PES in-
line filter using IV bags and infusion 
set materials that are DEHP-free
CrCl >10 mL/min and <30 mL/min:

One 250-mL IV bag containing GCV 
(see Table 7 for GCV dosage 
recommendations based on renal 
function)

One 250-mL IV bag ACV-matching 
placebo to be paired with IV GCV 
infusion (must be administered 
through a sterile 0.2-micron or 0.22-
micron PES in-line filter using IV 
bags and infusion set materials that 
are DEHP-free)
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LET Arm
VGCV Arm
Without 
Concomitant
CsA
CrCl ≥30 mL/min:

One 250-mL IV bag containing 
480 mg LET or 240 mg LET (must 
be administered through a sterile 
0.2-micron or 0.22-micron PES in-
line filter using IV bags and infusion 
set materials that are DEHP-free)

Two 250-mL IV bags, each 
containing ACV 250 mg/m2 × BSA
(each bag given every 12 hours)
CrCl >10 mL/min and <30 mL/min:

One 250-mL IV bag containing 
240 mg LET (must be administered 
through a sterile 0.2-micron or 0.22-
micron PES in-line filter using IV 
bags and infusion set materials that 
are DEHP-free)

One 250-mL IV bag containing ACV 
250 mg/m2 × BSA
CrCl ≥30 mL/min:

One 250-mL IV bag containing GCV
(see Table 7 for GCV dosage 
recommendations based on renal 
function)

Two 250-mL IV bags:  ACV-
matching placebo (each bag given 
every 12 hours); one of the ACV-
matching placebo doses, ie, the one to 
be paired with IV GCV infusion, must 
be administered through a sterile 
0.2-micron or 0.22-micron PES in-
line filter using IV bags and infusion 
set materials that are DEHP-free
CrCl >10 mL/min and <30 mL/min:

One 250-mL IV bag containing GCV 
(see Table 7 for GCV dosage 
recommendations based on renal 
function)

One 250 mL IV bag: ACV-matching 
placebo to be paired with IV GCV 
infusion (must be administered 
through a sterile 0.2-micron or 
0.22-micron PES in-line filter using 
IV bags and infusion set materials that 
are DEHP-free)
ACV = acyclovir; BSA= body surface area; CsA = cyclosporin A; GCV = ganciclovir; IV = intravenous; 
LET = letermovir; VGCV = valganciclovir
Dose of GCV and ACV will be modified based on creatinine clearance, see Section 7.2.
*The maximum concentration of ACV for IV infusion is not to exceed 7 mg/mL as specified per the product 
label.
If a participant’s dose of VGCV or VGCV matching placebo is modified due to renal 
insufficiency (see Section 7.2), the blinding to VGCV or VGCV matching placebo will be 
maintained.  Similarly, if a participant’s dose of ACV or ACV matching placebo is modified 
due to renal insufficiency (see Section 7.2), the blinding to ACV or ACV matching placebo 
will be maintained.
See Section 9.1.11 for a description of the method of unblinding a participant during the trial, 
should such action be warranted.
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Preparation/Handling/Storage/Accountability
Dose Preparation
For the oral formulation, participants will receive blinded bottles (each containing a 2-week 
supply of study therapy).  Kitting will not be used, and participants will be provided bottles 
of study drug representing the appropriate drug types used in the study per each treatment 
cycle.
For the IV formulation, open-label vials of LET, ACV and GCV will be supplied to the sites.  
The IV formulation will be dispensed in a blinded fashion by an unblinded pharmacist (or 
qualified study site personnel designated to prepare blinded IV therapy) as directed by the 
protocol to the appropriate dosage for each participant.
The LET IV formulation dosing volume will be 250 mL and the duration of infusion will be 
60 minutes.  LET IV will be administered through a sterile 0.2-micron or 0.22-micron PES 
in-line filter using IV bags and infusion set materials that are DEHP-free.  
To reduce the risk of unblinding, the same administration instructions for LET IV will apply
to the dose of IV placebo to ACV that is paired with the dosing of GCV IV (Table 11).
To further reduce the risk of unblinding, the infusion volume of GCV IV formulation will be 
250 mL and it will be dosed at 5 mg/kg body weight (see Table 7 for GCV dosing adjustment 
based on CrCl) and the duration of infusion will be 60 minutes. 
The ACV IV formulation will be 250 mL and dosed at 250 mg/m2 (see Table 9 for ACV 
dosing adjustment based on CrCl) BSA and the duration of infusion will be 60 minutes. The 
maximum concentration of ACV for IV infusion is not to exceed 7 mg/mL, as specified per 
the product label.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
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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 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.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
The investigator/study coordinator will train the participant in the use of the Study 
Medication Diary.  The participant will be instructed to record the number of tablets or 
capsules of study therapy taken during the study therapy period.  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 or 
comparable inpatient setting (including but not limited to skilled nursing facility or 
rehabilitation facility) in which non-study and study medications are administered by clinical 
personnel), 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 by blinded personnel.  The investigator/study coordinator will 
be responsible for transferring the appropriate information to the case report form.
Study therapy (ie, all three oral study medications or both IV study medications) may be 
interrupted for any reason for a time period of ≤7 consecutive days (including suspected 
CMV Disease; see Section 9.2.1); in such cases, all study therapy (ie, all three oral study 
medications or both IV study medications) should be interrupted.  Interruption of a subset of 
study therapy (eg, one or two out of three oral study medications or one out of two IV study 
medications) will not be permitted (except in the event of HSV/VZV infection, see 
Section 7.7.1).  Study therapy interruption due to post-randomization CrCl ≤10 mL/min or 
requirement for dialysis or plasmapheresis is described in Section 9.1.9.1.  Interruption from 
the protocol specified treatment for a time period of ≤7 consecutive days due to an AE 
followed by re-starting of protocol specified treatment upon resolution of the AE is 
permitted.
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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.
Concomitant Therapy
Medications/therapies listed in this section pertain to co-administration with LET, VGCV, 
and ACV.  When used, these agents should be administered in a manner consistent with the 
local product circular for these agents (if available for LET) including the complete list of 
prohibited medications (ie, those that are contraindicated or not recommended); the local 
product circular for these agents (if available for LET) supersedes Section 7.7 with respect to 
prohibited medications.  Additional information on LET use is provided in the IB.
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 
medication or vaccination specifically prohibited during the trial, discontinuation from trial 
therapy 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 therapy 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.
Given that the lists below are not comprehensive, the investigator should use his/her medical 
judgment when a participant presents with a medication not on the list and consult with the 
Sponsor when appropriate.
Prohibited Medication
Listed below are specific restrictions for concomitant therapy during the course of the trial.
•
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 for 
co-administered medication for drug interactions with CsA).
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The following medications/therapies are prohibited during the dosing period and for 14 days 
after the dosing period:

Certain HMG-CoA reductase inhibitors (statins): When LET is co-administered with 
CsA, the magnitude of the increase in statin plasma concentrations is expected to be 
greater than with LET alone.  
o
Simvastatin or pitavastatin with LET or when LET is co-administered with 
CsA.
o
Atorvastatin or lovastatin when LET is co-administered with CsA.

Note: see below for co-administration of LET with atorvastatin, 
fluvastatin, lovastatin, rosuvastatin, or pravastatin.

Fixed dose combination products containing statins are not allowed because the 
dosage of statins should be adjusted when LET is co-administered.

Strong inducers, such as rifampin, phenytoin, carbamazepine, St John’s wort 
(Hypericum perforatum), rifabutin and phenobarbital

Moderate inducers, such as nafcillin, thioridazine, modafinil and bosentan

Cytochrome P450 3A (CYP3A) substrates with narrow therapeutic range (NTR) that 
can lead to SAEs, including but not limited to:
o
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 torsade de pointes.
o
Ergot alkaloids: Concomitant administration of LET may result in increased 
concentration of ergot alkaloids (ergotamine and dihydroergotamine) due to 
inhibition of CYP3A by LET, which may lead to ergotism.

Repaglinide when LET is co-administered with CsA (Note: see below for co-
administration of LET with repaglinide).

Everolimus when LET is co-administered with CsA (Note: see below for 
co-administration of LET with everolimus).

Any investigational CMV antiviral agent/biologic therapy, including CMV vaccines
or CMV hyper-immune globulin except for GCV or VGCV as used as study 
medication in this trial.

The following medications/therapies are prohibited for the prevention/treatment of 
CMV while participants are on study therapy (except for cases of suspected CMV 
Disease; see Section 9.2.1).  Participants for whom cidofovir or foscarnet is 
administered for non-CMV infections (eg, cidofovir for treatment of BK virus 
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infection) must interrupt all study medications during cidofovir or foscarnet 
administration (see Section 7.6 regarding the duration of interruption of study 
medications). ACV, valacyclovir, and famciclovir may be used at thresholds lower 
than specified below (for a subset of these medications for which such thresholds are 
specified):
o
LET that is not part of study intervention
o
GCV or VGCV that is not part of study intervention
o
Foscarnet (see above)
o
Cidofovir (see above)
o
ACV (at doses >3200 mg PO per day or >25 mg/kg IV per day)
o
Valacyclovir (at doses >3000 mg or ≤500 mg PO per day, and not for 
HSV/VZV prophylaxis; see below)
o
Famciclovir (at doses >1500 mg or ≤1000 mg PO per day, and not for 
HSV/VZV prophylaxis; see below)
o
Note:  The use of oral ACV at doses stated in this protocol is allowed for 
prophylaxis of HSV or VZV infections at lower doses as per manufacturer’s 
recommendation.  The use of valacyclovir or famciclovir for HSV/VZV 
prophylaxis is not permitted in this trial.  The use of ACV, valacyclovir, or 
famciclovir for HSV/VZV infections (herpes labialis, herpes zoster, or genital 
herpes) within the dose ranges specified is permitted; during such instances, 
the use of ACV versus matching placebo should be stopped (see 
Section 7.7.1).

Imipenem-cilastatin 

Investigational Agents:  Unapproved investigational agents or investigational 
regimens involving combinations of approved agents (eg, immunosuppressive agents) 
are not permitted.

Herbal Supplements:  Herbal supplements are not permitted.
The following medications/therapies may require dose adjustment or closer monitoring 
during the dosing period and for 14 days after the dosing period:
•
Inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters:
o
CsA:  Co-administration of LET with CsA, a potent OATP1B1/3 inhibitor, 
increases the concentrations of LET. If LET is co-administered with CsA, the 
recommended dose of LET is 240 mg once daily.
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•
Substrates of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and/or 
CYP3A:
o
Statins:

Atorvastatin:  The dose of atorvastatin should not exceed a daily dose of 
20 mg.  Atorvastatin is prohibited when co-administered with LET and 
CsA (see above).

Fluvastatin, lovastatin, rosuvastatin, or pravastatin:  The dose of 
fluvastatin, lovastatin, rosuvastatin, or pravastatin may need to be adjusted 
when co-administered with LET.  Lovastatin is prohibited when co-
administered with LET and CsA (see above).  Monitoring for statin-
associated adverse reactions (eg, myalgias, rhabdomyolysis) is 
recommended during co-administration.
o
Glyburide, a substrate of OATP1B1/3: Frequent monitoring of glucose 
concentrations is recommended during co administration of glyburide with LET.
•
Substrates of CYP2C8 (repaglinide, rosiglitazone):
o
Repaglinide, rosiglitazone:  LET is an in vitro inhibitor of CYP2C8.  
Co-administration of LET with CYP2C8 substrates (eg, repaglinide, 
rosiglitazone) may increase the plasma concentrations of CYP2C8 substrates.  
Frequent monitoring of glucose concentrations is recommended during 
co-administration of repaglinide and rosiglitazone and LET.
•
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 (examples:  alfentanil, fentanyl, midazolam, quinidine).  
Therefore, frequent monitoring for adverse reactions related to these agents is 
recommended during co-administration.  When LET is co-administered with CsA, 
the combined effect on CYP3A substrates may be similar to a strong CYP3A 
inhibitor. Refer to the prescribing information for CsA and for co-administered 
medication for dosing of the CYP3A substrate with a strong CYP3A inhibitor.
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 accordingly.
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
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 accordingly.
When LET is co-administered with CsA, refer to the sirolimus 
prescribing information for specific dosing recommendations for use 
of sirolimus with CsA.

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 accordingly.

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 
above).

Amiodarone:  LET may increase the plasma concentrations of amiodarone 
(CYP3A and CYP2C8 substrates).  Frequent monitoring for adverse 
reactions related amiodarone is recommended during co-administration.  
Frequent monitoring of amiodarone concentrations should be performed 
when co-administered with LET.
•
Substrates of CYP2C9 and CYP2C19 (voriconazole, warfarin, omeprazole, and 
pantoprazole):
o
Voriconazole:  Co-administration of LET with voriconazole decreases the plasma 
concentrations of voriconazole likely due to induction of CYP2C9 and/or 2C19.  
If concomitant administration is necessary, close monitoring for reduced 
effectiveness of voriconazole is recommended.
o
Warfarin:  LET may decrease the plasma concentrations of CYP2C9 and/or 
CYP2C19 substrates (eg, warfarin).    Frequent monitoring of international 
normalized ratio (INR) should be performed while warfarin is co-administered 
with LET.
o
Proton Pump Inhibitors, omeprazole and pantoprazole:  LET may decrease the 
plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose 
adjustment may be needed.
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Concomitant Use with VGCV/GCV
Note: In vivo drug-drug interaction studies were not conducted with VGCV.  However, 
because VGCV is rapidly and extensively converted to GCV, drug-drug interactions 
associated with GCV will be expected for VGCV.  Drug-drug interaction studies with GCV 
were conducted in patients with normal renal function.  Following concomitant 
administration of VGCV and other renally excreted drugs, patients with impaired renal 
function may have increased concentrations of GCV and the co-administered drug.  
Therefore, these patients should be closely monitored for toxicity of GCV and the co-
administered drug [U.S. Prescribing Information 2017].
Potential drug interactions may occur when the following drugs are co-administered with 
VGCV/GCV and should therefore be closely monitored as described below:

CsA or amphotericin B: Monitor renal function because of potential increase in serum 
creatinine.

Probenecid:  May increase GCV levels.  Monitor for evidence of GCV toxicity (eg, 
neutropenia).

MMF:  In patients with renal impairment GCV concentrations and MMF metabolite 
concentrations may increase.  Monitor for GCV (eg, neutropenia) and MMF toxicity 
(eg, neutropenia, red-cell aplasia, viral infections, and/or lymphoproliferative 
disorders).

Didanosine: Patients should be closely monitored for didanosine toxicity (eg, 
pancreatitis).

Other drugs associated with myelosuppression or nephrotoxicity (eg, adriamycin, 
dapsone, doxorubicin, flucytosine, hydroxyurea, pentamidine, tacrolimus, 
trimethoprim/sulfamethoxazole, vinblastine, vincristine, and zidovudine): Because of 
potential for higher toxicity, co-administration with VGCV/GCV should be 
considered only if the potential benefits are judged to outweigh the risks [U.S. 
Prescribing Information 2017].
Note:  Please also see Section 6.3.1 for dietary restrictions.
Concomitant Use with ACV
Potential drug interactions with probenecid may occur when it is co-administered with 
intravenous ACV as co-administration of probenecid with ACV IV has been shown to 
increase the mean ACV half-life and the area under the concentration-time curve.  Dose 
adjustment may be required for ACV IV when co-administered with probenecid.
Concomitant medications and therapies that are discontinued or dose adjusted during the 
dosing period may be restarted or re-adjusted 2 weeks after the last dose of study drug is 
administered and may continue during the follow-up period.
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NOTE:  For other medications not listed here, please consult with the Sponsor as 
needed.
Rescue Medications & 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 start CMV treatment due to any other reason, study therapy 
will be discontinued (see Section 9.2.1) 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 7.7) can be used.
In the event of HSV/VZV infection (as diagnosed by the investigator; herpes labialis, herpes 
zoster, and genital herpes) during the study therapy period (ie, prior to completion or early 
discontinuation of study therapy), the ACV study medication will be interrupted and the 
participant may be treated according to the local SOC (outside the context of the study) while 
continuing other study medications (LET + VGCV matching placebo versus VGCV + LET 
matching placebo).  In this setting, valacyclovir or famciclovir or ACV at dose ranges 
outlined in Section 7.7 can be used.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind participants and to unmask study treatment identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 9.1.11). In the 
event that the emergency unblinding call center is not available for a given site in this trial, 
the central electronic treatment allocation/randomization system (IVRS/IWRS) should be 
used in order to unblind participants and to unmask study treatment identity.  The Sponsor 
will not provide random code/disclosure envelopes or lists with the clinical supplies.
See Section 9.1.11, Participant Blinding/Unblinding, for a description of the method of 
unblinding a participant during the trial, should such action be warranted.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
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will still continue to participate in the study as specified in Section 2 - Schedule of Activities 
and Section 9.11.4 – CMV Disease or Early Discontinuation Visit.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.10 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant develops confirmed or suspected CMV disease as determined by the 
investigator (Section 5.4.1.1).
o
The participant has a confirmed positive pregnancy test.
o
An investigator feels it is in the best interest of the participant to discontinue.
o
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.
o
The participant develops:

Both moderate hepatic insufficiency (Child-Pugh Class B; Appendix 8) and 
moderate-to-severe renal insufficiency (defined as CrCl <50 mL/min as calculated 
by the Cockcroft-Gault equation; see Section 6.2), 
OR

Severe hepatic insufficiency (Child-Pugh Class C; Appendix 8).
The participant may be discontinued from study therapy for any of the following reasons:
o
Any AE/SAE assessed by the investigator as possibly or probably related to study 
therapy.  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 therapy.
o
Failure to comply with the dosing, evaluations, or other requirements of the study.
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o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk through 
continued participation in the study or does not allow the participant to adhere to the 
requirements of the protocol (eg, if there is a clinical indication for any medication or 
vaccination specifically prohibited during the trial, discontinuation from trial therapy may 
be required [see Section 7.7]).
Participants who interrupt (see Section 9.2.1) or discontinue study therapy prior to Week 28
because they are suspected of developing CMV disease must complete a CMV Disease Visit
(Sections 2 (SoA) and 9.11.4.1).  A CMV Disease Visit may be performed at any time when 
one or more criteria for the CMV Disease Visit (Section 9.11.4.1) is fulfilled.  If the 
participant presents with signs/symptoms of CMV disease at a scheduled study visit, then the 
procedures for a CMV Disease 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 2), are performed at the CMV Disease Visit immediately 
prior to the initiation of treatment of CMV disease.  Most importantly, a confirmatory 
plasma sample for CMV DNA PCR testing, a plasma sample for CMV viral resistance 
testing (note:  once the CMV Disease visit occurs, another plasma sample for CMV viral 
resistance testing should be collected at the next scheduled visit; see Sections 9.5.8.2 and 
9.5.8.3), 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 2).  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.
Participants with confirmed CMV disease at any time during the study will complete all 
remaining scheduled visits (ie, through Week 52).
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, see Section 2 – Schedule of Activities (SoA), and Section 9.11.4 – CMV Disease or 
Early Discontinuation Visit for those procedures to be completed at each specified visit.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued,
he/she shall not be allowed to restart study treatment. 
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
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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 9.1.10 – Withdrawal/Discontinuation. The procedures to be performed 
should a participant repeatedly fail to return for scheduled visits and/or if the study site is 
unable to contact the participant are outlined in Section 8.3.
Lost to Follow Up
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:
o
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.
o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The Investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of trial site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
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●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the subject.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The amount of blood collected from each participant over the duration of the study is 
provided in Table 18.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial, or Future Biomedical Research, or optional PK collection at Week 1 (applicable 
for non-Asian participants). If there are changes to the participant’s status during the trial (eg, 
health or age of majority requirements), the investigator or qualified designee must ensure 
the appropriate consent is in place. 
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
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Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study at screening and on Day 1 
(randomization).
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized in the event of an emergency. The investigator or 
qualified designee will provide the participant with a Participant Identification Card 
immediately after the participant provides written informed consent. At the time of treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee at screening.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement.  This includes review of consumption of grapefruit, 
Seville oranges or their respective juices, and other quinine-containing drinks or food.  Prior 
medication taken by the participant within 30 days prior to randomization will be recorded.
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 therapy 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 
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follow-up period through Week 52, concomitant medication review and collection is limited 
to the above and all antimicrobials (antibacterials, antifungals, antiparasitic agents, and 
antivirals), oral hypoglycemic agents, insulin, granulocyte colony-stimulating factor 
(G-CSF), and immunosuppressant agents.
Kidney Transplant/Dialysis Details Review
All relevant data about the kidney transplant will be collected on Day 1 (at randomization).  
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.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Those participants who meet any of the laboratory exclusion criteria in Table 3 at screening 
and whose planned/scheduled kidney transplant was not performed may be rescreened for
study eligibility.  To reconfirm the participant’s eligibility, all screening evaluations should 
be repeated, after approval from the Sponsor.  Any participant who is screened multiple times 
will retain the original screening number assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.11.1.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
The first dose of study treatment will be administered at the trial site on Day 1 after 
randomization.  Subsequent oral dosing will be performed by the participant 
(eg, self-administered at his/her home).  See Section 7.6 for details regarding oral medication 
administered during any hospitalization or comparable inpatient setting (including but not 
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limited to skilled nursing facility or rehabilitation facility).  For IV formulation, the 
unblinded pharmacist (or qualified study site personnel designated to prepare blinded IV 
study therapy) will be responsible solely for the preparation of the IV study therapy.  The IV 
study therapy will be administered by blinded site personnel.  IV LET and, where 
appropriate, placebo to IV ACV will be administered through a sterile 0.2-micron or 
0.22-micron PES in-line filter and using DEHP-free IV bags and infusion set materials.  
Refer to the Pharmacy Manual for further details.
Timing of Dose Administration
Study therapy should be taken at approximately the same time each day for the duration of 
the study (ie, once daily for LET or VGCV; every 12 hours for ACV).  Tablets or capsules 
are to be swallowed whole (ie, no crushing or chewing is allowed).  Since VGCV tablets are 
recommended to be taken with food, study therapy in all treatment arms should be taken with 
food.  Treatment compliance is further described in Section 7.6.
If a participant misses a dose of study medication, the missed dose should be taken as soon as 
possible during the same day.  Then, the next dose should be taken at the normally scheduled 
time.  However, if more than 18 hours have elapsed 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.
Participants with post-randomization CrCl ≤10 mL/min or who require dialysis or 
plasmapheresis after randomization will have all of 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.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities 
scheduled for the Early Discontinuation Visit should be performed at the time of withdrawal.  
Any adverse events which are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 9.3 - Adverse Events.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the participant's consent for Future Biomedical Research will be withdrawn.  A letter will be 
sent from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of 
the investigator to inform the participant of completion of withdrawal.  Any analyses in 
progress at the time of request for withdrawal or already performed prior to the request being 
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received by the Sponsor will continue to be used as part of the overall research trial data and 
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 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.
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND THE PARTICIPANT UNLESS 
NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used 
by a participant and/or the dosage administered, he/she will contact the emergency 
unblinding call center by telephone and make a request for emergency unblinding.  As 
requested by the investigator or delegate the emergency unblinding call center will provide
the information to him/her promptly and report unblinding to the sponsor.  Prior to contacting 
the emergency unblinding call center to request unblinding of a participant’s treatment 
assignment, the investigator or delegate must enter the intensity of the adverse events 
observed, the relation to study drug, the reason thereof, etc., in the medical chart etc.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for participant safety.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the participant.  Every effort should be made not to unblind the participant unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be
unblinded so that the appropriate follow-up medical care can be provided to the participant.
Domiciling
For participants who will undergo intensive PK sampling, the investigator should make 
arrangements (including local accommodations outside the context of hospitalization, if 
needed/warranted) 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.
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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.
Volumetric pump (not provided by the Sponsor)
Efficacy Assessments 
CMV Disease Assessment
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 7. If CMV Disease is 
suspected, site should perform the CMV Disease Visit instead of the scheduled visit 
assessments (see Sections 2 (SoA) and 9.11.4.1) 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 7 will be collected.
For participants who develop suspected or confirmed CMV disease:  Clinical and 
laboratory evaluation of participants with suspected or confirmed CMV disease may be 
performed at the discretion of the site investigative team and at any time during the study 
therapy or follow-up period.  During such evaluations, if a blood sample for CMV viral DNA 
testing is collected for processing by a local laboratory by the site investigative team, clinical 
decisions and management will be made based on the results of the local CMV DNA PCR 
results and assessment of the participant’s CMV disease. When a CMV DNA PCR is 
collected for processing by a local laboratory, it is mandatory that a separate blood sample
also be collected for CMV DNA PCR and sent to the central laboratory for processing.
Note:  It is mandatory to send a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (ie, on the day of) initiating treatment for 
confirmed or suspected CMV disease.  In the event that the confirmatory result obtained on 
the day of anti-CMV treatment initiation is NOT available (eg, sample is lost or mishandled 
by the investigator site prior to shipment, or is inadequate upon receipt at the central 
laboratory), a subsequent sample must be obtained and sent to the central laboratory within 
7 days after initiation of anti-CMV treatment (preferably within 48-72 hours).
If CMV disease is confirmed by the investigator while the participant is on study treatment or 
a clinical decision is made by the investigator to stop study medication and start CMV 
treatment due to any other reason (eg, symptomatic CMV DNAemia without meeting the 
criteria for CMV syndrome):  The participant’s study therapy will be discontinued (see 
following bullet) and a CMV Disease Visit (including collection of CMV DNA PCR and a 
CMV viral resistance sample; see Section 2 (SoA)) will be completed prior to initiating 
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standard-of-care treatment for CMV disease, which may be started at the investigator’s 
discretion [Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S 2013].  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 SoA (Section 2).  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.

Following the CMV Disease Visit, a participant may interrupt study treatment (if the 
participant is on study treatment at the time of the CMV Disease Visit) and receive 
standard-of-care treatment for CMV Disease 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 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 standard-of-care treatment for CMV Disease 
and resume previously assigned study treatment.
If CMV disease is suspected or confirmed by the investigator during the post-treatment 
follow-up period (ie, after completion or early discontinuation of study therapy):  Participants 
may be started on standard-of-care treatment for CMV disease at the investigator’s discretion 
and will complete all remaining follow-up visits (through Week 52; Section 2).  See 
Section 2 (SoA) for procedures performed at the CMV Disease Visit.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
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From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, 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 to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 12 .
Table 12
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- subject 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
- subject 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
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
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 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
Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
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including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 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 treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints (Health Outcomes) including re-hospitalizations (including re-
hospitalizations 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 9.10.1 for a 
complete list) must be collected throughout the study (ie, during both treatment and 
follow-up). From the time of treatment allocation/randomization, through 14 days following 
cessation of treatment, these events must be reported as described in Section 9.3.1. 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 adverse events if they are assessed as serious and there is evidence to 
suggest a causal relationship between the drug and the adverse event. An external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial (see Appendix 3).
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
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reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial 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.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. 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 trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Treatment of Overdose
In this study, an overdose is any dose higher than two times the prescribed dose specified in 
Section 7.2 (Dose Modification [Escalation/Titration/Other]).  Overdose during the study will 
be a reportable safety event (see Section 9.3.1 and Appendix 4 for further details).
Safety 
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study (from screening through Week 52), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in Appendix 2, 
Table 18.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
All physical examinations must be performed by the principal investigator or subinvestigator 
(physician, physician assistant, or nurse practitioner).
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A complete physical examination, performed at the screening visit, Day 1 (randomization), 
and Week 28, includes the following assessments: general appearance, head, eyes,
ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and 
neurologic evaluations. Breast, rectal, and genitourinary/pelvic examinations should be 
performed when clinically indicated.
After randomization (Day 1), 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 2).
Weight and Height Assessment
The participant's weight and height will be assessed as indicated in the Study SoA
(Section 2).
Vital Signs
Vital signs will be assessed as indicated in the Study SoA (Section 2).
Vital signs will include heart rate (sitting), blood pressure (sitting), respiratory rate, and body 
temperature (oral preferred; see below).  Participants should be resting for at least 10 minutes 
prior to measurement of vital signs.
Note:  Temperatures should be taken orally, but if oral is not possible, tympanic, rectal, and 
axillary temperatures are acceptable.
12-Lead Electrocardiogram
As indicated in the SoA (Section 2), 12-Lead ECG measurements will be performed and read 
locally.  If participants have had ECG measurements collected within 3 months prior to 
screening and if such prior ECG measurements are available for the study, ECG 
measurements will not need to be obtained at screening.
Participants should be shaved as necessary for proper lead placement.  Participants should be 
resting in a semi-recumbent position for at least 10 minutes prior to having ECG readings 
obtained.
Child-Pugh Score
The Child-Pugh Score will be assessed as indicated in the Study SoA (Section 2) according 
to Appendix 8.  At the screening visit, the clinical assessment and the local 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 8.1, a participant must be 
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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 6.2), or develops severe hepatic insufficiency (Child-Pugh Class C).
Birth Control Confirmation
Participants must use acceptable methods of contraception from the time of consent through 
90 days after the last dose of study therapy (see Appendix 5).  Confirmation must be obtained 
by site personnel that participants and their partner(s) are using acceptable methods of 
contraception.  This assessment must be documented in the participant's study chart at each 
specified visit.
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 9.3 (Assessing and Recording Adverse Events) for further details.
Infusion-Site Adverse Events for Participants Administered IV Study Therapy
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 therapy.  Events will be entered on the AEs 
electronic case report form.  The study site guidance for assessment and follow-up for 
infusion-site AEs can be found in the Investigator Trial File Binder.
Clinical Safety Laboratory Assessments
Laboratory Safety Evaluations
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 must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
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●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
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 
treatment, 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. 
CMV DNA PCR Testing
Protocol-specified CMV DNA levels will be drawn at prespecified clinical visits:  at 
randomization, 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 2).
In this study, the monitoring of CMV DNA levels for the clinical management of participants 
will be performed locally, ie, “for cause” CMV DNA levels may be measured at any time 
during the study at the discretion of the site investigator and/or clinical management team.  
When a CMV DNA PCR is drawn at the site and sent to a local laboratory for clinical 
management of a participant, it is mandatory that a separate blood sample also be collected 
for CMV DNA PCR and sent to the central laboratory for processing.  There is no protocol-
specified threshold for diagnosis of CMV disease and/or stopping CMV prophylaxis and 
initiating CMV disease therapy.  “For cause” CMV DNA levels will be available to the site 
investigator.
At the CMV Disease Visit, a blood sample will be taken for a CMV DNA PCR assessment 
(see note below).
Note:  It is mandatory to send a confirmatory plasma sample for CMV DNA PCR testing to 
the central laboratory immediately prior to (ie, on the day of) initiating treatment for 
confirmed or suspected CMV disease.  In the event that the confirmatory result obtained on 
the day of anti-CMV treatment initiation is NOT available (eg, sample is lost or mishandled 
by the investigator site prior to shipment, or is inadequate upon receipt at the central 
laboratory), a subsequent sample must be obtained and sent to the central laboratory within 
7 days after initiation of anti-CMV treatment (preferably within 48-72 hours).
Central laboratory based CMV DNA levels (as well as “for cause” assessments; see above) 
will be retrospectively analyzed at the end of the study.  The central laboratory based CMV 
DNA levels will not be shared with the respective site investigators.
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
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CMV Viral Resistance Testing
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
CMV 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 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 Disease visit 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 CMV treatment; or (3) -initiation 
of CMV treatment during the follow-up period (see Section 2). Once the CMV Disease 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 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.
CMV UL55 (gB) Genotypic Testing
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
The CMV glycoprotein B (gB) genotype will be determined by DNA sequencing of the 
CMV UL55 gene in plasma samples collected from participants who meet the criteria for 
confirmed CMV disease or in whom study therapy was stopped and CMV treatment was 
started.  Five different gB genotypes (gB1/gB2/gB3/gB4/gB5) have been described for CMV 
clinical isolates, with a defined DNA sequence of the UL55 gene that is associated with each 
gB genotype.  To perform the gB genotyping, a portion of the UL55 gene will be amplified 
by PCR from total DNA isolated from plasma, and the DNA sequence of the PCR products 
will be determined by next-generation sequencing.  The genotyping procedure will be 
performed by an established contract laboratory with validated protocols in place.
The CMV gB genotyping report will identify any genotype(s) that were detected in each 
sample evaluated; for samples with more than one genotype detected, the relative abundance 
of each genotype will be reported.
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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 180 days of 
randomization 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 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.
Pharmacokinetics
Blood Collection for Plasma Letermovir
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
Population (sparse) PK samples 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.
The intensive PK samples will be collected at the Week 1 visit for participants (ie, of Asian
descent, and consenting participants of non-Asian descent; see Sections 2 and 5.4.1.4 for 
further details) who receive oral or IV formulation of study medication at the following 
timepoints:

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)

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)
The intensive PK samples will be collected for all participants who have received 
>5 consecutive days of IV administration – no more than ONCE during the entire study, 
regardless of how many times the IV therapy criterion is fulfilled during the study (see 
Sections 2 and 5.4.1.4 for further details).  The timing of the intensive PK collection will be 
after 5 days of consecutive administration of IV treatment (ie, 6th consecutive day of IV 
treatment) at the following timepoints prior to and after start of study medication infusion:

Pre-dose (within 0-2 hours prior to dose)

1 hour (within 10 min after infusion completion)
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
2.5 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)
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:

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.
Biomarkers
Collection of samples for other biomarker research is also part of this study. Blood samples 
for biomarker research are required and will be collected from all participants in this study as 
specified in the SoA.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.  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 Institutional 
Review Board (IRB)/Independent Ethics Committee (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 extract DNA will be stored for future biomedical 
research if the participant signs the Future Biomedical Research consent.
Health Outcomes and Quality of Life Assessments
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 2).  Select 
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OIs [Kidney Disease: Improving Global Outcomes Transplant Work Group 2009] [Trofe-
Clark, J. 2016] are as follows:

Pneumocystis jirovecii pneumonia (PJP)

BK virus infection

Human polyomavirus (non-BK virus) infection

HSV infection (including superficial, eg, oral HSV infection, and systemic HSV 
infection)

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
Quality of Life Assessments
Quality of life (QoL) will be assessed using two electronic instruments, the EQ-5D and the 
SF-36v2® Health Survey. Questionnaires will be administered as described in the Study SoA 
(Section 2).  The two questionnaires will be completed at the beginning of study visit 
(ie, before any other procedures are performed).  There will be no specific order for EQ-5D 
and SF-36v2® administration.
The EQ-5D measures Health-related (HR) QoL on 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) and a 20-cm vertical visual analog scale 
(VAS) that generates a self-rating of HRQoL. The EQ-5D has shown acceptable construct 
and concurrent validity in kidney transplant and is a valid instrument for measurement of 
health status in renal transplant patients [Cleemput, I., et al 2004].
The SF-36v2® Health Survey, Standard (4-week recall) Form, is a generic health survey 
which includes 36 questions to measure functional health and well-being from the 
participant’s perspective. The standard, 4-week recall version of the form was selected to 
detect overall changes in health status. The SF-36v2® measures each of the following eight 
health domains: Physical Functioning, Role Limitations-Physical, Bodily Pain, General 
Health, Vitality, Social Functioning, Role Limitations-Emotional, and Mental Health. The 
8 health domain scores contribute to the computation of the Physical Component Summary 
(PCS) and Mental Component Summary (MCS) scores [Barotfi, S., et al 2006].
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Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Screening of potentially eligible participants may begin on the day of transplantation 
(ie, prior to transplantation) or 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.  Participants will be randomized 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 9.5.7.
Potential participants will be evaluated to determine if they fulfill the Inclusion/Exclusion 
entry requirements as described in Sections 6.1 and 6.2.  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 2) will be performed and 
must be completed by Day 5 post-transplant (inclusive).  Participants will be instructed that 
they are required to use birth control, as described in Appendix 5, starting from the time of 
consent through 90 days after the last dose of study therapy (or longer if dictated by local 
regulations).  Participants will also be instructed about the restrictions for concomitant 
medications, as noted in Section 7.7.
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 
Table 17).  Laboratory values may be collected centrally with the exception of CrCl 
measurements performed locally prior to randomization (see Exclusion Criterion #6 in 
Section 6.2) as well as any other local laboratory measurements for participant management 
outside the context of the protocol.  
Human immunodeficiency virus (HIV) antibody test results documented at any time prior to 
randomization of the participant will be acceptable; a copy of this HIV report must be 
available. (See Exclusion Criterion #10 in Section 6.2).  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 screening should only be performed if not previously 
documented within the last 90 days.  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).
On the day of randomization, eligibility for enrollment into the study should be confirmed. 
Participants will be considered eligible for randomization once (a) they are determined to 
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have a documented negative serostatus and (b) have acceptable CrCl and liver function test 
values (ie, within the range allowed in this study, as outlined in Section 6.2 [Exclusion 
Criteria]).
Presence of CMV disease in the screening period will be assessed according to Appendix 7.
Rescreening
Those participants who meet any of the laboratory exclusion criteria in Table 3 and/or Child-
Pugh classification in Exclusion Criterion 8 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.
Treatment Period
Study therapy will begin within 7 days post-transplant and will continue through Week 28.  
The Day 1 Visit (as shown in the Study SoA, Section 2) will be the day the participant is 
randomized and study therapy 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 2).  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 2) for CMV viral 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 therapy.  Note that serum creatinine screening intervals should 
occur according to the recommendations listed in the Kidney Disease Improves Global 
Outcomes (KDIGO) Clinical Practice Guidelines [Kidney Disease: Improving Global 
Outcomes Transplant Work Group 2009] as part of a participant’s SOC post-kidney 
transplantation.
Day 1 Visit
Day 1 procedures/assessments listed in the Study SoA (Section 2) must be performed prior to 
initiation of study therapy.  Assessments of QoLs (ie, EQ-5D and SF-36v2®) should be 
completed prior to any study procedures at this visit.
Laboratory safety evaluations (hematology, chemistry, urinalysis, and other) specified in 
Section 9.5.8.1 will be performed prior to study therapy initiation.  These samples will be 
sent to the appropriate central laboratory (or laboratories) following the procedure(s) 
described in the manual(s).
For female participants, a urine pregnancy test will be performed at the site prior to study 
therapy initiation.  If the urine pregnancy test result is negative, the participant will be 
eligible for randomization and the remainder of the Day 1 testing/procedures will be 
performed.  If the urine pregnancy result is positive, the participant must not be randomized.
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A serum pregnancy test may be performed on Day 1 for those WOCBP participants who are 
anuric and/or unable to provide urine. 
For male participants, serum Inhibin B, LH, follicle stimulating hormone (FSH), and 
testosterone testing will be performed.
Study Therapy 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 randomized.  The site pharmacist or study 
coordinator will contact the IVRS at all dispensing visits for assignment of the study therapy 
to be administered.  Sites should not contact the IVRS for study therapy administration until 
the participant has met all criteria for the study and is ready to receive the first dose of study 
therapy on Day 1.
The first dose of study therapy (LET + placebo to VGCV + ACV, or VGCV + placebo to 
LET + placebo to ACV) will be administered at the trial site with monitoring by investigative 
site personnel at the Day 1 Visit (note:  after population PK sample collection on Day 1).  For 
participants who cannot swallow and/or have a condition that may interfere with the 
absorption of the oral formulation at or after randomization/Day 1, study therapy can be 
initiated/switched to the IV formulation.  Participants should be switched from the IV 
formulation back to oral study therapy 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.
Participants in the LET treatment arm who are not on CsA will receive LET 480 mg QD 
given orally (either as one 480 mg tablet or two 240 mg tablets, at the investigator’s
discretion based on participant’s swallowing capability).  Participants who were initiated 
with two tablets of the LET 240 mg or matching placebo should continue with that regimen. 
Participants in the LET treatment arm 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 be randomized 1:1 to receive either 240 mg QD of IV LET or 480 mg QD of IV 
LET (Section 5.1).  Participants requiring the IV formulation of LET who are on concomitant 
CsA will receive 240 mg QD of IV LET.  
If CsA is initiated after starting study therapy 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 therapy 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 initiated after starting study therapy at an 
IV dose of LET 240 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 maintained at 240 mg QD. 
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If CsA is discontinued during the study therapy period for more than 3 consecutive days, the 
dose of oral LET (next administered up to 24 hours later) should be increased from 240 mg 
to 480 mg QD. If CsA is discontinued during study therapy period for more than 
3 consecutive days and the subject is receiving IV formulation of LET 240 mg QD, then the 
subject will undergo 1:1 randomization to receive either 240 mg QD or 480 mg QD of IV 
formulation of LET (Section 5.1). If CsA is temporarily withheld (ie, 3 consecutive days) 
due to high levels detected by therapeutic blood monitoring, the dose of LET need not be 
adjusted.  Corresponding changes in tablets for oral formulation with changes in CsA dosing 
will also occur in the VGCV arm in an effort to maintain the study blind (Section 7.4).
For prophylaxis against HSV and VZV, all participants will receive either oral ACV 400 mg 
every 12 hours or matching placebo, depending on randomization into the LET or VGCV 
treatment arm, respectively.  If participants assigned to receive ACV cannot swallow 
capsules or tablets during the study, then such participants can also receive IV ACV at 
250 mg/m2 every 12 hours.  The HSV/VZV prophylaxis will continue to Week 28.  After 
Week 28, locally sourced ACV can be continued on an open-label basis at the discretion of 
the investigator.
After Day 1, study therapy will continue through Week 28, with the primary intent of 
preventing CMV disease.
The participant will be trained in the use of the Study Medication Diary.  Once the 
participant is discharged from the hospital, he/she will be instructed to enter the number of 
tablets or capsules of study therapy taken during the study therapy period.  See Section 7.6 
for details regarding oral medication administered during any hospitalization or comparable 
inpatient setting (including but not limited to skilled nursing facility or rehabilitation facility) 
and use of IV formulation.
Follow-up Period
After completion of study therapy at Week 28, participants will continue to be followed for 
efficacy and safety, 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, and (7) QoL measures using 
validated PRO tools.
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 2).  All scheduled study visits will be completed 
regardless of when cessation of study treatment occurs.
During the follow-up period, samples for CMV DNA PCR should be sent to the central 
laboratory as per the Study SoA (Section 2).
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CMV Disease or Early Discontinuation Visit
CMV Disease Visit
The CMV Disease 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 
2 [SoA] and Section 9.2.1). It is very important to ensure that all procedures, as outlined in 
the Study SoA (Section 2), are performed at the CMV Disease Visit immediately prior to
the initiation of treatment of CMV disease (ie, on the day anti-CMV therapy is initiated).  
Most importantly, a confirmatory plasma sample for CMV DNA PCR testing as well as a 
plasma sample for CMV viral resistance testing should be collected at this visit and sent to 
the central laboratory.  Additionally, a repeat plasma sample for CMV viral resistance testing 
should be collected at the next scheduled visit after the CMV Disease Visit (Section 9.5.8.3).
After the CMV Disease Visit, participants 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 2).  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.
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 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 (preferably within 48-72 hours; Section 9.5.8.2).
During the course of the study, a participant may undergo ≥1 CMV Disease Visit at the 
discretion of the investigator.
Discontinuation for Reasons Other Than CMV Disease
Study Therapy Discontinuation
Participants who discontinue study therapy prior to the last scheduled treatment visit for 
reasons other than CMV disease 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 2).  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.
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Early Study Discontinuation
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 2), 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.
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to analyses made 
after the protocol has been finalized, but prior to unblinding, will be documented in a 
supplemental Statistical Analysis Plan (SAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post-hoc exploratory analyses will be clearly identified in the CSR.  
Separate analysis plans (ie, separate documents from the supplemental SAP) will be 
developed to detail other planned analyses (ie, those specific to the analysis of PK data, 
genetic data, and PROs).
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Section 10.2 to Section 10.12.
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Study Design Overview
A Phase III, Randomized, Double-Blind, Comparator-controlled Study to 
Evaluate the Efficacy and Safety of MK-8228 (Letermovir) Versus 
Valganciclovir for the Prevention of Human Cytomegalovirus (CMV) 
Disease in Adult Kidney Transplant Recipients
Treatment Assignment
This is a double-blind study with a 1:1 randomization ratio.  Treatment 
allocation / randomization will be stratified by use or non-use of highly 
cytolytic anti-lymphocyte immunotherapy during induction.
Analysis Populations
Efficacy:  Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint
Proportion of participants with adjudicated CMV disease through 52 weeks 
post-transplant
Key Secondary Endpoints
Proportion of participants with adjudicated CMV disease through 28
weeks post-transplant
Time to onset of adjudicated CMV disease through 52 weeks post-
transplant
Statistical Methods for Key 
Efficacy Analyses
For the primary hypothesis, LET will be considered non-inferior to 
VGCV if the upper bound of the two-sided 95% CI for the proportion of 
participants with adjudicated CMV disease for (LET minus VGCV) is 
no higher than 0.10 (non-inferiority margin).
Statistical Methods for Key 
Safety Analyses
For safety events, p-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2)
for between-treatment differences in the percentage of participants with 
events will be calculated using the Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
Superiority for the primary hypotheses will be tested only if
non-inferiority is demonstrated. Due to the principles of closed testing, 
no adjustment for multiplicity is required for the superiority test.
Sample Size and Power 
The planned sample size is 600. For the proportion of participants with 
adjudicated CMV disease through 52 weeks post-transplant, the trial has 
90% power to demonstrate that LET is non-inferior to VGCV at an 
overall two-sided 5% alpha-level.
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.  Certain specific analyses such as those for 
PK, pharmacogenetics, and QoL measures will be the responsibility of the appropriate 
departments of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. 
The Clinical Biostatistics department will generate the randomized allocation schedules: both 
the initial randomization for study treatment assignment and the second allocation schedule 
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for IV dosing for those participants not on concomitant CsA.  Randomization will be 
implemented in the IVRS.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for between-treatment differences are 
listed below, followed by the descriptions of the derivations of selected endpoints.
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 5.4.1.1.
The primary efficacy endpoint will be the proportion of participants with adjudicated CMV 
disease through 52 weeks post-transplant.  If the primary objective of non-inferiority is 
achieved, superiority of LET versus VGCV will be evaluated by comparing the proportion of 
participants with adjudicated CMV disease through 52 weeks post-transplant.
CMV disease is defined as the presence of either CMV end-organ disease or CMV syndrome 
and will be confirmed by an independent, blinded 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.
Quantifiable CMV DNAemia is defined as any detected CMV (ie, with a numeric value and 
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.  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.  
The relationship of CMV infection to CMV disease is discussed in Section 5.4.1.1.
The secondary efficacy endpoints are:
1. Proportion of participants with adjudicated CMV disease through 28 weeks 
post-transplant
For this endpoint, adjudicated CMV disease will be defined in the same way it is for
the primary efficacy endpoint.
2. Time to onset of adjudicated CMV disease through 52 weeks post-transplant
The time to onset of adjudicated CMV disease will be calculated in days, from the 
day of randomization to the day of onset of CMV disease as determined by the CAC.
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Safety Endpoints
Leukopenia and neutropenia (see Section 5.4.1.3) will be assessed by evaluating the
proportion of participants who develop any of the following during the treatment phase.  This
is specified as a Tier 1 safety endpoint. 
1. Report an adverse event of leukopenia
2. Experience total WBC count ≤3,500 cells/µL
3. Report an adverse event of neutropenia
4. Experience ANC ≤1,000 cells/µL
The following are specified as events of interest (Tier-2 safety endpoints):
1. Proportion of participants with any adverse event
2. Proportion of participants with any drug-related adverse event
3. Proportion of participants with any SAE
4. Proportion of participants with any adverse event which is both drug-related and 
serious
5. Proportion of participants who discontinue due to an adverse event
6. Proportion of participants who report a total WBC count ≤3,500 cells/µL
7. Proportion of participants who report ANC ≤1,000 cells/µL
All AEs will be collected through 14 days after completion of the treatment period.  
Thereafter, all SAEs related to study medication will be collected through Week 52.
In addition, proportion of male participants with meaningful changes of Inhibin B, FSH, and 
LH testosterone serum concentrations will be evaluated to monitor testicular function.
Exploratory Endpoints
1. Proportion of participants with quantifiable CMV DNAemia through 28 weeks 
post-transplant and 52 weeks post-transplant
2. Proportion of participants experiencing allograft dysfunction and/or rejection through 
28 weeks post-transplant and 52 weeks post-transplant
a.
Proportion of participants who experience 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
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b. Proportion of participants who experience a biopsy-proven acute renal graft 
rejection through 28 weeks post-transplant and 52 weeks post-transplant
c.
Proportion of participants who experience graft loss through 28 weeks 
post-transplant and 52 weeks post-transplant
3. Proportion of participants who experience 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.
4. Selected health outcomes (in addition to NODAT, see above) as follows:
a.
Incidence of all-cause mortality through 28 weeks post-transplant and 52 weeks 
post-transplant
b. Incidence and duration of 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.
Incidence of select OIs (see Section 9.10.1) through 28 weeks post-transplant and 
52 weeks post-transplant
d. Proportion of participants who report 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.
5. Antiviral resistance to LET in prophylaxis failures through 52 weeks post-transplant
(see Section 9.5.8.3 for details)
6. Glycoprotein B (gB) genotype of CMV in prophylaxis failures through 52 weeks 
post-transplant (see Section 9.5.8.4 for details)
7. Genetic analyses (see Section 5.4.1.5 for details)
8. Patient-reported outcomes (EQ-5D and SF-36v2® scores)
9. Pharmacokinetic endpoints, including the evaluation of exposure-response 
relationships with selected efficacy and safety endpoints (reported in a separate 
Modeling and Simulation report; see Section 10.6.3.2 for details)
10. Proportion of participants with CMV-specific T cell responses (positive, 
indeterminate, or negative) as measured by the release of γ-interferon using the
QuantiFERON-CMV assay
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Analysis Populations
Efficacy Analysis Populations
Full Analysis Set (FAS)
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study.  The FAS population consists of all randomized participants who received at least 
one dose of study treatment, are D+/R-, and had no detectable CMV viral DNA (measured by
central laboratory) on Day 1.
Per Protocol (PP)
The PP population will serve as a supportive analysis population. The PP population
excludes participants due to important deviations from the protocol that may substantially 
affect the results of the primary and secondary efficacy endpoints.
Potential violations that may result in the exclusion of a participant from the PP population 
include:

Failure to reasonably adhere to the dosing schedule for the study medication

Failure to comply with specific inclusion/exclusion criteria

Use of a prohibited concomitant medication during the treatment period that may 
impact on the efficacy assessment
The final determination on protocol violations will be made prior to the final unblinding of 
the database and will be documented in a protocol violator memo.
Participants will be included in the treatment arm to which they are randomized for the
analysis of efficacy data using both the FAS and PP populations.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment arm 
corresponding to the study treatment they actually received for the analysis of safety data 
using the ASaT population.  For most participants this will be the treatment arm to which 
they are randomized.  Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment arm corresponding to the study treatment actually 
received.
At least one laboratory or vital sign 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.
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Statistical Methods
Statistical testing and inference for safety analyses are described in Section 10.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 10.8, Multiplicity. Nominal p-values will be
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.  Unless otherwise stated, all statistical tests will be 
conducted at the α=0.05 (2-sided) level.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
Primary Efficacy Analysis
To test the primary hypothesis that LET is non-inferior to VGCV in the prevention of CMV 
disease, the difference between the two treatment arms in the proportions of participants with 
adjudicated CMV disease through 52 weeks post-transplant and the associated two-sided 
95% CI will be calculated using the stratum-adjusted Mantel-Haenszel method with 
stratification by highly cytolytic anti-lymphocyte therapies. LET will be concluded to be 
non-inferior to VGCV if the upper bound of the two-sided 95% CI for the difference in 
proportion of participants with adjudicated CMV disease (LET - VGCV) is no higher than 
0.10.
Exposure to the lower LET IV dose (240mg without concomitant CsA) is not expected to 
impact the primary efficacy analysis.  For subjects randomized to receive IV LET (including 
240mg or 480mg without concomitant CsA and 240mg with concomitant CsA), the 
percentage of time exposed to IV LET is anticipated to be minimal.  Efficacy of the LET IV 
240 mg (with and without concomitant CsA) and LET IV 480 mg (without concomitant CsA) 
groups may be assessed in an exploratory manner.
The primary efficacy analysis will be performed on the FAS population, with the PP
population considered a supportive approach. A sensitivity analysis including those 
participants who were assessed by the investigator to have CMV disease regardless of the 
CAC determination will be performed.  An additional sensitivity analysis will be performed 
where any participant who discontinues study treatment but thereafter is started on CMV 
prophylaxis at the discretion of the investigator is considered a failure.
Provided non-inferiority is established, a hypothesis that LET is superior to VGCV in the 
prevention of CMV disease will be tested.  The stratum-adjusted Mantel-Haenszel method 
(with continuity correction) will be used to compare the two treatment arms with respect to 
the proportion of participants with adjudicated CMV disease through 52 weeks 
post-transplant using the stratification factor of highly cytolytic anti-lymphocyte therapies.  
LET will be concluded to be superior to VGCV if the upper bound of the two-sided 95% CI 
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for the difference in proportion of participants with adjudicated CMV disease (LET - VGCV) 
is less than 0.
Secondary Efficacy Analyses
To assess the difference in the proportion of participants with adjudicated CMV disease 
through 28 weeks post-transplant, similar to the primary endpoint the difference between 
arms and the associated 95% CI will be calculated using the stratum-adjusted Mantel-
Haenszel method with stratification by highly cytolytic anti-lymphocyte therapies.  Formal 
hypothesis testing will be done on this endpoint in the event that the second primary 
hypothesis of superiority is met.
Time to onset of adjudicated CMV disease through 52 weeks post-transplant will be 
estimated using the nonparametric Kaplan-Meier method. The Kaplan-Meier curve will be 
plotted by treatment arm and a p-value for the between arm difference in time to onset of 
adjudicated CMV disease will be provided using the stratified log-rank test with stratification 
by highly cytolytic anti-lymphocyte therapies. Observations will be censored at the time of 
discontinuation from the study, or at completion of the study.
Missing Data Handling
There are two types of missing values:

Intermittent missing values due to a missed or skipped visit. Note that this does not apply 
to the primary endpoint which is at the end of the trial but 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 missing due to premature discontinuation from the study
Table 13 provides a summary of approaches to handle missing values.
Table 13
Summary of Approaches to Handle Missing Values
Approach
Intermittent Missing
Monotone Missing 
NC = F
Failure
Failure
OF
Excluded
No failure
F = failure; NC = non-completer; OF = observed failure.
The primary missing data approach will be the Observed Failure (OF) approach.  Using this 
approach, participants who discontinue prematurely from the study for any reason are not 
considered failures.
The Non-Completer = Failure (NC = F) approach will be used as a supportive analysis.  
Non-completers refers to participants who prematurely discontinue from the study for any 
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reason without having developed CMV disease. Using the NC = F approach, these 
participants will also be considered failures.
Additional analysis to evaluate the potential effect of violations in assumptions about the 
missing data may be performed.
Table 14 summarizes the key efficacy analyses.
Table 14
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Timepoint)
Primary 
Versus
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach*
Primary Hypothesis/Endpoint
Proportion of participants with 
adjudicated CMV disease 
through 52 weeks post-transplant
P
Stratified M&H ‡
FAS
OF
S
Stratified M&H ‡
FAS
NC = F
S
Stratified M&H ‡
PP
OF
Secondary Endpoints
Proportion of participants with 
adjudicated CMV disease 
through 28 weeks post-transplant
P
Stratified M&H ‡
FAS
OF
S
Stratified M&H ‡
FAS
NC = F
Time to onset of adjudicated 
CMV disease through 52 weeks 
post-transplant
P
Kaplan-Meier
FAS
N/A
  †P = Primary approach; S = Supportive approach.
  * OF = observed failure; M&H = Mantel-Haenszel method; NC =F = non-completers equal failure; N/A = not 
applicable.
  ‡Stratum-adjusted Mantel-Haenszel method with stratification by highly cytolytic anti-lymphocyte therapies
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 15).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% CIs provided 
for between-arm comparisons. Other safety parameters will be considered Tier 2 or Tier 3.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for 
between-arm comparisons; only point estimates by treatment arm are provided for Tier 3 
safety parameters.
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Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change (PDLC) in laboratory parameters that are not pre-specified as Tier 1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of 
events observed.  Membership in Tier 2 requires that at least 4 participants in any treatment 
arm exhibit the event; all other adverse experiences and PDLC will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-arm 
difference in percent incidence will always include zero when treatment arms of equal size 
each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences.  Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-arm 
differences in adverse experiences and PDLC.
P-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2) will be provided for between-
treatment differences in the percentage of participants with events; these analyses will be 
performed using the Miettinen and Nurminen method - an unconditional, asymptotic method
[Miettinen, O. and Nurminen, M. 1985] and will not be stratified. All AEs will be analyzed 
through the end of the treatment period.  Drug-related SAEs which are collected throughout 
the study will also be analyzed through Week 52.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-2 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 15
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Reporting any of the following: 
AE of leukopenia, total WBC count ≤3,500 cell/µL, 
AE of neutropenia, ANC ≤1,000 cell/µL
X
X
X
Tier 2
Any AE
X
X
Any serious AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs (incidence 
≥4 participants in one of the treatment arms)
X
X
Total WBC count ≤3,500 cell/µL
X
X
ANC ≤1,000 cells/µL
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence 
<4 participants in both treatment arms)
X
Change from baseline results (laboratories, ECGs, 
vital signs)
X
AE = adverse event; ANC = absolute neutrophil count; CI = confidence interval; ECG = electrocardiogram; 
SOC = System Organ Class; PDLC = predefined limit of change; WBC = white blood cell; X = results will be 
provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment arms for each relevant characteristic will be assessed by 
the use of descriptive statistics.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of participants screened and randomized, and the 
primary reasons for screening failure, and discontinuation will be displayed.  Demographic 
variables (eg, age, gender), baseline characteristics, indication for kidney transplant, 
transplant and dialysis or plasmapheresis details (see Section 9.1.6), and prior and 
concomitant therapies will be summarized by treatment arm using descriptive statistics for 
continuous or categorical variables, as appropriate.
Pharmacokinetic Analyses
The PK data obtained from this study will be used to characterize the PK of LET in kidney 
transplant recipients and evaluate exposure-response relationships with selected efficacy and 
safety endpoints including dose for those participants not on concomitant CsA and requiring 
IV dosing.  The prospective details of this analysis will be specified in a separate Modeling 
and Simulation analysis plan.
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Interim Analyses
No interim analyses for efficacy are planned for this study. However, to ensure safe study 
conduct, an independent unblinded external Data Monitoring Committee (DMC) will be 
established.  The DMC will convene to review safety data approximately every 6 months 
during the study.
Multiplicity
The primary efficacy hypothesis for non-inferiority will be tested at a two-sided alpha level 
of 5% because no interim efficacy analyses will be performed.  If the primary efficacy 
hypothesis testing for non-inferiority of LET is met, the second primary hypothesis of 
superiority will be tested at the two-sided Type I error rate of 5%.  If the second primary 
hypothesis of superiority is met, similar step-down hypothesis testing will be performed for 
the secondary endpoint of adjudicated CMV disease through 28 weeks post-transplant.  Other 
efficacy analyses will be considered secondary or explanatory.
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
Three hundred (300) participants will be randomized into each treatment arm for a total of 
600 participants.  Assuming the true proportion of participants with adjudicated CMV 
disease is 0.17 for both treatment arms, this study has 90% power to demonstrate that LET is 
non-inferior to VGCV at an overall two-sided 5% alpha-level, using a non-inferiority margin 
of 0.10.  See section 5.4.1.1.3 for the rationale for the non-inferiority margin. The minimum 
criterion for success is that the upper bound of 95% CI of difference (LET minus VGCV) 
<0.10.  The observed proportion of participants in the LET arm needs to be less than 4% 
higher than that in the VGCV arm in order to declare non-inferiority.  If the observed 
proportion of participants in the LET arm is approximately 9% lower than in the VGCV arm, 
this is expected to demonstrate superiority with 90% power.
The adjudicated CMV disease incidence of 17% is supported by the results of the IMPACT 
study.  In this study, the primary efficacy endpoint was the proportion of D+/R– participants 
who developed CMV disease (as defined in Appendix 7) adjudicated by the CAC.  
Sample Size and Power for Safety Analyses
Table 16 summarizes the percentage point differences between the 2 treatment arms that 
could be detected with 90% probability for a variety of hypothetical underlying incidences of 
leukopenia (reported as AE) in the LET arm.  These calculations assume 300 participants in 
each treatment arm and are based on a 1-sided 2.5% alpha level.  The reported incidence of 
leukopenia AE in the IMPACT study is 38% for 200 days of VGCV [Humar, A., et al 2010].  
The calculations are based on an asymptotic method proposed by Farrington and Manning 
(1990) [Farrington, C. P. 1990].
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Table 16
Power to Show Superiority for a Variety of Hypothetical Underlying Incidences 
of Leukopenia Adverse Events (n = 300/arm)
Power to Show Superiority with n=300/arm
LET Rate
VGCV Response rate
18
20
22
24
26
28
30
93
81
61
<40
<40
<40
34
>99
97
91
78
57
<40
38
>99
>99
99
96
89
75
42
>99
>99
>99
>99
99
95
LET = letermovir; VGCV = valganciclovir
Subgroup Analyses
To assess the consistency of the treatment effect across various subgroups, the estimate of the 
between-arm treatment effect (with a nominal 95% CI) for the primary efficacy endpoint will 
be tabulated and plotted within each category of the following classification variables:

Age category (≤65 versus >65 years)

Sex (female, male)

Race (white, non-white)

Induction therapy (use, non-use of highly cytolytic, anti-lymphocyte immunotherapy 
during induction)

Region (US, Ex-US)
Other clinically relevant variables may be identified for which additional subgroup analyses 
may be performed.
Sample sizes within subgroups will be smaller than the overall trial sample size; therefore,
estimation may not be precise and the 95% CIs may be wide.  If any subgroup category has 
less than 15 participants in either treatment arm then only descriptive statistics will be 
displayed (no estimate of treatment difference and no CIs).  If there are less than 
15 participants in either treatment arm, the subgroup category will not be displayed in the 
forest plot.
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Compliance (Medication Adherence)
Study medication data for LET, VGCV, ACV, and placebos will be collected during the 
study.  A day within the study will be considered an “On-Therapy” day if the participant 
takes at least one dose.  For a participant who is followed for the entire study period, the 
“Number of Days Should be on Therapy” is the total number of days from randomization 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 randomization to the date of the last dose of study medication.
For each participant, percent compliance will then be calculated using the following formula:
Compliance rates will be summarized for each treatment arm and individual compliance rates 
will factor into the identification of protocol violators as discussed in Section 10.5.1.
Extent of Exposure
The extent of exposure of study treatment will be evaluated by summary statistics for the 
“Number of Days on Therapy” by treatment arm.
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kidney transplant recipients. Am J Transplant. 
2009 Nov;9 Suppl 3:S1-155.
04L62Y
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[Kotton CN, Kumar D, 
Caliendo AM, Asberg A, 
Chou S 2013]
Kotton CN, Kumar D, Caliendo AM, Asberg 
A, Chou S, Danziger-Isakov L, et al. Updated 
international consensus guidelines on the 
management of cytomegalovirus in solid-
organ transplantation. Transplantation 
2013;96(4):333-60.
03V29C
[Kranz, B., et al 2008]
Kranz B, Vester U, Wingen AM, Nadalin S, 
Paul A, Broelsch CE, et al. Acute rejection 
episodes in pediatric renal transplant 
recipients with cytomegalovirus infection. 
Pediatr Transplant. 2008 Jun;12(4):474-8.
04L62Z
[Kropeit, D., et al 2017]
Kropeit D, Scheuenpflug J, Erb-Zohar K, 
Halabi A, Stobernack HP, Hulskotte EGJ, et 
al. Pharmacokinetics and safety of letermovir, 
a novel anti-human cytomegalovirus drug, in 
patients with renal impairment. Br J Clin 
Pharmacol. 2017 Sep;83(9):1944-1953.
04QX5X
[Kute, V. B., et al 2012]
Kute VB, Vanikar AV, Shah PR, Gumber 
MR, Patel HV, Godara SM, et al. Post-renal 
transplant cytomegalovirus infection: study of 
risk factors. Transplant Proc. 2012 
Apr;44(3):706-9.
04L632
[Lischka, P., et al 2010]
Lischka P, Hewlett G, Wunberg T, 
Baumeister J, Paulsen D, Goldner T, et al. In 
vitro and in vivo activities of the novel 
anticytomegalovirus compound AIC246. 
Antimicrob Agents Chemother. 2010 
Mar;54(3):1290-7
03RRNQ
[Ljungman, P., et al 2016]
Ljungman P, Boeckh M, Hirsch HH, 
Josephson F, Lundgren J, Nichols G, et al. 
Definitions of Cytomegalovirus Infection and 
Disease in Transplant Patients for Use in 
Clinical Trials. Clin Infect Dis. 2016 Sep 28. 
[Epub ahead of print].
04K6N0
[Lowance, D., et al 1999]
Lowance D, Neumayer H-H, Legendre CM, 
Squifflet J-P, Kovarik J, Brennan PJ, et al. 
Valacyclovir for the prevention of 
cytomegalovirus disease after renal 
transplantation. N Engl J Med 
1999;340:1462-70.
03RT6R
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[Lurain, N. S. and Chou, S. 
2010]
Lurain NS, Chou S. Antiviral drug resistance 
of human cytomegalovirus. Clin Microbiol 
Rev 2010;23(4):689-712.
03RRNP
[Manuel, O., et al 2013]
Manuel O, Husain S, Kumar D, Zayas C, 
Mawhorter S, Levi ME, et al. Assessment of 
cytomegalovirus-specific cell-mediated 
immunity for the prediction of 
cytomegalovirus disease in high-risk solid-
organ transplant recipients: a multicenter 
cohort study. Clin Infect Dis 2013;56(6):817-
24.
03VTR9
[Martin, S. I. 2013]
Martin SI, Fishman JA; AST Infectious 
Diseases Community of Practice. 
Pneumocystis pneumonia in solid organ 
transplantation. Am J Transplant. 2013 
Mar;13 Suppl 4:272-9.
04MZPT
[Marty, F. M., et al 2017]
Marty FM, Ljungman P, Chemaly RF, 
Maertens J, Dadwal SS, Duarte RF, et al. 
Letermovir prophylaxis for cytomegalovirus 
in hematopoietic-cell transplantation. N Engl 
J Med. 2017 Dec 21;377(25):2433-44.
04XH3T
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O, Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-
26.
03RVNK
[Muller PY and Dieterle F 
2009]
Muller PY and Dieterle F. Tissue-specific, 
non-invasive toxicity biomarkers: translation 
from preclinical safety assessment to clinical 
safety monitoring. Expert Opin Drug Metab. 
Toxicol. 2009 Sep;5(9):1023-38
04F7WL
[National Cancer Institute 
2009]
National Cancer Institute. Common 
terminology criteria for adverse events 
(CTCAE) version 4.0. U.S.Department of 
Health and Human Services; 2009. 79p.
03RCHC
[Paya, C., et al 2004]
Paya C, Humar A, Dominguez E, Washburn 
K, Blumberg E, Alexander B, et al. Efficacy 
and safety of valganciclovir vs. oral 
ganciclovir for prevention of cytomegalovirus 
disease in solid organ transplant recipients. 
Am J Transplant. 2004 Apr;4(4):611-20.
04L5YM
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[Pergam, S. A. 2009]
Pergam SA, Limaye AP; AST Infectious 
Diseases Community of Practice. Varicella 
zoster virus (VZV) in solid organ transplant 
recipients. Am J Transplant. 2009 Dec;9 
Suppl 4:S108-15.
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[Razonable, R. R. 2013]
Razonable RR. Management strategies for 
cytomegalovirus infection and disease in solid 
organ transplant recipients. Infect Dis Clin 
North Am. 2013 Jun;27(2):317-42.
04MZPY
[Rubin, R. H. 2007]
Rubin RH. The pathogenesis and clinical 
management of cytomegalovirus infection in 
the organ transplant recipient: the end of the 
'silo hypothesis'. Curr Opin Infect Dis. 2007 
Aug;20(4):399-407.
04L5YJ
[Schnitzler, M. A., et al 
2003]
Schnitzler MA, Lowell JA, Hardinger KL, 
Boxerman SB, Bailey TC, Brennan DC. The 
association of cytomegalovirus sero-pairing 
with outcomes and costs following cadaveric 
renal transplantation prior to the introduction 
of oral ganciclovir CMV prophylaxis. Am J 
Transplant. 2003 Apr;3(4):445-51.
04L5F5
[Szende, A., et al 2005]
Szende A, Leidy NK, Revicki D. Health-
related quality of life and other patient-
reported outcomes in the European 
centralized drug regulatory process: a review 
of guidance documents and performed 
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Tomblyn M, Chiller T, Einsele H, Gress R, 
Sepkowitz K, Storek J, et al. Guidelines for 
preventing infectious complications among 
hematopoietic cell transplantation recipients: 
A global perspective. Biol Blood Marrow 
Transplant 2009;15(10):1143.
03R3X3
[Trofe-Clark, J. 2016]
Trofe-Clark J, Sawinski D. BK and other 
polyomaviruses in kidney transplantation. 
Semin Nephrol. 2016 Sep;36(5):372-385.
04N5S9
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U.S. Food and Drug Administration. 
Testicular toxicity: Evaluation during drug 
development guidance for industry [Internet]. 
Washington: U.S. Department of Health and 
Human Services; 2015. Available from:  
http://www.fda.gov/downloads/Drugs/Guidan
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04KD05
[U.S. Prescribing 
Information 2017]
U.S. Prescribing Information: CYTOVENE-
IV (ganciclovir sodium) for injection, for 
intravenous use: Jul 2017.
04XDDD
[U.S. Prescribing 
Information 2017]
U.S. Prescribing Information: VALCYTE 
(valganciclovir hydrochloride) tablets, 
VALCYTE (valganciclovir hydrochloride) for 
oral solution: Jun 2017.
04XDG8
[Valentine, V. G., et al 
2008]
Valentine VG, Weill D, Gupta MR, Raper B, 
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04QG9Y
[Winston, D.J., et al 2012]
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Abouljoud M, Garcia-Diaz JB, Goss JA, et al. 
Efficacy and safety of maribavir dosed at 100 
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in solid organ transplant patients. Am J 
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04MYQY
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation/Term
Definition
ACV
Acyclovir/aciclovir
ADA
American Diabetes Association
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASaT
All Subjects 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
BID
Twice daily
BSA
Body surface area
CAC
Clinical Adjudication Committee
CBC/diff
Complete blood count with differential
CI
Confidence interval
CMV
Cytomegalovirus
CrCl
Creatinine clearance
CsA
Cyclosporin A
CSR
Clinical Study Report
DB
Dense body
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DNAemia
Detection of DNA in samples of plasma, whole blood, and isolated 
peripheral blood leukocytes or in buffy-coat specimens.
DNQ
Detected, Not Quantifiable
ECG
Electrocardiogram
ECI
Event of clinical interest
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EQ
EuroQol
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Abbreviation/Term
Definition
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle-stimulating hormone
G-CSF
Granulocyte colony-stimulating factor
gB
Glycoprotein B
GCV
Ganciclovir
HBsAg
Hepatitis B surface antigen
HCV-Ab
Hepatitis C virus antibody
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
HSCT
Hematopoietic stem cell transplant
HSV
Herpes simplex virus
IB
Investigator’s Brochure
ICF
Informed consent form
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
INR
International normalized ratio
IRB
Institutional Review Board
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Integrated web response system
KDIGO
Kidney Disease Improves Global Outcomes
LAM
Lactational amenorrhea method 
LET
Letermovir
LH
Luteinizing hormone
LLoQ
Lower limit of quantification
MCS
Mental Component Summary
MDRD
Modification of Diet in Renal Disease
MMF
Mycophenolate mofetil
NA
Not applicable
NODAT
New onset diabetes mellitus after transplant
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Abbreviation/Term
Definition
NTR
Narrow therapeutic range
OF
Observed Failure
OI
Opportunistic infection
PCR
Polymerase chain reaction
PCS
Physical Component Summary
PDLC
Predefined limits of change
PET
Pre-emptive therapy
P-gp
P-glycoprotein
PJP
Pneumocystis jirovecii pneumonia
PK
Pharmacokinetic
PO
Orally
PRO
Patient-reported outcome
PT
Prothrombin time
QD
Once daily
QoL
Quality of life
γ-IFN
γ-interferon
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCR
Screening
SF-36v2®
36-Item Short Form Health Survey Version 2.0
SoA
Schedule of activities
SOC
Standard of care
SOT
Solid organ transplant
Tp
Transplant
TRD
Treatment-related discontinuation
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
US
United States
VAS
Visual analog scale
VGCV
Valganciclovir
VZV
Varicella zoster virus
WBC
White blood cell
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Abbreviation/Term
Definition
WHO
World Health Organization
WOCBP
Woman of childbearing potential
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Appendix 2: Clinical Laboratory Tests 

The tests detailed in Table 17 will be performed by the central laboratory unless 
otherwise specified within the protocol.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Sections 6.1 and 6.2 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 17
Protocol-Required Safety Laboratory Assessments
Hematologya
Chemistrya
Urinalysisa
Other
Hematocrit
Albumin
Blood
FSH, LH, testosterone, and 
Inhibin B levels in males
Hemoglobin
Alkaline phosphatase
Glucose
Urine β-hCGe
Platelet count
ALT
Protein
HBsAgb
WBC (total and 
differential)
AST
Specific gravity 
HCV-Abb
Bicarbonate
Microscopic examination, 
if abnormal results are 
noted
Hepatitis C RNA PCRb
Calcium
HIV antibodyb
Chloride
CMV DNA PCRc
Creatinine
CMV viral resistance testingd
Creatinine Clearance
QuantiFERON-CMV Assay
Glucose
Coagulation:  PT/INRa
Phosphorus
eGFR calculation
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin
Indirect Bilirubin
Total protein
Blood Urea Nitrogen
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin;
CMV = cytomegalovirus; FSH = follicle-stimulating hormone; HBsAg = Hepatitis B surface antigen; HCV-Ab
= Hepatitis C virus antibody; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
INR = International normalized ratio; LET = letermovir; LH = luteinizing hormone; PCR = polymerase chain 
reaction; PT = prothrombin time; 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 
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 randomization 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 who discontinue study treatment due to 
CMV disease or in whom study medication is stopped and CMV treatment is started.
e.  May use local or central laboratory serum pregnancy test if unable to provide urine.
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Investigators must document their review of each laboratory safety report.
Table 18 summarizes the approximate blood volumes collected by study visit and sample 
types.
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Table 18
Approximate Blood/Tissue Volumes Drawn/Collected by Study Visit and by Sample Types
Study Period
Pre-
Treat
ment
Treatment
Follow-up
CMV Disease
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
4
4
4
4
4
4
4
4
4
4
4
4
Coagulationa
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
Serum Inhibin B, LH, FSH, 
Testosterone Levels in Men
12
12
12
12
HIV and Hepatitis B and C 
Screenb
16
Blood for Genetic Analysis
8.5
CMV DNA PCRc
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
CMV serology (IgG)
Xd
QuantiFERON-CMV Assay
3
3
3
3
3
3
CMV Viral Resistance 
Testing/gB Genotypic 
Testinge
10
10f
Population PK
5
5
5
5
5
5
5
5
5
5
5
5
5
Intensive PK at Week 1 for:
-participants of Asian 
descent; and
-for participants of 
non-Asian descent who 
consent to intensive PK
25
Intensive PK (during IV 
administration for >5 
consecutive days)
----------25 (performed at most once during the study; this volume is 
NOT included in the Expected Total volume)-----------
Expected Total (mL)
38+X
31.5 40.5 13.5 19.5
9.5
19.5
9.5
22.5
19.5
19.5
19.5
34.5
14.5
4
7
4
4
29
44.5
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Study Period
Pre-
Treat
ment
Treatment
Follow-up
CMV Disease
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
CMV = cytomegalovirus; D = Day; DNA= deoxyribonucleic acid; FSH = follicle-stimulating hormone; gB = glycoprotein B; HIV = human immunodeficiency virus; IgG = 
immunoglobulin G; IV = intravenous; LET = letermovir; LH = luteinizing hormone; 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 
randomization 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.
Only if not previously documented within 180 days prior to randomization (see Section 6.1, Inclusion Criteria).  Performed locally per SOC at the site.
e.
To be performed only for participants who discontinue study treatment due to CMV disease or in whom study medication is stopped and CMV treatment is started.  DNA extracted 
from the plasma samples used for CMV viral resistance testing will be used for the CMV UL55 (gB) genotypic testing.
f.
A repeat sample should be collected at the next scheduled visit after the CMV disease visit.
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (eg, contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
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Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck trial at any time, without any influence on their access to,
or receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll participants in its trials.  However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
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V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
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except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Committees Structure
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (eg, they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
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The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 10.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
Clinical Adjudication Committee
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 10 – Statistical Analysis 
Plan, as well as evaluating the presence of confounding factors.
1) CMV disease, as defined in Appendix 7: This role is important to standardize the 
evaluation (ie, adjudication) of all suspected cases of CMV disease occurring during 
the trial.
All personnel involved in the adjudication process will remain blinded to study treatment 
allocation throughout the trial.  Specific details regarding endpoint definitions can be found 
in the Adjudication Charter.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial 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 trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, 
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www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial 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 trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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 trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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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. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
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investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose 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 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a Merck product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
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●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which 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 one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported
Additional Events which require reporting 
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor.
●
Is a cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
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●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
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 trials, 
awareness of symptoms, but easily tolerated)
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities. (for pediatric trials, definitely acting like something is wrong)
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric trials, extremely distressed or unable to do usual activities).
Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified 
assessment of causality was done.  This initialed document must be retained for 
the required regulatory time frame.  The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship 
between the test product and the adverse event based upon the available 
information
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●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the adverse event:
●
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, 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 trials 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 trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
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 trial is a single-dose drug trial); or (3) 
Sponsor's product(s) is/are used only one time.)
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NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the case report forms /worksheets
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence 
of the AE onset relative to the administration of the Sponsor's product is 
reasonable.  The AE is more likely explained by the Sponsor's product than by 
another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
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Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
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SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
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
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 hormonal 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 non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.1:
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant.
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o
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 condom with cap, diaphragm or sponge with spermicide.
▪
Male and female condom cannot be used together.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 19 during the protocol-defined time frame in Section 6.1.
Table 19
Highly Effective Contraceptive Methods That Have Low User Dependency
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progesterone-only implanta
●
Intrauterine hormone-releasing system (IUS)
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner 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. 
●
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 treatment. 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. 
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation.
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Pregnancy Testing
Women of childbearing potential should only be included after a negative highly sensitive 
urine or serum pregnancy test (per SOC at the site) and in accordance with local 
requirements.
Following initiation of treatment, additional pregnancy testing will be performed at monthly 
intervals during the treatment period, 4, 8, 12 weeks after the last dose of study treatment for 
participants who complete the treatment period, and at CMV disease visit and/or early 
discontinuation visit.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
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 Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
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 Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
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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 
trial 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 trial site under secure 
storage for regulatory reasons.  
A template of each trial 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 electronic Case Report Forms (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 trial purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial 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 trial site.  No personal identifiers will 
appear on the specimen tube.  
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial 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 
trial, the trial 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 Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For Future Biomedical Research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (ie, only leftover samples are being 
retained).
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 e-mailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 7: 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.
Hepatitis
N/A
Abnormal liver function tests
AND
CMV documented in tissue by 
histopathology, 
immunohistochemistry, virus 
isolation, rapid culture, or DNA 
hybridization techniques
AND
Absence of other documented 
cause of hepatitis

Detection of CMV by 
PCR alone is insufficient 
as it may represent 
transient DNAemia.  
Hence, PCR is 
insufficient to diagnose 
CMV hepatitis.

Documentation of CMV 
in liver biopsy specimen 
(ie, by culture, 
histopathology, 
immunohistochemical 
analysis or in situ
hybridization) is needed. 

Coinfection with other 
pathogens like HCV may 
be present without 
excluding the diagnosis of 
CMV hepatitis.
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CMV 
Disease 
Type
Probable
Proven
Notes
Encephalitis 
/ ventriculitis
CNS symptoms 
AND
Abnormal imaging results or 
evidence of encephalitis on 
electroencephalography
AND
Detection of CMV in CSF 
without visible contamination of 
blood
CNS symptoms
AND
Detection of CMV in CNS tissue 
by virus isolation, rapid culture, 
immunohistochemistry, in situ
hybridization, or (preferably) 
quantitative PCR
N/A
Retinitis
N/A
Lesions typical of CMV retinitis 
confirmed by an 
ophthalmologist.
N/A
Nephritis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in situ
hybridization in a kidney 
allograft biopsy specimen 
obtained from a patient with 
renal dysfunction
AND
Identification of histologic 
features of CMV infection

Detection of CMV in 
urine by PCR or culture is 
insufficient for the 
diagnosis of CMV 
nephritis.
Cystitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in situ
hybridization in a bladder biopsy 
specimen obtained from a patient 
with cystitis
AND
Identification of conventional 
histologic features of CMV 
infection

Detection of CMV in 
urine by PCR or culture is 
insufficient for the 
diagnosis of CMV
cystitis.
Myocarditis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in situ
hybridization in a heart biopsy 
specimen obtained from a patient 
with myocarditis
AND
Identification of conventional 
histologic features of CMV 
infection
N/A
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CMV 
Disease 
Type
Probable
Proven
Notes
Pancreatitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in situ
hybridization in a pancreatic 
biopsy specimen obtained from a 
patient with pancreatitis
AND
Identification of conventional 
histologic features of CMV 
infection
N/A
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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Appendix 8: Child-Pugh Classification for Severity of Liver Disease
Scoring by Anomaly
Signs or symptom 
1 point 
2 points 
3 points 
Hepatic encephalopathya
absent 
Grade 1 or Grade 2 
Grade 3 or Grade 4 
Ascites 
absent 
mild
moderate 
Bilirubin
<2 mg/dL
2 – 3 mg/dL
>3 mg/dL 
Albumin (g/dL) 
>3.5 g/dL
2.8 – 3.5 g/dL
<2.8 g/dL
INRb
<1.7 
1.7 – 2.3 
>2.3 
a
Hepatic encephalopathy grading: 
Grade 1:  Altered mood/confusion
Grade 2:  Inappropriate behavior, impending stupor, somnolence
Grade 3:  Markedly confused, stuporous but arousable
Grade 4:  Comatose/unresponsive
b
For participants with no known medical history of hepatic impairment or signs or 
symptoms attributable to hepatic impairment and on anticoagulation therapy within 10 
days (inclusive) preceding the INR measurement, the corresponding INR value should 
be scored as 1 point for calculating the Child Pugh score for inclusion/exclusion and
study discontinuation criteria.
INR = international normalized ratio
Child-Pugh Score Interpretation
5 – 6 points
Child-Pugh stage A (mild hepatic insufficiency)
7 – 9 points
Child-Pugh stage B (moderate hepatic insufficiencyc)
>10 points
Child-Pugh stage C (severe hepatic insufficiency)
c
If hypoalbuminemia is the only abnormality noted, the participant will need 
to have a score of ≥7 to qualify for moderate hepatic insufficiency for this 
study.
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT03443869 
Document Date: 
15-Jun-2022
A Phase III, Randomized, Double-Blind, Active Comparator-
Controlled Study to Evaluate the Efficacy and Safety of MK-8228 
(Letermovir) Versus Valganciclovir for the Prevention of Human 
Cytomegalovirus (CMV) Disease in Adult Kidney Transplant
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Supplemental Statistical Analysis Plan (sSAP)
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TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................2
1
INTRODUCTION............................................................................................................3
2
SUMMARY OF CHANGES...........................................................................................3
3
ANALYTICAL AND METHODOLOGICAL DETAILS ...........................................4
3.1
Statistical Analysis Plan Summary.......................................................................4
3.2
Responsibility for Analyses/In-House Blinding ..................................................4
3.3
Hypotheses/Estimation ..........................................................................................5
3.4
Analysis Endpoints.................................................................................................5
3.4.1
Efficacy Endpoints.......................................................................................5
3.4.2
Safety Endpoints ..........................................................................................6
3.4.3
Exploratory endpoints.................................................................................6
3.5
Analysis Populations..............................................................................................8
3.5.1
Efficacy Analysis Populations.....................................................................8
3.5.2
Safety Analysis Populations ........................................................................8
3.6
Statistical Methods.................................................................................................9
3.6.1
Statistical Methods for Efficacy Analyses..................................................9
3.6.2
Statistical Methods for Safety Analyses...................................................12
3.6.3
Statistical Methods for Exploratory Analyses.........................................14
3.6.4
Summaries of Baseline Characteristics, Demographics, and Other
Analyses Demographic and Baseline Characteristics.............................15
3.6.4.1
Demographic and Baseline Characteristics .......................................15
3.6.4.2
Pharmacokinetic Analyses .................................................................15
3.7
Interim Analyses ..................................................................................................15
3.8
Multiplicity ...........................................................................................................15
3.9
Sample Size and Power Calculations .................................................................16
3.9.1
Sample Size and Power for Efficacy Analyses.........................................16
3.9.2
Sample Size and Power for Safety Analyses............................................16
3.10
Subgroup Analyses...............................................................................................17
3.11
Compliance (Medication Adherence).................................................................17
3.12
Extent of Exposure...............................................................................................18
4
LIST OF REFERENCES..............................................................................................18
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1
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of 
confirmatory analyses for this trial, this supplemental SAP provides additional statistical 
analysis details/data derivations and documents modifications or additions to the analysis 
plan that are not “principal” in nature and result from information that was not available at 
the time of protocol finalization.
2
SUMMARY OF CHANGES 
The following changes will be summarized in detail in later sections of this document.
-
Clarification of primary endpoint
-
Clarification of missing data in OF approach
-
Added exploratory endpoint of eGFR<60 through Week 28
-
Deleted exploratory endpoints through week 52 which require laboratory measurements 
not collected past Week 32 
-
Relative day ranges for efficacy endpoints and safety endpoints added
-
Added details of analysis of exploratory endpoints
-
Compliance calculation 
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ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Study Design Overview
A Phase III, Randomized, Double-Blind, Comparator-controlled Study to 
Evaluate the Efficacy and Safety of MK-8228 (Letermovir) Versus 
Valganciclovir for the Prevention of Human Cytomegalovirus (CMV) 
Disease in Adult Kidney Transplant Recipients
Treatment Assignment
This is a double-blind study with a 1:1 randomization ratio.  Treatment 
allocation / randomization will be stratified by use or non-use of highly 
cytolytic anti-lymphocyte immunotherapy during induction.
Analysis Populations
Efficacy:  Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint
Proportion of participants with adjudicated CMV disease through 52 weeks 
post-transplant
Key Secondary Endpoints
Proportion of participants with adjudicated CMV disease through 28
weeks post-transplant
Time to onset of adjudicated CMV disease through 52 weeks post-
transplant
Statistical Methods for Key 
Efficacy Analyses
For the primary hypothesis, LET will be considered non-inferior to 
VGCV if the upper bound of the two-sided 95% CI for the proportion of 
participants with adjudicated CMV disease for (LET minus VGCV) is no 
higher than 0.10 (non-inferiority margin). 
Statistical Methods for Key 
Safety Analyses
For safety events, p-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2)
for between-treatment differences in the percentage of participants with 
events will be calculated using the Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
Superiority for the primary hypotheses will be tested
only if
non-inferiority is demonstrated. Due to the principles of closed testing, 
no adjustment for multiplicity is required for the superiority test.
Sample Size and Power 
The planned sample size is 600. For the proportion of participants with 
adjudicated CMV disease through 52 weeks post-transplant, the trial has 
90% power to demonstrate that LET is non-inferior to VGCV at an 
overall two-sided 5% alpha-level.
3.2
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. Certain specific analyses such as those for 
PK, pharmacogenetics, and QoL measures will be the responsibility of the appropriate 
departments of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
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performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedules: both 
the initial randomization for study treatment assignment and the second allocation schedule 
for IV dosing for those participants not on concomitant CsA. Randomization will be 
implemented in the IVRS.
3.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4 of the protocol.
3.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for between-treatment differences are 
listed below, followed by the descriptions of the derivations of selected endpoints.
3.4.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 5.4.1.1 of the protocol.
The primary efficacy endpoint will be the proportion of participants with adjudicated CMV 
disease through 52 weeks post-transplant. Adjudicated CMV disease cases are defined as 
those cases that are adjudicated by the clinical adjudication committee (CAC) as a “yes” to 
CMV disease.   If the primary objective of non-inferiority is achieved, superiority of LET 
versus VGCV will be evaluated by comparing the proportion of participants with adjudicated 
CMV disease through 52 weeks post-transplant.
CMV disease is defined as the presence of either CMV end-organ disease or CMV syndrome 
and will be confirmed by an independent, blinded 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.
Quantifiable CMV DNAemia is defined as any detected CMV (ie, with a numeric value and 
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.  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.  The relationship of CMV infection to CMV disease is discussed in Section 
5.4.1.1.
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The secondary efficacy endpoints are:
1. Proportion of participants with adjudicated CMV disease through 28 weeks post 
transplant
For this endpoint, adjudicated CMV disease will be defined in the same way it is for the 
primary efficacy endpoint.
2. Time to onset of adjudicated CMV disease through 52 weeks post transplant
The time to onset of adjudicated CMV disease will be calculated in days, from the day 
of randomization to the day of onset of CMV disease as determined by the CAC.
3.4.2
Safety Endpoints
Leukopenia and neutropenia (see Section 5.4.1.3 of the protocol) will be assessed by 
evaluating the proportion of participants who develop any of the following during the 
treatment phase.  This is specified as a Tier 1 safety endpoint. 
1.
Report an adverse event of leukopenia
2.
Experience total WBC count ≤3,500 cells/µL
3.
Report an adverse event of neutropenia
4.
Experience ANC ≤1,000 cells/µL
The following are specified as events of interest (Tier-2 safety endpoints):
1.
Proportion of participants with any adverse event
2.
Proportion of participants with any drug-related adverse event
3.
Proportion of participants with any SAE
4.
Proportion of participants with any adverse event which is both drug-related and serious
5.
Proportion of participants who discontinue due to an adverse event
6.
Proportion of participants who report a total WBC count ≤3,500 cells/µL 
7.
Proportion of participants who report ANC ≤1,000 cells/µL
All AEs will be collected through 14 days after completion of the treatment period.  
Thereafter, all SAEs related to study medication will be collected through Week 52.
In addition, proportion of male participants with meaningful changes of Inhibin B, FSH, and 
LH testosterone serum concentrations will be evaluated to monitor testicular function.
3.4.3
Exploratory endpoints
1.
Proportion of participants with quantifiable CMV DNAemia through 28 weeks post 
transplant and 52 weeks post-transplant
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2.
Proportion of participants experiencing allograft dysfunction and/or rejection through 28 
weeks post transplant and 52 weeks post-transplant
a.
Proportion of participants who experience 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. 
b.
Proportion of participants with eGFR<60 ml/min/1.73m2 from 4 weeks post 
transplant (baseline) through 28 weeks post transplant
c.
Proportion of participants who experience a biopsy-proven acute renal graft 
rejection through 28 weeks post transplant and 52 weeks post-transplant
d.
Proportion of participants who experience graft loss through 28 weeks post 
transplant and 52 weeks post-transplant
3.
Proportion of participants who experience 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.
4.
Selected health outcomes (in addition to NODAT, see above) as follows:
a.
Incidence of all-cause mortality through 28 weeks post transplant and 52 weeks 
post-transplant
b.
Incidence and duration of 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.
Incidence of select OIs (see Section 9.10.1) through 28 weeks post transplant and 
52 weeks post-transplant 
d.
Proportion of participants who report 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.
5.
Antiviral resistance to LET in prophylaxis failures through 52 weeks post transplant (see 
Section 9.5.8.3 for details)
6.
Glycoprotein B (gB) genotype of CMV in prophylaxis failures through 52 weeks post 
transplant (see Section 9.5.8.4 for details)
7.
Genetic analyses (see Section 5.4.1.5 for details)
8.
Patient-reported outcomes (EQ-5D and SF-36v2® scores)
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9.
Pharmacokinetic endpoints, including the evaluation of exposure-response relationships 
with selected efficacy and safety endpoints (reported in a separate Modeling and 
Simulation report; see Section 10.6.3.2 for details)
10. Proportion of participants with CMV-specific T cell responses (positive, indeterminate, 
or negative) as measured by the release of γ-interferon using the QuantiFERON CMV 
assay
3.5
Analysis Populations
3.5.1
Efficacy Analysis Populations
Full Analysis Set (FAS)
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study.  The FAS population consists of all randomized participants who received at least 
one dose of study treatment, are D+/R-, and had no detectable CMV viral DNA (measured by 
central laboratory) on Day 1.
Per Protocol (PP)
The PP population will serve as a supportive analysis population.  The PP population 
excludes participants due to important deviations from the protocol that may substantially 
affect the results of the primary and secondary efficacy endpoints.
Potential violations that may result in the exclusion of a participant from the PP population 
include:
•
Failure to reasonably adhere to the dosing schedule for the study medication
•
Failure to comply with specific inclusion/exclusion criteria
•
Use of a prohibited concomitant medication during the treatment period that may impact 
on the efficacy assessment
The final determination on protocol violations will be made prior to the final unblinding of 
the database and will be documented in a protocol violator memo.
Participants will be included in the treatment arm to which they are randomized for the 
analysis of efficacy data using both the FAS and PP populations.
3.5.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment arm 
corresponding to the study treatment they actually received for the analysis of safety data 
using the ASaT population.  For most participants this will be the treatment arm to which 
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they are randomized.  Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment arm corresponding to the study treatment actually 
received.
At least one laboratory or vital sign 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.
3.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 10.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I
error control strategy are described in Section 10.8, Multiplicity. Nominal p-values will be
computed for other efficacy analyses, but should be interpreted with caution due to potential
issues of multiplicity, sample size, etc. Unless otherwise stated, all statistical tests will be
conducted at the α=0.05 (2-sided) level.
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary
objectives.
Primary Efficacy Analysis
To test the primary hypothesis that LET is non-inferior to VGCV in the prevention of CMV
disease, the difference between the two treatment arms in the proportions of participants with  
adjudicated CMV disease through 52 weeks post-transplant and the associated two-sided
95% CI will be calculated using the stratum-adjusted Mantel-Haenszel method with
stratification by highly cytolytic anti-lymphocyte therapies [Koch, G. G., et al 1990].  LET
will be concluded to be  non-inferior to VGCV if the upper bound of the two-sided 95% CI 
for the difference in proportion of participants with adjudicated CMV disease (LET - VGCV) 
is no higher than 0.10.
Exposure to the lower LET IV dose (240mg without concomitant CsA) is not expected to
impact the primary efficacy analysis. For subjects randomized to receive IV LET (including
240mg or 480mg without concomitant CsA and 240mg with concomitant CsA), the
percentage of time exposed to IV LET is anticipated to be minimal. Efficacy of the LET IV
240 mg (with and without concomitant CsA) and LET IV 480 mg (without concomitant CsA)
groups may be assessed in an exploratory manner.
The primary efficacy analysis will be performed on the FAS population, with the PP
population considered a supportive approach. A sensitivity analysis including those
participants who were assessed by the investigator to have CMV disease regardless of the
CAC determination will be performed. An additional sensitivity analysis will be performed  
where any participant who discontinues study treatment but thereafter is started on CMV
prophylaxis at the discretion of the investigator is considered a failure.
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Provided non-inferiority is established, a hypothesis that LET is superior to VGCV in the
prevention of CMV disease will be tested. The stratum-adjusted Mantel-Haenszel method
(with continuity correction) will be used to compare the two treatment arms with respect to
the proportion of participants with adjudicated CMV disease through 52 weeks post-
transplant using the stratification factor of highly cytolytic anti-lymphocyte therapies. LET
will be concluded to be superior to VGCV if the upper bound of the two-sided 95% CI for the
difference in proportion of participants with adjudicated CMV disease (LET – VGCV) is less 
than 0.
Secondary Efficacy Analyses
To assess the difference in the proportion of participants with adjudicated CMV disease
through 28 weeks post-transplant, similar to the primary endpoint the difference between
arms and the associated 95% CI will be calculated using the stratum-adjusted Mantel-
Haenszel method with stratification by highly cytolytic anti-lymphocyte therapies. Formal  
hypothesis testing will be done on this endpoint in the event that the second primary
hypothesis of superiority is met.
Time to onset of adjudicated CMV disease through 52 weeks post-transplant will be
estimated using the nonparametric Kaplan-Meier method. The Kaplan-Meier curve will be
plotted by treatment arm and a p-value for the between arm difference in time to onset of
adjudicated CMV disease will be provided using the stratified log-rank test with stratification 
by highly cytolytic anti-lymphocyte therapies. Observations will be censored at the time of
discontinuation from the study, or at completion of the study.
Missing Data Handling
There are two types of missing values:

Intermittent missing values due to a missed or skipped visit. Note that this does not 
applyto the primary endpoint which is at the end of the trial but 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 missing due to premature discontinuation from the 
study.
Table 1 provides a summary of approaches to handle missing values.
Table 1
Summary of Approaches to Handle Missing Values
Approach
Intermittent Missing
Monotone Missing
NC = F
Failure
Failure
OF
No failure
No failure
F = failure; NC = non-completer; OF = observed failure.
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The primary missing data approach will be the Observed Failure (OF) approach. Using this 
approach, participants who discontinue prematurely from the study for any reason or are 
missing data at the timepoint are not considered failures.
The Non-Completer = Failure (NC = F) approach will be used as a supportive analysis. Non-
completers refers to participants who prematurely discontinue from the study for any reason
without having developed CMV disease. Using the NC = F approach, these participants will 
also be considered failures.
Additional analysis to evaluate the potential effect of violations in assumptions about the 
missing data may be performed.
Table 2 summarizes the key efficacy analyses.
Table 2
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Timepoint)
Primary
Versus
Supportive
Approach†
Statistical Method
Analysis
Population
Missing Data
Approach*
Primary
Hypothesis/Endpoint
Proportion of participants with
adjudicated CMV disease
through 52 weeks post-
transplant
P
Stratified M&H ‡
FAS
OF
S
Stratified M&H ‡
FAS
NC
= F
S
Stratified M&H ‡
PP
OF
Secondary Endpoints
Proportion of participants with
adjudicated CMV disease
through 28 weeks post-
transplant
P
Stratified M&H ‡
FAS
OF
S
Stratified M&H ‡
FAS
NC
= F
Time to onset of adjudicated
CMV disease through 52
weekspost-transplant
P
Kaplan-Meier
FAS
N/A
†
P = Primary approach; S = Supportive approach.
*
OF = observed failure; M&H = Mantel-Haenszel method; NC =F = non-completers equal failure; N/A =
not applicable.
‡
Stratum-adjusted Mantel-Haenszel method with stratification by highly cytolytic anti-lymphocyte
therapies
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Efficacy Time Window
Table 3 lists the definition of time windows and the target relative day for the scheduled 
visits in the study which will be used for all efficacy analyses by timepoint.  Where there are 
multiple measures within a window, the one closest to the target day will be used.  
Table 3
Definition of Study Timepoints for Efficacy Analyses
Treatment Phase
Protocol Time
Relative Day 
Rangesa
Target 
Relative 
Daya
CSR Timeb
Pre-treatment
Day of Transplant
≤1
1
Baseline
Day 1
≥1 to ≤7
Baseline
End of Treatment
Week 28
183 and 210
197
Week 28 Post-transplant
Post-treatment 
Follow-up 2
Week 52
≥ 351
365
Week 52 Post-transplant
a Relative days and target day are counted from the day of transplant.  
b The clinical study report (CSR) time is the time point label to be used in the analysis tables.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be
subject to inferential testing for statistical significance with p-values and 95% CIs provided
for between-arm comparisons. Other safety parameters will be considered Tier 2 or Tier 3. 
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
arm comparisons; only point estimates by treatment arm are provided for Tier 3 safety
parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined
limits of change (PDLC) in laboratory parameters that are not pre-specified as Tier 1
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of
events observed. Membership in Tier 2 requires that at least 4 participants in any treatment
arm exhibit the event; all other adverse experiences and PDLC will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-arm
difference in percent incidence will always include zero when treatment arms of equal size
each have less than 4 events and thus would add little to the interpretation of potentially
meaningful differences. Because many 95% CIs may be provided without adjustment for
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in
review, not a formal method for assessing the statistical significance of the between-arm
differences in adverse experiences and PDLC.
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P-values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2) will be provided for between-
treatment differences in the percentage of participants with events; these analyses will be 
performed using the Miettinen and Nurminen method - an unconditional, asymptotic method 
[Miettinen, O. and Nurminen, M. 1985] and will not be stratified. All AEs will be analyzed 
through the end of the treatment period. Drug-related SAEs which are collected throughout 
the study will also be analyzed through Week 52.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters that are not pre-specified as Tier-2 endpoints will be considered Tier 3 safety
parameters. Summary statistics for baseline, on-treatment, and change from baseline values
will be provided by treatment group in table format.
Table 4
Analysis Strategy for Safety Parameters
Safety
Tier
Safety
Endpoint
p-Value
95% CI for
Treatment
Comparison
Descriptive
Statistics
Tier 1
Reporting any of the following:
AE of leukopenia, total WBC count ≤3,500 
cell/µL,AE of neutropenia, ANC ≤1,000 
cell/µL
X
X
X
Tier 2
Any AE
Any serious AE
Any drug-related AE
Any serious and drug-related AE
Discontinuation due to AE
Specific AEs, SOCs, or PDLCs (incidence
≥4 participants in one of the treatment arms)
Total WBC count ≤3,500 cell/µL
ANC ≤1,000 cells/µL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence
<4 participants in both treatment arms)
Change from baseline results (laboratories, 
ECGs,vital signs)
X
X
AE = adverse event; ANC = absolute neutrophil count; CI = confidence interval; ECG = 
electrocardiogram; SOC = System Organ Class; PDLC = predefined limit of change; WBC = white 
blood cell; X = results will beprovided.
Time Window for Safety Analyses
Table 5 lists the definition of time windows and the target relative day for the scheduled 
visits in the study which will be used for all safety analyses by timepoint.  Where there are 
multiple measures within a window, the one closest to the target day will be used.  
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Table 5
Definition of Study Timepoints for Safety Analyses
Treatment Phase
Protocol
Time
Relative Day Ranges
Target 
Relative 
Day
CSR Timea
Baseline
Day 1 (Baseline)
1
1
Day 1
Treatmentb
Week 1
>1 and  11
8
Week 1
Week 2
12 and  21
15
Week 2
Week 4
22 and 35
29
Week 4
Week 6
36 and 49
43
Week 6
Week 8
50 and 63
57
Week 8
Week 10
64 and 77
71
Week 10
Week 12
78 and 98
85
Week 12
Week 16
99 and 126
113
Week 16
Week 20
127 and 154
141
Week 20
Week 24
155 and 182
169
Week 24
Week 28
183 and 210
197
Week 28
Post-treatment Follow-upc
Week 32
211 and 238
225
Week 32
Week 36
239 and 266
253
Week 36
Week 40
267 and 294
281
Week 40
Week 44
295 and 322
309
Week 44
Week 48
323 and 350
337
Week 48
Week 52
351
365
Week 52
a
The clinical study report (CSR) time is the time label to be used in the analysis tables.
b
In the treatment phase, relative days and target day are counted from the first day of study medication.
c
In the post-treatment follow-up phase, relative days and target day are counted from the day of 
transplant.
3.6.3
Statistical Methods for Exploratory Analyses
Exploratory endpoints will be assessed via point estimates with 95% CIs provided for
between-arm comparisons.  For continuous outcomes means and standard deviations will be 
reported by treatment group. 
For the endpoint of proportion of participants with quantifiable CMV DNAemia through 28 
weeks post-transplant and 52 weeks post-transplant, the primary analysis will be performed 
using central lab data.  A supporting analysis will be done including local lab data.  
For the endpoint of proportion of participants with CMV-specific T cell responses (positive, 
indeterminate, or negative) as measured by the release of γ-interferon using the 
QuantiFERON CMV assay, point estimates and 95% CIs will also be provided by those with 
and without the primary endpoint.  
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Patient reported outcomes 
Two patient-reported outcome measures were used in this study.  The EQ-5D measures 
Health Related (HR)QoL on five dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a 20-cm vertical visual analog scale (VAS) that 
generates a self-rating of HRQoL. The SF-36 (SF-36v2®) measure consists of eight scaled 
scores, which are in turn use to calculate two combined scores: the mental component 
summary (MCS) and physical component summary (PCS).  Means and standard deviations 
for the scores and change from baseline will be provided by treatment group for the VAS 
score from the EQ-5D and for both the MCS and PCS for the SF-36.  
3.6.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
3.6.4.1
Demographic and Baseline Characteristics 
The comparability of the treatment arms for each relevant characteristic will be assessed by
the use of descriptive statistics. No statistical hypothesis tests will be performed on these
characteristics. The number and percentage of participants screened and randomized, and the
primary reasons for screening failure, and discontinuation will be displayed. Demographic
variables (e.g., age, gender), baseline characteristics, indication for kidney transplant,
transplant and dialysis or plasmapheresis details (see Section 9.1.6), and prior and
concomitant therapies will be summarized by treatment arm using descriptive statistics for
continuous or categorical variables, as appropriate.
3.6.4.2
Pharmacokinetic Analyses
The PK data obtained from this study will be used to characterize the PK of LET in kidney
transplant recipients and evaluate exposure-response relationships with selected efficacy and
safety endpoints. The prospective details of this analysis will be specified in a separate 
Modeling and Simulation analysis plan. 
3.7
Interim Analyses
No interim analyses for efficacy are planned for this study. However, to ensure safe study
conduct, an independent unblinded external Data Monitoring Committee (DMC) will be
established. The DMC will convene to review safety data approximately every 6 months
during the study.
3.8
Multiplicity
The primary efficacy hypothesis for non-inferiority will be tested at a two-sided alpha level
of 5% because no interim efficacy analyses will be performed. If the primary efficacy
hypothesis testing for non-inferiority of LET is met, the second primary hypothesis of
superiority will be tested at the two-sided Type I error rate of 5%. If the second primary
hypothesis of superiority is met, similar step-down hypothesis testing will be performed for
the secondary endpoint of adjudicated CMV disease through 28 weeks post-transplant. Other 
efficacy analyses will be considered secondary or explanatory.
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3.9
Sample Size and Power Calculations
3.9.1
Sample Size and Power for Efficacy Analyses
Three hundred (300) participants will be randomized into each treatment arm for a total of 
600 participants. Assuming the true proportion of participants with adjudicated CMV disease 
is 0.17 for both treatment arms, this study has 90% power to demonstrate that LET is non-
inferior to VGCV at an overall two-sided 5% alpha-level, using a non-inferiority margin of 
0.10. See section 5.4.1.1.3 for the rationale for the non-inferiority margin. The minimum 
criterion for success is that the upper bound of 95% CI of difference (LET minus VGCV) 
<0.10. The observed proportion of participants in the LET arm needs to be less than 4% 
higher than that in the VGCV arm in order to declare non-inferiority. If the observed 
proportion of participants in the LET arm is approximately 9% lower than in the VGCV arm, 
this is expected to demonstrate superiority with 90% power.
The adjudicated CMV disease incidence of 17% is supported by the results of the IMPACT 
study. In this study, the primary efficacy endpoint was the proportion of D+/R– participants 
who developed CMV disease (as defined in Appendix 7) adjudicated by the CAC.
3.9.2
Sample Size and Power for Safety Analyses
Table 6 summarizes the percentage point differences between the 2 treatment arms that could 
be detected with 90% probability for a variety of hypothetical underlying incidences of 
leukopenia (reported as AE) in the LET arm. These calculations assume 300 participants in 
each treatment arm and are based on a 1-sided 2.5% alpha level. The reported incidence of 
leukopenia AE in the IMPACT study is 38% for 200 days of VGCV [Humar, A., et al 2010]. 
The calculations are based on an asymptotic method proposed by Farrington and Manning 
(1990) [Farrington, C. P. and Manning, G. 1990]. 
Table 6
Power to Show Superiority for a Variety of Hypothetical Underlying
Incidencesof Leukopenia Adverse Events (n = 300/arm)
Power to Show Superiority with n=300/arm
LET Rate
VGCV Response rate
18
20
22
24
26
28
30
93
81
61
<40
<40
<40
34
>99
97
91
78
57
<40
38
>99
>99
99
96
89
75
42
>99
>99
>99
>99
99
95
LET = letermovir; VGCV = valganciclovir
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3.10
Subgroup Analyses
To assess the consistency of the treatment effect across various subgroups, the estimate of the
between-arm treatment effect (with a nominal 95% CI) for the primary efficacy endpoint will
be tabulated and plotted within each category of the following classification variables:

Age category (≤65 versus >65 years)

Sex (female, male)

Race (white, non-white)

Induction therapy (use, non-use of highly cytolytic, anti-lymphocyte immunotherapyduring
induction)

Region (US, Ex-US)
Other clinically relevant variables may be identified for which additional subgroup analyses
may be performed.
Sample sizes within subgroups will be smaller than the overall trial sample size; therefore,
estimation may not be precise and the 95% CIs may be wide. If any subgroup category has
less than 15 participants in either treatment arm then only descriptive statistics will be
displayed (no estimate of treatment difference and no CIs). If there are less than 15
participants in either treatment arm, the subgroup category will not be displayed in the forest
plot.
3.11
Compliance (Medication Adherence)
Study medication data for LET, VGCV, ACV, and placebos will be collected during the
study. A day within the study will be considered an “On-Therapy” day if the participant
takes at least one dose. For a participant who is followed for the entire study period, the
“Number of Days Should be on Therapy” is the total number of days from randomization to
the last scheduled day for treatment administration for that participant.  Dose days which are 
missed at the discretion of the investigator (physician’s decision to titrate) will not count as 
“Number of Days Should be on Therapy”. For a participant whodiscontinued from the study 
medication, the “Number of Days Should be on Therapy” is the total number of days from
randomization to the date of the last dose of study medication.
For each participant, percent compliance will then be calculated using the following formula:
Compliance rates will be summarized for each treatment arm and individual compliance rates
will factor into the identification of protocol violators as discussed in Section 10.5.1.
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3.12
Extent of Exposure
The extent of exposure of study treatment will be evaluated by summary statistics for the
“Number of Days on Therapy” by treatment arm.
4
LIST OF REFERENCES 
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O, Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-
26.
[03RVNK]
[Koch, G. G., et al 1990]
Koch GG, Carr GJ, Amara IA, Stokes ME, 
Uryniak TJ. Statistical methodology in the 
pharmaceutical sciences. Berry DA. editor. 
New York: Marcel Dekker, Inc.; c1990. 
Chapter 13, Categorical data analysis; p. 
389-473.
[04YBDZ]
[Humar, A., et al 2010]
Humar A, Lebranchu Y, Vincenti F, 
Blumberg EA, Punch JD, Limaye AP, et al. 
The efficacy and safety of 200 days 
valganciclovir cytomegalovirus prophylaxis 
in high-risk kidney transplant recipients. 
Am J Transplant 2010;10:1228-37.
[03RTLD]
[Farrington, C. P. and 
Manning, G. 1990]
Farrington CP, Manning G. Test statistics 
and sample size formulae for comparative 
binomial trials with null hypothesis of non-
zero risk difference or non-unity relative 
risk. Stat Med 1990;9:1447-54.
[03QQR8]
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