A Phase 3 Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Letermovir (LET) Prophylaxis When Extended From 100 Days to 200 Days Post-transplant in Cytomegalovirus (CMV) Seropositive Recipients (R+) of an Allogenic Hematopoietic Stem Cell Transplant (HSCT)
Phase: PHASE3
Conditions: Cytomegalovirus Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03930615 
Document Date: 
10-Jan-2020
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial to Evaluate the Safety and Efficacy of Letermovir (LET) 
Prophylaxis When Extended From 100 Days to 200 Days Post-
Transplant in Cytomegalovirus (CMV) Seropositive Recipients (R+) 
of an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3 randomized, double-blind, placebo-controlled clinical trial to 
evaluate the safety and efficacy of letermovir (LET) prophylaxis when extended from 
100 days to 200 days post-transplant in cytomegalovirus (CMV) seropositive recipients (R+) 
of an allogeneic hematopoietic stem cell transplant (HSCT)
Protocol Number: 040-02
Compound Number: MK-8228
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
EudraCT
IND
2018-001038-17
104,706 (tablet); 118,361 (IV)
Approval Date: 10 January 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
10-JAN-2020
The primary purpose of this protocol amendment is to limit enrollment of participants 
who have anti-thymocyte globulin as the only high-risk category for CMV reactivation to 
20% of the total trial population.  This is to ensure that the preponderance of evidence 
does not come from participants with anti-thymocyte globulin as the only high-risk 
category for late CMV reactivation.
Amendment 01
23-AUG-2019
The primary purpose of this protocol amendment is 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 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, 
the matching placebo to the IV formulation of LET must also 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.
Original Protocol 
(Version 00)
03-DEC-2018
Original protocol
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [02]
Overall Rationale for the Amendments:
The primary purpose of this protocol amendment is to limit enrollment of participants who have anti-thymocyte globulin as the only 
high-risk category for CMV reactivation to 20% of the total trial population.  This is to ensure that the preponderance of evidence 
does not come from participants with anti-thymocyte globulin as the only high-risk category for late CMV reactivation.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.1
Inclusion Criteria
Criterion #5 (“at high risk of CMV disease, 
defined as meeting one or more of the 
following criteria”); 
Subpart “f”:
Was:“receipt of anti-thymocyte globulin”
Now: “receipt of anti-thymocyte 
globulin (Note: enrollment of participants 
whose ONLY high-risk factor is the use of 
anti-thymocyte globulin will be restricted 
to 20% of all enrolled participants)”
To ensure adequate representation of all other 
subgroups of participants that are at high risk of 
CMV infection.
Subpart “e”:
Was:“having T-cell–depleted grafts”
Now: “having ex-vivo T-cell–depleted 
grafts”
To clarify that this criterion should be restricted 
to participants with ex vivo T-cell depletion only. 
 
 
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Section # and Name
Description of Change 
Brief Rationale 
6.1
Study Intervention(s) 
Administered
Footnote added to Table 1 (Study Therapy –
Oral [Tablet] Formulation) and Table 2 
(Study Therapy – Intravenous Formulation) 
within the column header for “IMP/NIMP”:
“The classification of Investigational 
Medicinal Product (IMP) and Non-
Investigational Medicinal Product (NIMP) 
in this table is based on guidance issued 
by the European Commission and applies 
to countries in the European Economic 
Area (EEA). Country differences with 
respect to the definition/classification of 
IMP/NIMP may exist. In these 
circumstances, local legislation is 
followed.”
To align with updated template text, allowing for 
country differences with respect to 
definition/classification of IMP/NIMP.
8.2.1CMV DNA PCR Testing
Language added requiring sites in Japan to 
conduct pp65 antigen testing locally at the 
CMV infection visit along with the 
confirmatory CMV-DNA PCR test sample 
being sent to the central laboratory.
Most sites in Japan use pp65 antigen testing to 
drive decisions to initiate PET.  Section modified 
to specify that such sites are required to obtain a 
repeat pp65 antigen test locally immediately prior 
to initiating anti-CMV therapy.  
 
 
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Section # and Name
Description of Change 
Brief Rationale 
10.2 Appendix 2: Clinical 
Laboratory Tests
Table of laboratory tests [Table 9] 
restructured to identify those tests that must 
be performed by the central laboratory from 
those that may be performed by the central or 
the local laboratory. 
Table renamed (from “Laboratory 
Assessments Performed by the Central 
Laboratory” to “Laboratory Assessments”)
Modified for improved clarity.  
Global
Minor grammatical, typographical, and 
syntactical modifications made for improved 
accuracy and clarity, and to ensure 
consistency of language across the protocol.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities (SoA)................................................................................19
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Preclinical and Completed Clinical Studies.................................................25
2.2.3
Ongoing Clinical Studies.............................................................................26
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................26
4
STUDY DESIGN............................................................................................................29
4.1
Overall Design......................................................................................................29
4.2
Scientific Rationale for Study Design.................................................................30
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Other Endpoints .................................................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.3
Justification for Dose...........................................................................................34
4.4
Beginning and End of Study Definition .............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................34
5
STUDY POPULATION ................................................................................................35
5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................36
5.3
Lifestyle Considerations......................................................................................39
5.3.1
Meals and Dietary Restrictions....................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................42
 
 
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6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.2.3
Participant-level Study Medication Accountability.....................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Allowed Medications/Therapies to be Administered with Clinical 
and/or Drug Level Monitoring when Coadministered with Study 
Therapy ........................................................................................................44
6.5.2
Prohibited Medications................................................................................46
6.5.2.1
Medications Prohibited with Study Medication ................................47
6.5.2.2
Additional Medications Prohibited When Study Medication is 
Co-administered with CsA.................................................................48
6.5.3
Rescue Medications and Supportive Care ...................................................49
6.6
Dose Modification (Escalation/Titration/Other)...............................................49
6.7
Intervention After the End of the Study............................................................49
6.8
Clinical Supplies Disclosure................................................................................49
6.9
Standard Policies..................................................................................................50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................50
7.1
Discontinuation of Study Intervention...............................................................50
7.2
Participant Withdrawal From the Study...........................................................52
7.3
Lost to Follow-up .................................................................................................52
8
STUDY ASSESSMENTS AND PROCEDURES........................................................53
8.1
Administrative and General Procedures ...........................................................54
8.1.1
Informed Consent.........................................................................................54
8.1.1.1
General Informed Consent.................................................................54
8.1.2
Inclusion/Exclusion Criteria ........................................................................54
8.1.3
Participant Identification Card.....................................................................55
8.1.4
Medical History ...........................................................................................55
8.1.5
Prior and Concomitant Medications Review...............................................55
8.1.5.1
Prior Medications...............................................................................55
8.1.5.2
Concomitant Medications..................................................................55
8.1.6
Assignment of Screening Number...............................................................55
8.1.7
Assignment of Treatment/Randomization Number.....................................56
8.1.8
Study Intervention Administration ..............................................................56
 
 
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8.1.8.1
Timing of Dose Administration.........................................................56
8.1.9
Discontinuation and Withdrawal .................................................................57
8.1.10
Participant Blinding/Unblinding..................................................................57
8.1.11
Domiciling ...................................................................................................57
8.1.12
Calibration of Equipment.............................................................................58
8.2
Efficacy Assessments ...........................................................................................58
8.2.1
CMV DNA PCR Testing .............................................................................58
8.2.2
CMV DNA Resistance Analysis..................................................................59
8.3
Safety Assessments...............................................................................................59
8.3.1
Physical Examinations.................................................................................59
8.3.2
Vital Signs....................................................................................................60
8.3.3
Electrocardiograms ......................................................................................60
8.3.4
Child-Pugh Score.........................................................................................60
8.3.5
Clinical Safety Laboratory Assessments .....................................................60
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................61
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................61
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......63
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...63
8.4.4
Regulatory Reporting Requirements for SAE .............................................64
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................64
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................64
8.4.7
Events of Clinical Interest (ECIs) ................................................................64
8.5
Treatment of Overdose........................................................................................65
8.6
Pharmacokinetics.................................................................................................65
8.7
Pharmacodynamics..............................................................................................65
8.8
Future Biomedical Research Sample Collection...............................................65
8.9
Planned Genetic Analysis Sample Collection....................................................65
8.10
Biomarkers ...........................................................................................................65
8.11
Health Outcomes Assessment .............................................................................66
8.12
Visit Requirements...............................................................................................66
8.12.1
Screening......................................................................................................66
8.12.2
Treatment Period..........................................................................................66
8.12.2.1
Day 1 Visit.........................................................................................67
8.12.2.2
Study Medication Administration......................................................67
8.12.3
Optional Nurse Visit and Telephone Visit (Weeks 32 and 36 Only) ..........68
 
 
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8.12.4
Follow-up Period/Visits...............................................................................68
8.12.5
Discontinued Participants Continuing to be Monitored in the Study..........68
8.12.5.1
Discontinuation of Study Medication due to CMV Infection............68
8.12.5.2
Discontinuation for Reasons Other Than CMV Infection.................69
8.12.6
Survival Status .............................................................................................69
9
STATISTICAL ANALYSIS PLAN .............................................................................69
9.1
Statistical Analysis Plan Summary.....................................................................69
9.2
Responsibility for Analyses/In-house Blinding .................................................71
9.3
Hypotheses/Estimation ........................................................................................71
9.4
Analysis Endpoints...............................................................................................71
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................71
9.4.1.1
Efficacy Endpoints.............................................................................71
9.4.2
Safety Endpoints..........................................................................................73
9.4.3
Exploratory Endpoints .................................................................................73
9.5
Analysis Populations............................................................................................74
9.5.1
Efficacy Analysis Populations .....................................................................74
9.5.2
Safety Analysis Populations ........................................................................74
9.6
Statistical Methods...............................................................................................75
9.6.1
Statistical Methods for Efficacy Analyses...................................................75
9.6.2
Statistical Methods for Safety Analyses ......................................................79
9.7
Interim Analyses ..................................................................................................80
9.8
Multiplicity ...........................................................................................................81
9.9
Sample Size and Power Calculations .................................................................81
9.9.1
Sample Size and Power for Efficacy Analysis ............................................81
9.9.2
Sample Size and Power for Safety Analysis................................................82
9.10
Subgroup Analyses...............................................................................................83
9.11
Compliance (Medication Adherence).................................................................84
9.12
Extent of Exposure...............................................................................................84
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................85
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........85
10.1.1
Code of Conduct for Clinical Trials.............................................................85
10.1.2
Financial Disclosure.....................................................................................87
10.1.3
Data Protection.............................................................................................87
10.1.3.1
Confidentiality of Data ......................................................................88
10.1.3.2
Confidentiality of Participant Records...............................................88
10.1.3.3
Confidentiality of IRB/IEC Information............................................88
10.1.4
Committees Structure...................................................................................88
 
 
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10.1.4.1
Scientific Advisory Committee..........................................................88
10.1.4.2
Executive Oversight Committee........................................................88
10.1.4.3
External Data Monitoring Committee ...............................................89
10.1.4.4
Clinical Adjudication Committee (CAC) ..........................................89
10.1.5
Publication Policy........................................................................................89
10.1.6
Compliance with Study Registration and Results Posting Requirements ...90
10.1.7
Compliance with Law, Audit, and Debarmen .............................................90
10.1.8
Data Quality Assurance ...............................................................................91
10.1.9
Source Documents .......................................................................................91
10.1.10
Study and Site Closure.................................................................................92
10.2
Appendix 2: Clinical Laboratory Tests..............................................................93
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................97
10.3.1
Definition of AE ..........................................................................................97
10.3.2
Definition of SAE ........................................................................................98
10.3.3
Additional Events Reported.........................................................................99
10.3.4
Recording AE and SAE ...............................................................................99
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the
Sponsor ......................................................................................................103
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................104
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................105
10.5.1
Definitions..................................................................................................105
10.5.2
Contraception Requirements......................................................................105
10.5.3
Pregnancy Testing......................................................................................107
10.6
Appendix 6: Country-specific Requirements..................................................108
10.7
Appendix 7 Definition of CMV Disease in Hematopoietic Stem Cell 
Transplant (HSCT) Recipients.........................................................................109
10.8
Appendix 8 Child-Pugh Classification for Severity of Liver Disease............112
10.9
Appendix 9: Abbreviations ...............................................................................113
11
REFERENCES.............................................................................................................115
 
 
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LIST OF TABLES
Table 1
Study Therapy – Oral (Tablet) Formulation .....................................................41
Table 2
Study Therapy – Intravenous Formulation .......................................................41
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ..................................................................................62
Table 4
Summary of Approaches to Handle Missing Values........................................75
Table 5
Analysis Strategy for Key Efficacy Variables ..................................................78
Table 6
Analysis Strategy for Safety Parameters...........................................................80
Table 7
Power(%) Under Various Assumptions (With 144 Participants 
Randomized in 200-day Arm and 72 in 100-day Arm) ....................................82
Table 8
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs ..............................................83
Table 9
Laboratory Assessments....................................................................................94
Table 10 Approximate Blood/Tissue Volumes Drawn/Collected by Study Visit and 
by Sample Types...............................................................................................96
Table 11 Contraceptive Methods ...................................................................................106
 
 
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LIST OF FIGURES
Figure 1
Study Design.....................................................................................................18
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 randomized, double-blind, placebo-controlled clinical trial to 
evaluate the safety and efficacy of letermovir (LET) prophylaxis when extended from 100 
days to 200 days post-transplant in cytomegalovirus (CMV) seropositive recipients (R+) of 
an allogeneic hematopoietic stem cell transplant (HSCT)
Short Title: Extension of LET from Day 100 to Day 200 post-transplant for the prevention 
of CMV infection in HSCT participants
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with the objectives in the Objectives and Endpoints table.
In CMV seropositive recipients (R+) of an allogeneic HSCT who have received LET 
prophylaxis through Day 100 post-transplant and are at high risk for CMV infection and/or 
disease after ~100 days post-transplant:
Primary Objectives
Primary Endpoints
Objective: To evaluate the efficacy of 
letermovir (LET) versus placebo when LET 
prophylaxis is extended from 100 to 
200 days post-transplant, as measured by 
the proportion of participants with clinically 
significant CMV infection from Week 14 
(~100 days) post-transplant through 
Week 28 (~200 days) post-transplant
Hypothesis (H1): LET is superior to placebo 
in the prevention of clinically significant 
CMV infection when LET prophylaxis is 
extended from 100 to 200 days 
post-transplant
Clinically significant CMV infection 
(CS-CMVi, defined as initiation of 
pre-emptive therapy [PET] for documented 
CMV viremia and/or CMV end-organ 
disease)
 
 
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Secondary Objectives
Secondary Endpoints
To evaluate the safety and tolerability of 
LET versus placebo when LET prophylaxis 
is extended from 100 to 200 days 
post-transplant based on the proportion of 
participants with adverse events from 
Week 14 post-transplant through Week 28 
post-transplant.
AEs
Study drug discontinuations due to AEs
To evaluate the efficacy of LET versus 
placebo when LET prophylaxis is extended 
from 100 to 200 days post-transplant, as 
measured by the following: 
- Proportion of participants with clinically 
significant CMV infection from Week 14 
post-transplant through Week 38 and from 
Week 14 post-transplant through Week 48 
post-transplant
- Time to onset of clinically significant 
CMV infection from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant
- Proportion of participants with pre-
emptive therapy (PET) for CMV viremia 
from Week 14 post-transplant through 
Week 28 post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant
- Proportion of participants with all-cause 
mortality from Week 14 post-transplant 
through Week 28 post-transplant, and from 
Week 14 post-transplant through Week 48 
post-transplant
- Time to all-cause mortality from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant
Clinically significant CMV infection
Initiation of anti-CMV PET for documented 
CMV viremia
All-cause mortality
 
 
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Prevention of clinically significant CMV infection in adult
allogeneic HSCT recipient
Population
CMV seropositive recipients post-transplant who have 
received LET prophylaxis through Day 100 
post-transplant and are at high risk for CMV infection 
and/or disease after ~100 days post-transplant
Study Type
Interventional
Intervention Model
Parallel
A multi-site study
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Investigator
Participant
Care Provider
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 36 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 216 participants will be randomized/enrolled.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Drug
Dose
Strength
Dose 
Frequency
Route of 
Administration
Use
LET
LET (for 
participants on 
CsA)
240 mg
Once daily
Oral a or IV b c
Experimental
LET (for 
participants not 
on CsA)
480 mg 
Once daily
Oral a or IV b c
Experimental
PLACEBO
Placebo for LET
Not 
Applicable
Once daily
Oral a or IV b c
Placebo 
comparator
Duration: Interventions will be given from post-transplant Week 14 to 
post-transplant Week 28
LET = letermovir; CsA = Cyclosporin A; IV = intravenous
a: The number of placebo tablets will mimic the LET dosing scheme in an effort to maintain the 
blind (ie, 1 matching placebo tablet if on CsA to mimic one 240-mg tablet; 1 or 2 matching 
placebo tablets if not on CsA to mimic one 480-mg tablet or two 240-mg tablets, respectively).
b: LET IV formulation dosing volume is 250 mL and duration of infusion will be approximately 
60 minutes. LET IV will be provided as a sterile liquid concentrate for dilution (20 mg/mL), one 
vial to be used for the 240-mg dose and two vials for the 480-mg dose. Locally supplied sterile 
IV dextrose or saline diluent will be used as the placebo to LET IV as prepared by the site 
unblinded pharmacist.
c: The IV formulation should be switched to oral study therapy (ie, at the next planned dose) as 
soon as participants are able to swallow and/or the condition necessitating the use of the IV 
formulation resolves.
Total 
Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 36 weeks
from the time the participant signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of up to 2 weeks, each 
participant will be receiving assigned intervention for approximately 
14 weeks.  After the end of treatment each participant will be followed for 
20 weeks.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Treatment Period
(14 weeks of study therapy;
Weeks 14-28 or ~100-200 days 
post-transplant)
Follow-up
CMVi 
or 
Early 
D/C a, b
Notes
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Post-transplant Week
SCR c
14 d
(D1) 16
18
20
22
24
26
28
30
32 e
34
36 e
38
40
44
48
D1 = Day 1 of study = day of 
randomization which should 
occur at 14 weeks (100 days)
±1 week post-transplant
Visit Window
-14 days
±3 days
±7 days
±14 days
Administrative Procedures
Informed consent
×
Participant ID card
×
Will be updated once 
randomized
Inclusion /exclusion
×
×
Medical history
×
×
Prior/conmeds review
×
×
×
×
×
×
×
×
×

×
×
×
×
×
×
HSCT details review
×
Collect conditioning regimen;
date and type of transplant;
source of stem cells; type of 
graft manipulation; presence of 
GVHD; and GVHD prophylaxis 
regimen (if any) 
Treatment allocation
×
Study therapy dispensing
×
×
×
×
×
×
×
Contact IRT at all dispensing 
visits (See Section 8.1.8)
Study medication administration
×
×
×
×
×
×
×
×
 
 
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Study Period
Treatment Period
(14 weeks of study therapy;
Weeks 14-28 or ~100-200 days 
post-transplant)
Follow-up
CMVi 
or 
Early 
D/C a, b
Notes
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Post-transplant Week
SCR c
14 d
(D1) 16
18
20
22
24
26
28
30
32 e
34
36 e
38
40
44
48
D1 = Day 1 of study = day of 
randomization which should 
occur at 14 weeks (100 days)
±1 week post-transplant
Visit Window
-14 days
±3 days
±7 days
±14 days
Study Medication Diary review
×
×
×
×
×
×
×
×
Participant will be trained on 
the use of Study Medication 
Diary on Day 1.  Study 
Medication Diary will be 
collected/ redistributed at each 
visit after Day 1.
Clinical Procedures/
Assessments
Full Physical Examination
×
×
Targeted physical examination
×
×
×
×
×
×
×
×
×
×
×
×
×
×
Performed only when clinically 
indicated
Weight
×
×
×
×
×
×
×
×
×
×
Height
×
Vital signs 
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
HR, BP, respiratory rate, body 
temperature
12-lead ECG
×
Read locally. Values collected 
within 1 month prior to 
screening may be used for 
Visit 1.
Semi-recumbent position.
Child-Pugh score
×
×
×
×
×
×
×
×
×
×
Only when participant is on 
study medication. Laboratory 
testing for Child-Pugh scoring 
to be done locally after Visit 1
Confirm birth control (WOCBP 
only)
×
×
×
×
×
×
×
×
×
×
×
×
Acceptable methods of 
contraception to be used from 
the time of consent through 
28 days after the last dose of 
study therapy.
 
 
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Study Period
Treatment Period
(14 weeks of study therapy;
Weeks 14-28 or ~100-200 days 
post-transplant)
Follow-up
CMVi 
or 
Early 
D/C a, b
Notes
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Post-transplant Week
SCR c
14 d
(D1) 16
18
20
22
24
26
28
30
32 e
34
36 e
38
40
44
48
D1 = Day 1 of study = day of 
randomization which should 
occur at 14 weeks (100 days)
±1 week post-transplant
Visit Window
-14 days
±3 days
±7 days
±14 days
AE monitoring
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
All AEs will be reported 
through 14 days after last dose 
of study medication.  
Thereafter, only drug-related 
SAEs or SAEs leading to death 
to reported until study 
completion (see Section 8.4) 
Chemistry/ hematology
×
×
×
×
×
×
×
×
×
×
×
Refer to Section 8.3.4 for 
further details 
Coagulation PT/INR
×
×
×
×
×
×
×
×
×
×
Performed centrally at 
Screening visit; locally 
thereafter
Urinalysis
×
×
×
Refer to Section 8.3.4 for 
further details regarding the 
laboratory safety tests
Serum (β-hCG)
(WOCBP only)
×
Urine pregnancy (WOCBP only)
×
×
×
×
×
Performed locally; serum 
pregnancy test must be 
performed to confirm a positive 
urine test result.
 
 
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Study Period
Treatment Period
(14 weeks of study therapy;
Weeks 14-28 or ~100-200 days 
post-transplant)
Follow-up
CMVi 
or 
Early 
D/C a, b
Notes
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Post-transplant Week
SCR c
14 d
(D1) 16
18
20
22
24
26
28
30
32 e
34
36 e
38
40
44
48
D1 = Day 1 of study = day of 
randomization which should 
occur at 14 weeks (100 days)
±1 week post-transplant
Visit Window
-14 days
±3 days
±7 days
±14 days
HIV, Hepatitis B and C screen
×
Documented neg HIV results at 
any time prior to screening 
acceptable. HBV/HCV to be done
if not documented within the 
previous 6 months. If hepatitis C 
virus antibody is positive, RNA 
PCR results should be provided.
CMV Procedures/ Assessments
CMV DNA PCR
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
CMV disease assessment
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
All clinical signs and symptoms 
of CMV disease and review of 
relevant laboratory parameters
QuantiFERON-CMV assay
×
×
×
×
CMV DNA sequence analysis 
× f
To be performed ONLY in 
participants with clinically 
significant CMV infection. 
Repeat samples should be 
collected at the next scheduled 
visit after the CMV Infection 
Visit.
Health Outcome Assessments
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
×
Collect re-
hospitalizations, all-cause 
mortality, intravenous 
medications, select OIs, GVHD
 
 
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β-hCG = β-Human Chorionic Gonadotropin; CMV = cytomegalovirus; DNA = deoxyribonucleic acid; D = day; FU = follow-up; GVHD = graft-versus-host disease; HIV = human 
immunodeficiency virus; HSCT = hematopoietic stem cell transplant; IRT = interactive response technology; IV = intravenous; LET = letermovir; OI = opportunistic infection(s); 
PCR = polymerase chain reaction; PET = pre-emptive therapy; PT/INR = prothrombin time / international normalized ratio; SCR = screening; TP = Transplant; WOCBP = woman 
of childbearing potential.
a.
This visit will be a CMV Infection Visit for all participants who meet the endpoint of CS-CMVi (defined as the occurrence of CMV disease or the initiation of PET) 
through Week 48 post-transplant.  During the treatment period, LET must be discontinued at this visit (if the participant is still on LET).  All procedures at the visit 
indicated in the SoA should be completed immediately prior to initiating PET for CMV infection or treatment for CMV disease at this visit (ie, on the day anti-CMV 
therapy is initiated).  Most importantly, a plasma sample for CMV PCR testing at the central laboratory should be collected at this visit.
b.
The visit will be an Early Study Discontinuation Visit for those participants who are prematurely discontinued from the study (not study medication alone) through 
Week 48 post-transplant. 
c.
Screening should begin after obtaining documented consent and must begin up to 14 days prior to the planned randomization date. The day of randomization (Day 1) will 
be approximately 14 weeks (100 days) ±1 week post-transplant.  Participants will have plasma samples tested for CMV viremia using the CMV DNA PCR assay by the 
central laboratory. 
d. Day 1 of the study is the day of randomization, and will occur 14 weeks (100 days) ±1 week post-transplant.  On Day 1, eligibility for enrollment into the study will be 
confirmed.  At that time, participants should have no documented quantifiable CMV viremia, as confirmed by CMV DNA PCR assay at the central laboratory in a 
plasma sample collected within 14 days prior to randomization. Creatinine clearance and liver function test results should also be available within 14 days prior to 
randomization. It is required that eligible participants have no more than 14 days of LET interruption prior to randomization. 
Study therapy must begin on Day 1. Day 1 procedures/assessments must be performed prior to the first dose of study therapy.
e.
A visiting nurse service may be utilized (if locally available and approved for use) for these visits in coordination with an investigator CMV assessment by phone.  If a 
visiting nurse service is utilized, the investigator phone call should occur on the same day as the nurse visit, or as soon as possible.  Refer to the nursing manual for 
additional details.
f.
For participants with clinically significant CMV infection, a sample for CMV DNA sequence analysis for LET resistance should be collected at the CMVi visit and a 
second, confirmatory sample should be collected at the next scheduled visit following the CMVi visit.
 
 
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2
INTRODUCTION
2.1
Study Rationale
Individuals who receive stem-cell or organ transplantation undergo immunosuppressive 
treatments that put them at high risk for select opportunistic infections.  Cytomegalovirus 
(CMV) is the most common clinically significant viral infection after transplant, causing
substantial morbidity and mortality in transplant recipients due to direct (eg, pneumonia, 
hepatitis, retinitis, encephalitis) [Boeckh, M. and Geballe, A. P. 2011] [Ljungman, P., et al 
2002] [Boeckh, M. 2011], and indirect (eg, increased risk of select opportunistic bacterial 
and invasive fungal infections, graft-versus-host disease [GVHD], delayed engraftment or 
graft failure/rejection, increased overall mortality) effects [Craddock, C., et al 2001] [Miller, 
W., et al 1986] [Özdemir, E., et al 2007] [Martino, R., et al 2001] [Söderberg, C., et al 1993] 
[Larsson, K., et al 2004] [Marty, F. M. and Boeckh, M. 2011] [Ariza-Heredia, E. J., et al 
2014].  Hematopoietic stem cell transplant (HSCT) recipients are at highest risk for CMV 
infection and/or disease within the first 100 days (approximately 14 weeks) after 
transplantation.  
Letermovir (LET, also known as MK-8228, AIC246, AIC001) is a potent inhibitor of the 
CMV viral terminase and is approved for prophylaxis of CMV infection and/or disease in 
adult CMV seropositive recipients (R+) of an allogeneic HSCT.  LET was overall 
well-tolerated and efficacious in a pivotal Phase 3 study (P001) for the prophylaxis of CMV
infection or disease in adult CMV recipients R+ of an allogeneic HSCT [Marty, F. M., et al 
2017].  In this randomized, placebo-controlled Phase 3 study, LET prophylaxis when started 
within 28 days post-transplant and continued until Week 14 (~100 days) post-transplant
effectively prevented clinically significant CMV viremia through Week 24 post-transplant.  
At Week 14 post-transplant (end of study treatment), 19.1% participants on LET developed 
clinically significant CMV infection compared to 50% participants on placebo
(non-completer=failure analysis, NC=F).  After stopping LET at Week 14 post-transplant, 
there was an increase in clinically significant CMV infection through Week 24 
post-transplant with 37.5% of participants on LET developing clinically significant CMV 
infection compared to 60.6% participants on placebo (p<0.0001) at Week 24 post-transplant
(NC=F).  The all-cause mortality at Weeks 24 and 48 after transplantation was lower in the 
LET group (10.2% and 20.9%, respectively) than the placebo group (15.9% and 25.5%, 
respectively).  LET was well-tolerated with no evidence of myelotoxicity; participants who 
received LET had a similar time to engraftment (defined as the process of transplanted stem 
cells reproducing new cells) compared to those who received placebo. 
The risk for CMV infection in HSCT recipients is reduced after the first 100 days 
post-transplant as the immune system reconstitutes.  However, there are certain HSCT 
populations who remain at high risk for CMV infection beyond 100 days post-transplant due 
to delayed immune reconstitution, ongoing immunosuppression as a result of treatment for
GVHD, or onset of new GVHD when immunosuppression is tapered.  In a post-hoc analysis 
of results from P001, factors predictive of the development of clinically significant CMV 
infection between Weeks 14 and 24 post-transplant include high risk stratum at baseline 
(based on donor relatedness and degree of matching, stem-cell source, and T-cell depleted 
 
 
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grafts), occurrence of GVHD, and steroid use following randomization.  CMV infection 
occurring after ~100 days post-transplant is associated with morbidity and is an independent 
predictor of mortality [Erard, V, Guthrie, K. A. 2015].  However, the benefit of prolonged 
prophylaxis for prevention of CMV infection/disease after 100 days post-transplant in HSCT 
recipients remains unclear. The standard of care for prevention of CMV infection/disease 
after 100 days post-transplant remains pre-emptive therapy (PET), which is defined as the 
practice of active surveillance for viral replication with antiviral treatment started only when 
CMV viremia is detected [Ljungman, P., et al 2002]. In a randomized, double-blind trial of 
CMV prophylaxis with valganciclovir (VGCV) compared to placebo/PET between ~3-6 
months post-HSCT, CMV viremia was reduced in the VGCV group compared to placebo 
(11% vs 36% respectively, p<0.001), but there was no difference in survival between the two 
arms [Boeckh, M., et al 2015]. 
The objective of this study is to evaluate the occurrence of clinically significant CMV 
infection when LET prophylaxis is extended from Day 100 to Day 200 post-transplant in 
CMV R+ recipients of an allogeneic HSCT who have received LET prophylaxis through 
Day 100 post-transplant and are at high risk for CMV infection and/or disease after
~100 days post-transplant.  The data from this study may guide the clinical management of 
CMV in allogeneic HSCT recipients who continue to be at high risk of CMV infection after 
~100 days post-transplant.  
2.2
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on LET.
2.2.1
Pharmaceutical and Therapeutic Background
LET is a novel inhibitor of the CMV viral enzyme DNA terminase (UL56/UL89/UL51), an 
enzyme that plays an important role in the cleavage of newly synthesized concatenated CMV 
DNA into individual unit-length viral genomes that are subsequently inserted into CMV 
procapsids to generate infectious CMV virions [Goldner, T., et al 2011]. LET has 
demonstrated potent, selective, and reversible inhibition of CMV activity in preclinical 
studies in vitro and efficacy against the virus in vivo [Lischka, P., et al 2010] [Goldner, T., et 
al 2011].
LET is currently available commercially as oral tablet formulations and an intravenous 
formulation.  Participants in this study will either receive the currently marketed oral adult 
tablets (240-mg or 480-mg strength) or marketed intravenous formulation or placebo.
2.2.2
Preclinical and Completed Clinical Studies
Details of preclinical studies and completed clinical studies conducted with LET can be 
found in the accompanying IB.
 
 
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2.2.3
Ongoing Clinical Studies
One clinical study (P002) with LET is currently ongoing.  It is a Phase 3 randomized, 
multi-site, double-blind active comparator trial to evaluate the efficacy and safety of LET 
versus VGCV in adult kidney transplant recipients.  Adult CMV donor seropositive 
(D+)/recipient seronegative (R-) kidney transplant recipients are being enrolled to receive 
either LET or VCVG starting within 7 days post-transplant and continuing through Week 28 
post-transplant.  Efficacy will be measured by the proportion of participants with adjudicated 
CMV disease through Week 52 post-transplant.  Safety and tolerability in kidney transplant 
recipients will also be evaluated.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with the objectives in the Objectives and Endpoints table.
In CMV seropositive recipients (R+) of an allogeneic HSCT who have received LET 
prophylaxis through Day 100 post-transplant and are at high risk for CMV infection and/or 
disease after ~100 days post-transplant:
Objectives
Endpoints
Primary

Objective: To evaluate the efficacy of
letermovir (LET) versus placebo when 
LET prophylaxis is extended from 100 
to 200 days post-transplant, as 
measured by the proportion of 
participants with clinically significant 
CMV infection from Week 14 
(~100 days) post-transplant through
Week 28 (~200 days) post-transplant

Hypothesis (H1): LET is superior to 
placebo in the prevention of clinically 
significant CMV infection when LET 
prophylaxis is extended from 100 to 
200 days post-transplant

Clinically significant CMV 
infection (CS-CMVi, defined as 
initiation of pre-emptive therapy 
[PET] for documented CMV 
viremia and/or CMV end-organ 
disease)
 
 
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Objectives
Endpoints
Secondary

To evaluate the safety and tolerability 
of LET versus placebo when LET 
prophylaxis is extended from 100 to 
200 days post-transplant based on the 
proportion of participants with adverse 
events from Week 14 post-transplant 
through Week 28 post-transplant.

AEs

Study drug discontinuations due 
to AEs

To evaluate the efficacy of LET versus 
placebo when LET prophylaxis is 
extended from 100 to 200 days 
post-transplant, as measured by the 
following: 

Proportion of participants with 
clinically significant CMV infection
from Week 14 post-transplant through 
Week 38 and from Week 14 
post-transplant through Week 48 
post-transplant

Time to onset of clinically significant 
CMV infection from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant

Proportion of participants with pre-
emptive therapy (PET) for CMV 
viremia from Week 14 post-transplant
through Week 28 post-transplant, and 
from Week 14 post-transplant through 
Week 48 post-transplant

Proportion of participants with all-
cause mortality from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant

Clinically significant CMV 
infection

Initiation of anti-CMV PET for 
documented CMV viremia

All-cause mortality
 
 
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Objectives
Endpoints

Time to all-cause mortality from 
Week 14 post-transplant through 
Week 28 post-transplant, and from 
Week 14 post-transplant through 
Week 48 post-transplant
Exploratory

To evaluate the efficacy of LET versus 
placebo when LET prophylaxis is 
extended from 100 to 200 days 
post-transplant, as measured by the 
following:

Proportion of participants with CMV 
end-organ disease from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant

Proportion of participants with 
documented CMV viremia from 
Week 14 post-transplant through 
Week 28 post-transplant, and from 
Week 14 post-transplant through 
Week 48 post-transplant

CMV end-organ disease

Documented CMV viremia
≥300 copies/mL

To evaluate health outcomes in LET 
versus placebo from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant

Recurrent episodes of CMV 
infection

Select opportunistic infections 
other than CMV infection

Graft-versus-host disease 
(GVHD)

All re-hospitalizations and re-
hospitalizations for CMV 
infection/disease

Intravenous medications other 
than LET
 
 
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Objectives
Endpoints

To evaluate the antiviral resistance to 
LET in subjects with clinically 
significant CMV infection from 
Week 14 post-transplant through
Week 48 post-transplant.

Antiviral resistance to LET in 
prophylaxis failures
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blinded, efficacy 
and safety study of extending LET prophylaxis in CMV R+ HSCT recipients who have 
already received LET prophylaxis through Week 14 (~100 days) post-transplant and who are
at high risk for CMV infection and/or disease thereafter.  This trial will enroll approximately 
216 allogeneic CMV R+ HSCT recipients who have already received LET prophylaxis that 
started within 28 days after HSCT and continued through approximately 14 weeks
post-transplant prior to randomization in this study. Eligible participants will be randomized 
in a 2:1 ratio to continue their LET treatment uninterrupted for an additional 14 weeks 
(~100 days of LET treatment for a total of 200 days of LET post-transplant) or to begin 
receiving placebo (a total of 100 days of LET post-transplant).  LET will be administered as 
either 480 mg QD or 240 mg QD for those participants who are receiving concomitant 
cyclosporin A (CsA).  The LET dose is reduced to 240 mg QD when coadministered with 
CsA based on an increase in LET exposures of approximately 2-fold in healthy volunteers 
(P010) and Phase 3 study (P001).  Participants will receive 14 weeks of study treatment 
through Week 28 post-transplant and be followed to Week 48 post-transplant to evaluate 
post-prophylaxis CMV infection events.  
In order to ensure safe study conduct, an independent external Data Monitoring Committee 
(DMC) will be established for safety evaluation.  The DMC will review safety data at 
proposed time points outlined in Section 9.7 and as detailed in the DMC charter.  The DMC 
will review safety data, consider the overall risk and benefit of continuing the study to study 
participants, and make a recommendation to the Sponsor to continue, modify, or end the 
study.  
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. 
Participants who discontinue study medication early (ie, prior to Week 28 post-transplant) 
are intended to complete all remaining treatment period visits through Week 28
post-transplant, as well as all remaining visits through Week 48 post-transplant as outlined in 
the Schedule of Activities (SoA).  All scheduled study visits will be completed regardless of 
when cessation of study treatment occurs.  
 
 
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A visiting nurse service may be utilized (if locally available and approved for use) for the 
Weeks 32 and 36 post-transplant visits in the follow-up phase of the study.  Refer to the 
nursing manual for additional details.
For participants who develop clinically significant CMV infection, the participant should 
have a CMV Infection Visit. It is very important to ensure that all procedures, as outlined in 
the SoA, are performed at the CMV Infection Visit immediately prior to the initiation of 
treatment for CMV disease or initiation of PET. Such participants will continue to be 
followed in the study (despite discontinuing study therapy, and if applicable, initiating anti-
CMV therapy) and are intended to complete all remaining study visits (including all 
subsequent treatment period visits). 
Participants who discontinue the study prior to Week 48 post-transplant should complete an 
Early Discontinuation Visit.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Population 
Overall, HSCT recipients who are CMV R+ have increased non-relapse mortality compared 
to CMV seronegative recipients [Teira, P., et al 2016].  Additional risk factors for 
developing clinically significant CMV infection beyond the first 100 days post-transplant
that may require extended CMV prophylaxis therapy include HLA mismatch, T-cell 
depletion [Huang, Y. T., et al 2016] including the use of anti-thymocyte globulin, receipt of 
cord blood allograft [Boeckh, M. and Nichols, W. G. 2004] or allograft from haploidentical 
donor, and recipients who have GVHD requiring the use of high dose steroids.  As such, 
CMV R+ HSCT recipients who have one or more of these high-risk factors for developing 
clinically significant CMV infection beyond 100 days post-transplant are selected for this 
study.
Randomization and Stratification
Study P001 demonstrated that LET prophylaxis during the first 14 weeks after HSCT is 
effective and well-tolerated in preventing clinically significant CMV infection.  In the 
present study, CMV R+ HSCT recipients who have received LET prophylaxis through 
Week 14 post-transplant are randomized to receive either 14 weeks of LET or placebo until 
Week 28 post-transplant.  The timing of randomization of participants at Week 14 
(~Day 100) post-transplant is selected to reflect the time the clinical decision is made of 
whether to extend the duration of CMV prophylaxis.  This study will randomize in a 2:1 ratio 
with a total of 216 participants with 144 in the LET (200-day) arm and 72 in the placebo
(100-day) arm in order to allow more participants to potentially benefit from LET 
prophylaxis.  Randomization will be stratified by study center in order to balance varying 
clinical practices of PET initiation and types of transplants at different centers.  In addition, 
 
 
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randomization will also be stratified by participants who received cells from a haploidentical 
donor, as this represents a defined large population with a baseline risk factor for CMV 
infection.  Note that it is possible that some sites will only enroll participants with the same 
haploidentical donor status (either all yes or all no).  The number of participants who 
received cells from a haploidentical donor will be capped at ~30% of total participants.
Treatment Duration
A study in recipients of solid-organ transplants demonstrated that the incidence of CMV 
disease at 12 months post-transplant can be significantly reduced if 200 days of prophylaxis 
is implemented instead of 100 days [Humar, A., et al 2010].  Similarly, the prolongation of 
prophylaxis to Week 28 post-transplant could be a potential strategy to decrease the 
incidence of clinical significant CMV infection in certain HSCT recipients at high risk for 
CMV infection.  As such, an additional 100 days of LET or placebo beyond the initial LET 
prophylaxis after 100 days post-transplant HSCT will be evaluated in HSCT recipients who 
are at high risk of CMV infection after 100 days post-transplant.  The proportion of clinically
significant CMV infection will be assessed at the end of study therapy at Week 28
post-transplant as the primary endpoint.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint of the study will be the proportion of participants with 
clinically significant CMV infection post-transplant, which is defined as the occurrence of 
either one of the following outcomes: 

onset of CMV end-organ disease (probable or proven)
OR

initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, 
valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and 
the clinical condition of the participant
The composite endpoint of clinically significant CMV infection used in study P001 was 
selected for this study because CMV infection (as measured by CMV viremia) is associated 
with increased morbidity and mortality in HSCT recipients.  It is difficult to use CMV end-
organ disease alone as the sole clinical endpoint due to low incidence of CMV disease in 
HSCT recipients as a result of PET.  The results of P001 demonstrate that the composite 
endpoint of clinically significant CMV infection is a relevant clinical endpoint [Marty, F. M., 
et al 2017]. The primary endpoint will be assessed at the end of study therapy (Week 28 
post-transplant).  This endpoint will also be assessed at multiple time points post-transplant
as secondary endpoints in order to describe the natural history of clinically significant CMV 
infection after an extended duration of LET prophylaxis. 
 
 
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In this study, CMV DNA PCR testing will be measured from plasma samples using the
Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which will be performed 
by the central laboratory.  The lower limit of quantification (LLoQ) for this assay is 
137 IU/mL, which is approximately 151 copies/mL (using a conversion factor of 
1.1 copies/IU as per the assay package insert).  The CMV DNA levels in IU/mL will be 
reported as one of the following:

<137 NOT DETECTED

<137 DETECTED NOT QUANTIFIABLE

A numeric value

>910,000,000
In this study, any quantifiable CMV viral DNA result on a confirmatory sample obtained 
immediately prior to (ie, on the day of) the initiation of treatment for CMV disease or PET 
using central CMV PCR assay is acceptable for documenting viremia as a component of the 
efficacy endpoint.  In addition to documented CMV viremia, the investigator should also take 
into account the clinical condition of the study participant when deciding to initiate PET.  
Quantifiable CMV viral DNA alone without initiation of anti-CMV therapy will not be 
considered as a case for clinically significant CMV infection in the primary efficacy analysis.
While any quantifiable CMV viral DNA results in the Roche CAP/CTM assay from 
confirmatory plasma sample sent to the central laboratory is acceptable for the purpose of 
documenting viremia as a component of the primary endpoint, it is recommended that 
investigators consider initiating PET when CMV DNA viral load is approximately 
>274 IU/mL or >300 copies/mL.  This threshold for initiation of PET is provided as guidance 
and is not mandated since a participant’s clinical condition and the need for PET is best 
assessed by the investigator.
All cases of potential CMV disease will be determined using the definitions in Appendix 7
(Section 10.7) and confirmed by an independent, blinded CAC.  The CAC will review 
clinical, virological, and histopathological data as well as the investigator’s assessment for 
adjudicating all potential cases of CMV disease.  The adjudication of cases by the CAC will 
take precedence over the investigator’s assessment for the purpose of analysis.
4.2.1.2
Safety Endpoints
The safety and tolerability of LET will be assessed by a clinical evaluation of adverse 
experiences and evaluation of other study parameters including vital signs, physical 
examination, and standard laboratory safety tests at appropriate time points.  
 
 
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4.2.1.3
Other Endpoints
CMV Immune Response
CMV-specific T-cell immunity 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].  A delayed recovery of T-cell immunity 
post-transplant has been observed with long-term viral suppression [Reusser, P., et al 1991], 
which may potentially lead to continued risk of CMV infection.  However, the association 
between antiviral prophylaxis and delayed immune reconstitutions is inconsistent [Zaia, J. 
A., et al 1997] [Boeckh, M., et al 2006].  Preclinical data 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].  As
DBs are immunogenic and are known to prime lymphocytes and neutralizing antibodies in 
mice, it is possible that the release of noninfectious, immunogenic DB during LET 
prophylaxis may facilitate the development of antiviral immune response following HSCT.  
In order to understand the impact that prolonged LET prophylaxis has on the development of 
CMV-specific T-cell responses in individuals who are at high risk of clinically significant 
CMV infection/disease beyond the initial 100 days post-transplant, the correlation between 
the proportion of participants who develop CMV-specific T-cell responses and clinically 
significant CMV infection in the LET and placebo groups will be assessed as an exploratory 
endpoint in this study.  The proportion of participants with positive QuantiFERON-CMV 
assay results will be correlated with the incidence of clinically significant CMV infection
through Week 48 post-transplant and assessed as an exploratory endpoint.  
Health Outcomes Assessment
The occurrence and treatment of CMV infection is associated with significant resource 
utilization in the first 6 months post-transplant [Martin, P. J. 2008].  Use of intravenous 
medications serve as a proxy measure of patient medication burden, especially if they need to 
travel to a healthcare facility to receive the treatment.  It is important to collect healthcare 
resource utilization data since an extended duration of prophylaxis will be accompanied by 
increases in the total cost of the prophylaxis regimen.  Payers, public healthcare systems, 
insurance providers, clinicians, and other decision makers will require data on health-
outcomes measures (such as incidence of all-cause mortality, rehospitalizations, GVHD, 
select opportunistic infections, intravenous medication use, and recurrent CMV infection) to 
inform analyses of budget impact and cost effectiveness.  Clinical trials are important sources 
of health economic data as they have high internal validity and can produce unbiased 
estimates of economic benefits.  As such, to evaluate if extended duration of LET 
prophylaxis is associated with changes in the utilization of healthcare resources, healthcare 
resource utilization data are collected for all participants throughout the study.  The data 
collected may be used to conduct exploratory economic analyses.
 
 
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4.2.2
Rationale for the Use of Comparator/Placebo
It has not yet been shown that there is clinical benefit to continuing CMV prophylaxis in 
HSCT recipients after 100 days post-transplant.  Therefore, the efficacy and safety of LET 
with monitoring/PET will be compared against placebo and monitoring/PET, which is the 
standard of care for CMV management for allogeneic HSCT recipients who are at risk of 
CMV infection/disease after Day 100 post-transplant.  The trial is designed to evaluate if 
LET is superior to placebo in the prevention of clinically significant CMV infection when 
LET prophylaxis is extended from 100 to 200 days post-transplant.  The use of a placebo-
controlled design will also allow a robust evaluation of the safety profile of LET beyond the 
initial 100 days post-transplant.  
4.3
Justification for Dose
The doses of LET selected in this study are 480 mg QD orally or intravenously, or 240 mg 
QD orally or intravenously when coadministered with CsA. The LET dose is reduced to 
240 mg QD when coadministered with CsA based on the observed increase in LET
exposures in a Phase 1 DDI trial in healthy subjects (P010) and Phase 3 study (P001).  These
LET doses have been approved for prophylaxis of CMV in HSCT recipients.  Since the oral 
formulation of LET demonstrates no clinically significant food effect, participants may take 
the study drug orally without regard to food.  Refer to the IB for details on dose justification; 
the rationale for the doses selected is briefly summarized in this section.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criterion specified below:

The DMC recommends termination of the study and the Executive Oversight 
Committee (EOC) agrees as stated in the DMC charter.

The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study
population as a whole is unacceptable.  
Details for the discontinuation of study medication for any given participant are provided in 
Section 7.1.
 
 
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5
STUDY POPULATION
Male and female CMV R+ participants of at least 18 years of age who had an allogeneic
HSCT and have received LET as primary CMV prophylaxis that started within 28 days of 
HSCT and continued through 14 weeks post-transplant will be enrolled in this study.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. have documented positive CMV serostatus (CMV IgG seropositive) for recipient (R+) at 
the time of transplant.
2. history of allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood 
transplant) within ~100 days prior to randomization.
3. have undetectable CMV DNA or detectable/not quantifiable CMV DNA (central 
laboratory) from a plasma sample collected within 14 days prior to randomization.
4. have received LET as primary prophylaxis that started within 28 days of HSCT and 
continued through Week 14 post-transplant (100 days) ±1 week prior to randomization.
5. at high risk of CMV disease, defined as meeting one or more of the following criteria:
a.
having a related donor with at least one mismatch at one of the specified three HLA 
gene loci (HLA-A, B, or DR); 
b. having an unrelated donor with at least one mismatch at one of the specified four 
HLA gene loci (HLA-A, B, C, and DRB1); 
c.
having a haploidentical donor; 
d. having umbilical cord blood as the stem-cell source; 
e.
having ex-vivo T-cell–depleted grafts;
f.
receipt of anti-thymocyte globulin (Note: enrollment of participants whose ONLY 
high-risk factor is the use of anti-thymocyte globulin will be restricted to 20% of all 
enrolled participants);
g. receipt of alemtuzumab;
h. having GVHD or other conditions, requiring the use of systemic prednisone (or 
equivalent) at a dose of ≥1 mg/kg of body weight per day within 6 weeks of 
randomization.
 
 
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Demographics
6. Participant is ≥18 years of age at the time of signing the informed consent.
Female Participants
7. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 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 contraceptive guidance in Appendix 5 during the 
treatment period and for at least 28 days after the last dose of study medication.
Informed Consent
8. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study.  
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. has a history of CMV end-organ disease or preemptive treatment therapy for CMV after 
HSCT prior to randomization.
2. has a history of >14 days total of LET interruption during the first 100 days 
post-transplant prior to randomization.
3. has suspected or known hypersensitivity to active or inactive ingredients of LET 
formulations.
4. has severe hepatic insufficiency defined as Child-Pugh Class C (see Appendix 8, 
Section 10.8) within 14 days prior to randomization.
5. has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5× the 
upper limit of normal (ULN) within 14 days prior to randomization.  
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have repeat testing done one time prior to randomization.  If the repeat 
value does not meet this criterion, they may continue in the screening process.  Only 
the specific out of range value should be repeated (not the entire panel).
 
 
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6. has end-stage renal impairment with a creatinine clearance less than 10 mL/min, as 
calculated by the Cockcroft-Gault equation using serum creatinine within 14 days prior to 
randomization
Creatinine Clearance (Males) = weight in kg × (140 – age in years)
72 × serum creatinine in mg/dL
Creatinine Clearance (Females) = 0.85× the value obtained with formula above
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have repeat testing done one time within 14 days prior to randomization.  
If the repeat value does not meet this criterion, they may continue in the screening 
process.  Only the specific out of range value should be repeated (not the entire 
panel).
7. has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency. 
Note: Moderate hepatic insufficiency is defined as Child-Pugh Class B (see 
Appendix 8); moderate-to-severe renal insufficiency is defined as a creatinine 
clearance less than 50 mL/min, as calculated by the Cockcroft-Gault equation (as 
above), respectively.
8. has an uncontrolled infection on the day of enrollment.
9. requires mechanical ventilation or is hemodynamically unstable at the time of enrollment.
10. has a documented positive result for a human immunodeficiency virus antibody 
(HIV-Ab) test at any time prior to screening, or for hepatitis C virus antibody (HCV-Ab) 
with detectable HCV RNA, or hepatitis B surface antigen (HBsAg) within the 6 months 
prior to screening.
11. has active solid tumor malignancies (with the exception of localized basal cell or 
squamous cell skin cancer).
 
 
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Prior/Concomitant Therapy
12. Received within 7 days prior to screening any of the following:

ganciclovir or valganciclovir

foscarnet

acyclovir (at doses greater than those recommended for HSV/VZV prophylaxis; see 
Sec. 6.5.2.1)

valacyclovir (at doses greater than those recommended for HSV/VZV prophylaxis;
see Sec. 6.5.2.1) 

famciclovir (at doses greater than those recommended for HSV/VZV prophylaxis; 
see Sec. 6.5.2.1)
13. Received within 30 days prior to screening any of the following:

cidofovir

CMV immunoglobulin 
Prior/Concurrent Clinical Study Experience
14. is currently participating or has participated in a study with an unapproved investigational 
compound, monoclonal antibody, or device within 28 days or 5× half-life of the 
investigational compound or monoclonal antibody, whichever is longer, of initial dosing 
in this study.  
Note: Investigational chemotherapy regimens involving approved agents and 
investigational antimicrobial regimens involving approved 
antibacterial/antifungal/antiviral agents, investigational radiotherapy or GVHD 
agents, or other observational studies are allowed.
15. has previously participated in this study or any other study involving LET, 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 
16. is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the 
time of consent through 28 days after the last dose of study therapy.
17. is expecting to donate eggs starting from the time of consent through 28 days after the 
last dose of study therapy.
 
 
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18. has clinically relevant drug or alcohol abuse within 12 months of screening that may 
interfere with participant treatment, assessment, or compliance with the protocol as 
assessed by the investigator.
19. 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 would be put at undue risk as judged by 
the investigator, such that it is not in the best interest of the participant to participate in 
this study.
20. is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
The oral formulation of LET demonstrates no clinically significant food effect, thus 
participants may take the study drug orally without regard to food.  However, there may be 
restrictions with other nonstudy treatment agents the participant is taking during the study 
and therefore it is important for investigators to refer to the product information for those 
agents (ie, participants who are taking CsA concomitantly with LET must avoid consumption 
of grapefruit and grapefruit juice).  
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study medication or withdraws from the study will not 
be replaced.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies, study intervention(s) provided by the Sponsor will be packaged to support 
enrollment.  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study medication(s) to be used in this study are outlined in Table 1 (oral formulation) 
and Table 2 (IV formulation).  Both the 240-mg (for participants on CsA) and 480-mg (for 
participants not on CsA) oral formulations of LET will be made available by the Sponsor. 
Approximately 216 participants who have received LET through 100 days post-transplant are 
planned for randomization in a 2:1 ratio to receive either an additional 100 days (14 weeks) 
of once-daily LET (n=144 participants) or placebo (n=72 participants) from the day of 
enrollment (Day 1—ie, 100 days [14 weeks] post-transplant) through 28 weeks
post-transplant.  Participants on 480 mg will receive either one 480-mg tablet or two 240-mg 
tablets (based on the participants’ tolerance to swallowing the larger 480-mg tablet).  The IV 
formulation of LET will be available for participants randomized to LET who develop a 
condition that may interfere with their ability to swallow, or a condition that interferes with 
the absorption of the oral formulation (eg, vomiting, diarrhea, or a malabsorptive condition).  
Participants randomized to placebo who develop a condition that may interfere with their 
ability to swallow, or a condition that interferes with the absorption of the oral formulation 
will be able to receive IV administration of placebo.  The simultaneous use of IV and oral 
study therapy is not permitted.  Use of the IV formulation should generally be limited to a 
duration of 4 weeks or less; however, IV administration beyond 4 weeks will be permitted if, 
in the investigator’s judgment, the benefit/risk supports continued administration.  There is 
no sponsor-provided placebo for IV LET.  On-site blinding will be administered by an 
unblinded pharmacist using open label IV LET (20 mg/mL, 12-mL fill vial) and locally 
supplied sterile IV dextrose or saline diluent as the placebo.
 
 
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Table 1
Study Therapy – Oral (Tablet) Formulation
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
IMP/ 
NIMP a
Sourcing
LET (for participants 
on CsA)
240 mg
Once daily
Oral
From Week 14 post-transplant
to Week 28 post-transplant
Experimental
IMP
Sponsor
LET (for participants 
not on CsA)
480 mg (one 480-
mg tablet or two 
240-mg tablets)
Once daily
Oral
From Week 14 post-transplant
to Week 28 post-transplant
Experimental
IMP
Sponsor
Placebo for LET b
NA
Once daily
Oral
From Week 14 post-transplant
to Week 28 post-transplant
Placebo
IMP
Sponsor
CsA = Cyclosporin A; IMP = investigational medicinal product; LET = letermovir; NIMP = noninvestigational medicinal product 
a:
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European Commission and 
applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is 
followed.
b:
The number of placebo tablets will mimic the LET dosing scheme in an effort to maintain the blind (ie, 1 matching placebo tablet if on CsA; 1 or 2 matching placebo tablets if not on CsA to 
mimic one 480-mg tablet or two 240-mg tablets, respectively).
Table 2
Study Therapy – Intravenous Formulation
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
IMP/ 
NIMP a
Sourcing
LET (for participants 
on CsA) b
240 mg
Once daily
IV
From Week 14 post-transplant to 
Week 28 c post-transplant
Experimental
IMP
Sponsor
LET (for participants 
not on CsA) b
480 mg
Once daily
IV
From Week 14 post-transplant to 
Week 28 c post-transplant
Experimental
IMP
Sponsor
Placebo for LET b
NA
Once daily
IV
From Week 14 post-transplant to 
Week 28 c post-transplant
Placebo
IMP
Site locally
CsA = Cyclosporin A; IMP = investigational medicinal product; LET = letermovir; NIMP = noninvestigational medicinal product 
a:
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European Commission and 
applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is 
followed.
b:
LET IV formulation dosing volume is 250 mL and duration of infusion will be 60 minutes. LET IV will be provided as a sterile liquid concentrate for dilution (20 mg/mL), one vial to be used 
for the 240-mg dose and two vials for the 480-mg dose. Locally supplied sterile IV dextrose or saline diluent will be used as the placebo to LET IV as prepared by the site unblinded pharmacist.
c:
The IV formulation should be switched to oral study therapy (ie, at the next planned dose) as soon as participants are able to swallow and/or the condition necessitating the use of the IV 
formulation resolves.
 
 
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All supplies indicated in Table 1 and Table 2 will be provided per the "Sourcing" row 
depending upon local country operational requirements. Every attempt should be made to 
source these supplies from a single lot/batch number. The study site is responsible for 
recording the lot number, manufacturer, and expiry date for any locally purchased product 
per local guidelines unless otherwise instructed by the Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.2.3
Participant-level Study Medication Accountability 
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 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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system.  There are 2 study medication arms.  Participants will be 
randomized 2:1 to receive either LET (dosage of 240 mg or 480 mg dependent on CsA 
status) or placebo for LET.
6.3.2
Stratification
Treatment allocation/randomization will be stratified by:
1) study center and 
2) haploidentical donor (yes/no)
6.3.3
Blinding
In this study a double-blinding technique with in-house blinding will be used.  The 
participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the 
study medication administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
Oral LET tablets will be packaged identically so that treatment blind/masking is maintained.  
A placebo image to LET (both 240 mg and 480 mg) will be implemented to maintain study 
blinding and placebo tablets will be indistinguishable from LET.  Participants on CsA will 
receive either 1 tablet of 240 mg LET or 1 tablet of matching placebo.  Participants not on 
CsA will receive either 480 mg LET (administered as 1 tablet of 480 mg LET or 2 tablets of 
240 mg LET) or 1 or 2 tablets of matching placebo.
IV LET matching placebo (see Section 6.1) will be prepared in a blinded fashion by an 
unblinded pharmacist (or qualified study site personnel designated to prepare blinded IV 
study therapy).  The unblinded pharmacist will obtain the IV treatment assignment from IRT.  
The Sponsor will provide opaque covers for the IV bags in order to assist with blinding IV 
study therapy.
 
 
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Because this is a double-blind study, the investigator, study personnel, and participant must 
remain blinded to the IV study therapy.  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.
Patients who have their treatment inadvertently unblinded will not be discontinued from the 
study.
6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment for ≥7 days require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
It is important for investigators to review each medication (prescription and non-prescription) 
the participant is taking before starting the study and at each study visit.

At each visit, participants should be questioned about any new drug they are taking.

To minimize the risk of adverse drug interactions, every effort should be made to 
limit the number of concomitant drugs to those that are truly essential.
Given that the lists below are not comprehensive, the investigator should use his/her medical 
judgment when a participant presents with a medication not on the list and consult with the 
Sponsor when appropriate.
6.5.1
Allowed Medications/Therapies to be Administered with Clinical and/or Drug 
Level Monitoring when Coadministered with Study Therapy
The following medications/therapies are allowed when coadministered with study therapy, 
but should be used with clinical monitoring for AEs related to these agents and/or drug level 
monitoring of these agents (please refer to the prescribing information of each local product 
circular).
 
 
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Note: Since the drug-drug interactions may be different when LET is coadministered
with CsA than when drugs are coadministered with LET without CsA, please refer to 
Section 6.5.2.2 for additional recommendations when study therapy is coadministered
with CsA.

CYP3A substrates:

Coadministration of LET with drugs that are CYP3A substrates may result in 
clinically relevant increases in the plasma concentrations of co-administered 
CYP3A substrates (eg, alfentanil, fentanyl, and midazolam).  Therefore, frequent 
monitoring for adverse reactions related to these agents is recommended during 
coadministration.  

Dose adjustment of CYP3A substrates with narrow therapeutic range (NTR) may 
be needed when coadministered with LET (a moderate CYP3A inhibitor).  Please
consult current prescribing information for monitoring and dosing of these 
products with moderate inhibitors of CYP3A.

Cyclosporin A (CsA):  Coadministration of LET with CsA increases CsA 
concentrations.  Frequent monitoring of CsA whole blood concentrations 
should be performed during and at discontinuation of LET with the dose of 
CsA to be adjusted as appropriate.

Sirolimus:  Coadministration of LET with sirolimus increases concentrations 
of sirolimus.  Frequent monitoring of sirolimus whole blood concentrations 
should be performed during and at discontinuation of LET with the dose of 
sirolimus to be adjusted as appropriate.  When LET is co-administered with 
CsA, refer to the sirolimus prescribing information for specific dosing 
recommendations for use of sirolimus with CsA.

Tacrolimus:  Coadministration of LET with tacrolimus increases tacrolimus 
concentrations.  Frequent monitoring of tacrolimus whole blood 
concentrations should be performed during and at discontinuation of LET with
the dose of tacrolimus to be adjusted as appropriate.

Everolimus:  Coadministration of LET with everolimus may increase 
everolimus concentrations.  Frequent monitoring of everolimus blood 
concentrations should be performed during and at discontinuation of LET with
the dose of everolimus to be adjusted as appropriate.  (Note: Please see 
Section 6.5.2.2 for recommendation of everolimus when LET is co-
administered with CsA).

Amiodarone: LET may increase the plasma concentrations of amiodarone 
(CYP3A and CYP2C8 substrates).  Frequent monitoring for adverse reactions 
related amiodarone is recommended during coadministration.  Frequent 
monitoring of amiodarone concentrations should be performed when co-
administered with LET.
 
 
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
Certain HMG-CoA reductase inhibitors (statins) as substrates of organic anion-
transporting polypeptide 1B1/3 (OATP1B1/3) and/or CYP3A:

Atorvastatin:  The dose of atorvastatin should not exceed a daily dose of 20 mg.  
(Note: Please see Section 6.5.2.2 for recommendation of atorvastatin when LET is 
co-administered with CsA)

Fluvastatin, lovastatin, rosuvastatin, or pravastatin:  The dose of fluvastatin, 
lovastatin, rosuvastatin, or pravastatin may need to be adjusted when co-
administered with LET.  Monitoring for statin-associated adverse reactions (eg, 
myalgias, rhabdomyolysis) is recommended during co-administration with LET. 

Substrates of CYP2C9 and CYP2C19 (voriconazole, warfarin, phenytoin, 
omeprazole, and pantoprazole):

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.

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.

Proton Pump Inhibitors, omeprazole, and pantoprazole:  LET may decrease the 
plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose 
adjustment may be needed.

Medications for Diabetes:  

Glyburide, repaglinide, or rosiglitazone:  LET may increase the plasma 
concentrations of these diabetic medications.  Frequent monitoring of glucose 
concentrations is recommended during co-administration with LET.  (Note: 
please see Section 6.5.2.2 for recommendation of repaglinide when LET is co-
administered with CsA)
6.5.2
Prohibited Medications
Medications/therapies that are prohibited during coadministration with study therapy during 
the time periods specified are outlined in Section 6.5.2.1.  Since the drug-drug interaction on 
co-administered drugs may be different when LET is co-administered with CsA than when 
drugs are co-administered with LET without CsA, additional prohibited medications when 
study therapy is co-administered with CsA are outlined in Section 6.5.2.2.
 
 
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Study therapy should be administered in a manner consistent with the LET local product
circular, including the complete list of prohibited medications (ie, those that are 
contraindicated or not recommended) in the circular.  The local product circular for LET 
supersedes this section when the product circular is more restrictive.
If there is a clinical indication for one of these or other medications specifically prohibited 
during the study, discontinuation from study therapy may be required.  The investigator 
should discuss any questions regarding this with the Sponsor.  The final decision on any 
supportive therapy rests with the investigator and/or the participant’s primary physician.  
However, the decision to continue the participant on study therapy requires the mutual 
agreement of the investigator, the Sponsor, and the participant.  Given that the list below is 
not comprehensive, the investigator should use his/her medical judgment when a participant 
presents with a medication not on the list and consult with the Sponsor.
6.5.2.1
Medications Prohibited with Study Medication

Antiviral drugs or therapies for prevention/treatment of CMV are prohibited during 
the study (Week 14 to 48 post-transplant), including but not limited to:

letermovir that is not part of study medication

ganciclovir or valganciclovir

foscarnet

cidofovir

acyclovir (at doses greater than those recommended for HSV/VZV prophylaxis, 
such as >3200 mg PO per day or >25 mg/kg IV per day)

valacyclovir (at doses greater than those recommended for HSV/VZV 
prophylaxis, such as >3000 mg)

famciclovir (at doses greater than those recommended for HSV/VZV prophylaxis, 
such as >1500 mg) 

CMV immunoglobulin 

any investigational CMV antiviral agent/biologic therapy, including CMV 
vaccines
Note: these agents may be used for other indications while participants are on 
study therapy (eg, foscarnet for the treatment of HHV-6 or acyclovir for treatment 
of disseminated zoster)
 
 
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The following medications/therapies are prohibited during the dosing period and for 
14 days after study medication is discontinued: 

Investigational Agents:  Unapproved investigational agents or investigational 
regimens involving combinations of approved agents are not permitted except

Investigational chemotherapy regimens involving approved agents and 
investigational antimicrobial regimens involving approved 
antibacterial/antifungal/antiviral agents, investigational radiotherapy studies, or 
other observational studies are allowed.

Herbal Supplements:  Herbal supplements are not permitted.

CYP3A substrates with NTR, including but not limited to:

Pimozide: Concomitant administration of LET may result in increased 
concentrations of pimozide due to inhibition of CYP3A by LET, which may lead 
to QT prolongation and torsade de pointes.

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.

Certain HMG-CoA reductase inhibitors (statins) (Note: See Section 6.5.2.2. for 
additional statins that are prohibited for use when LET is coadministered with CsA):

Simvastatin and pitavastatin

Fixed dose combinations of statins

Strong inducers, such as rifampin, phenytoin, carbamazepine, St John’s wort 
(Hypericum perforatum), rifabutin and phenobarbital 

Moderate inducers, such as nafcillin, thioridazine, modafinil and bosentan
6.5.2.2
Additional Medications Prohibited When Study Medication is 
Co-administered with CsA
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered 
drugs may be different when LET is co-administered with CsA than when drugs are co-
administered with LET without CsA.  In addition to the prohibited medications listed above 
in Section 6.5.2.1, medications listed in this section are additional medications that are 
prohibited when coadministered with LET and CsA during the dosing period and for 14 days 
after the dosing period.  When used together, they should be administered in a manner 
consistent with the local product circulars (for CsA and LET), including the complete list of 
prohibited medications including those that are contraindicated or not recommended.  The 
 
 
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local product circular for LET supersedes this section when the product circular is more 
restrictive.

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.  

atorvastatin and lovastatin (Note: please see Section 6.5.2.1 for additional 
prohibited statins when coadministered with LET alone).  

Everolimus (Note: please see Section 6.5.1 for recommendation of everolimus when 
co-administered with LET alone)

Repaglinide (Note: please see Section 6.5.1 for recommendation of repaglinide when 
co-administered with LET alone)
6.5.3
Rescue Medications and Supportive Care
In the event of clinically significant CMV infection (CMV disease or initiation of PET based 
on CMV viremia and the clinical condition of the participant) at any time during the 28-week
post-transplant period, study therapy will be discontinued, and the participant may be treated 
according to the local standard of care (outside the context of the study).  In this setting, any 
of the prohibited anti-CMV medications (outlined in Section 6.5) may be used.
6.6
Dose Modification (Escalation/Titration/Other)
See Section 4.3 for the LET dose to be used with or without co-administered CsA.
If CsA is initiated after starting study medication, the next dose of the study medication
should be decreased to 240 mg once daily.  If CsA is discontinued permanently or for the 
long term in a participant already receiving study medication, the next dose of study 
medication should be increased to 480 mg once daily.  If CsA is temporarily withheld due to 
high levels detected by therapeutic blood monitoring, the dose of study medication need not 
be adjusted.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention /randomization schedule for 
the study to unblind participants and to unmask study medication identity.  The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10).  In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
 
 
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unblind participants and to unmask study medication identity.  The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the investigational medicinal product 
(IMP) to provide the following advice:
“You have participated in a study conducted by the Sponsor.  This letter is to advise you that 
you were among those who received a look-alike tablet created by the Sponsor to resemble 
the drug letermovir as much as possible.  You did not receive the active drug letermovir as 
manufactured by MSD.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to 
discontinue study intervention.

The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, placed the participant at unnecessary risk 
from continued administration of study intervention.

The participant has a confirmed positive serum pregnancy test.
 
 
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
The investigator feels it is in the best interest of the participant to discontinue.

The participant develops clinically significant CMV infection as determined by the 
investigator (Section 4.2.1.3).

The participant develops one of the following:
-
Both moderate hepatic insufficiency (Child-Pugh Class B; Sections 8.3.4 
and 10.8) and moderate-to-severe renal insufficiency (defined as CrCl 
<50 mL/min as calculated by the Cockcroft-Gault equation), 
OR
-
Severe hepatic insufficiency (Child-Pugh Class C; Sections 8.3.4 and 10.8)

Needs dialysis or develops end-stage renal impairment with creatinine clearance 
≤10 mL/min as calculated by the Cockcroft-Gault equation as follows:
Creatinine Clearance (Males) = weight in kg × (140 – age in years)
72× serum creatinine in mg/dL
Creatinine Clearance (Females) = 0.85× the value obtained with formula above
Note: Child-Pugh class (see Appendix 8) and creatinine clearance using the 
Cockcroft-Gault equation should be assessed at the Day 1 and every visit until 
the study medication is discontinued (including at the CMVi or Early 
discontinuation visit if study medication is being discontinued at those visits) in 
order to ensure timely discontinuation of study medication.

The participant may be discontinued from study medication for any of the following 
reasons:

Any AE/SAE assessed by the investigator as 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.

Failure to comply with the dosing, evaluations, or other requirements of the study.

The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or Sponsor, does not allow the participant to adhere to 
the requirements of the protocol (eg, if there is a clinical indication for any 
medication or vaccination specifically prohibited during the trial, discontinuation 
from trial therapy may be required [see Section 6.5]).
For participants who are discontinued from study medication but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
 
 
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Note: Participants who have their treatment unblinded should not be discontinued from the 
study.
Participants may be allowed to begin study medication again if deemed medically 
appropriate unless the participant’s treatment assignment has been unblinded by the 
investigator, delegate, and/or nonstudy treating physician. There may be instances where 
confirmatory central laboratory test results for CMV DNA PCR results obtained on the day 
of PET initiation may be CMV DNA undetectable or detected, but not quantifiable, and the 
investigator may wish to discontinue PET.  The decision to stop PET resides with the 
investigator caring for the subject.  Therefore, in the event the confirmatory CMV DNA 
sample at PET initiation is CMV DNA undetectable or detected, but not quantifiable, the 
Sponsor will allow for study therapy to be restarted at the investigator’s discretion, once PET 
is discontinued.  In such instances, study therapy should be restarted within 7 days from the 
date on which study therapy was stopped.  It is important to note that the status of the 
subject’s study therapy in IRT should NOT be changed until the CMV DNA PCR 
result is confirmed and the investigator is certain that study therapy will be 
permanently discontinued.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
 
 
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
Note: A participant is not considered lost to follow-up until the last scheduled 
visit for the individual participant. The missing data for the participant will be 
managed via the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a 
qualified physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained from 
the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 255 mL; see Appendix 2 (Section 10.2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study.  If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
 
 
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8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at screening.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement.  Prior medications such as antivirals, chemotherapy 
agents, and immunosuppressant agents taken by the participant 30 days prior to screening 
should be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medications, if any, taken by the 
participant during the study treatment through 2 weeks after the study medication is 
discontinued.  In addition, anti-CMV medications (including LET that is not part of the study 
medication, ganciclovir, valganciclovir, acyclovir, valacyclovir, famciclovir, foscarnet, 
cidofovir) administered for treatment of CMV disease or for initiation of PET, and all 
drug/biologic therapies used to prevent/treat GVHD should be recorded at every visit through 
Week 48 post-transplant (Visit 17).  During the follow-up period through Week 48, 
concomitant medication review and recording of data is outlined in data entry guidelines.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
 
 
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a treatment
/randomization number.  The treatment /randomization number identifies the participant for 
all procedures occurring after treatment allocation/randomization.  Once a treatment 
/randomization number is assigned to a participant, it can never be re-assigned to another 
participant.
A single participant cannot be assigned more than 1 treatment /randomization number.
8.1.8
Study Intervention Administration
The first dose of study intervention will be administered at the study site at Visit 2 (Day 1; 
~Week 14 post-transplant). Subsequent dosing will be performed once daily by the 
participant (ie, unsupervised at his/her home) at approximately the same time each day.
For participants who develop a condition that interferes with their ability to swallow, or a 
condition that interferes with the absorption of the oral formulation (eg, vomiting, diarrhea, 
or a malabsorptive condition), a LET IV formulation is available for those participants 
randomized to LET and IV placebo (saline or 5% dextrose) would be administered to those 
randomized to placebo.  IV administration is for short-course administration (up to 
approximately 4 weeks).  The study pharmacist will be responsible solely for the preparation 
of the IV study medication.  Site personnel will administer the IV study medication through a 
sterile 0.2-micron or 0.22-micron polyethersulfone (PES) in-line filter, using only IV bags 
and infusion set materials that are diethylhexyl phthalate (DEHP)-free. Refer to the
Pharmacy Manual document for further details.
8.1.8.1
Timing of Dose Administration
Study therapy should be administered/taken at the same time each day.  Tablets are to be 
swallowed whole (ie, no crushing or chewing the tablet is allowed).  Study therapy may be 
administered with or without food (please refer to Section 5.3.1 for food restrictions 
applicable to those participants who are taking concomitant CsA). 
If a participant misses a dose, the missed dose should be given as soon as possible during the 
same day.  If more than 18 hours have gone by after the regular dosing time, then the missed 
dose should be skipped, and the normal dosing schedule should be resumed.  The next dose 
should not be doubled in order to “make up” what has been missed.  
If a participant vomits within 2 hours of an oral administration, the full oral dose can be 
repeated one time within 6 hours after vomiting.  If a participant vomits and it has been 
longer than 2 hours from the time of oral administration, the dose should not be repeated.  
Take the next dose at the usual time.
 
 
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8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation Visit should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4 and Visit Requirements as 
outlined in Section 1.3 (SoA).
8.1.10
Participant Blinding/Unblinding
STUDY MEDICATION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT.  EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and /or the
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding.  As requested by the investigator or medically
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor.  Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study medication, the reason thereof, etc, in the 
medical chart.  If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition.  In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Domiciling
Not applicable.
 
 
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
CMV DNA PCR Testing
Protocol-specified CMV DNA levels will be drawn at prespecified clinical visits and the 
CMV Infection Visit as indicated in the Study SoA (Section 1.3) and sent to the central 
laboratory where CMV DNA PCR testing will be performed using a quantitative CMV 
DNA PCR assay at the central laboratory  In this study, CMV DNA levels may be monitored 
using local laboratory results for the clinical management of participants any time during the 
study. It is MANDATORY, however, to collect and send a confirmatory plasma sample for 
CMV DNA PCR testing to the central laboratory immediately prior to (ie, on the day of) 
initiating PET or treatment for confirmed or suspected CMV disease (CMV infection visit).  
(Note:  for any site in Japan where a positive local pp65 antigen test is used to drive the 
decision to initiate anti-CMV therapy, in addition to a confirmatory CMV DNA PCR testing, 
a blood sample must be collected for confirmatory local pp65 antigen testing prior to 
initiating PET; the confirmatory test results are not required for initiating PET.)
In the event test results from the central laboratory are not available within the time frame the 
investigator wishes to initiate anti-CMV therapy (including PET), the investigator may use a 
positive local laboratory test (CMV DNA PCR or pp65 antigen only) result in order to make 
the decision.  However, as described above, a confirmatory plasma samples for CMV DNA 
PCR testing must also be sent to the central laboratory prior to initiating PET.  The local 
laboratory result must also be reported in such instances.
In the event that the confirmatory result obtained on the day of anti-CMV treatment
(including PET) initiation is NOT available (eg, sample is lost or mishandled by the 
investigator site prior to shipment, or is inadequate upon receipt at the central laboratory), a 
subsequent sample must be obtained and sent to the central laboratory within 48-72 hours
after initiation of anti-CMV treatment.  Sample collection, storage, and shipment instructions 
for plasma samples will be provided in the operations/laboratory manual.
Assessment of CMV Disease
CMV disease will be assessed at every visit from screening through Week 48 post-transplant.  
Diagnostic criteria for the evaluation of CMV infection are outlined in Appendix 7.  If CMV 
disease is suspected, site should perform the CMV Infection Visit instead of the scheduled 
visit assessments (see Section 1.3, Schedule of Activities).  The investigator will ensure that 
clinical information, radiology results, and specimens for the appropriate diagnostic tests 
 
 
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(including, but not limited to, viral culture, histopathology, immunohistochemical analysis, in 
situ hybridization, CMV DNA PCR) as outlined in Appendix 10.7 will be collected.
8.2.2
CMV DNA Resistance Analysis
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the central laboratory manual.
CMV DNA sequence analysis will be performed on samples from participants who meet the 
criteria for clinically significant CMV infection.  Resistance to LET will be assessed by 
genotypic analysis of the CMV terminase complex genes (UL56, UL89, and UL51) in DNA 
extracted from plasma samples collected as indicated in the Schedule of Activities
(Section 1.3). All CMV resistance genotyping samples with detectable CMV DNA will be 
analyzed by next-generation sequencing technology through an established contract 
laboratory with validated protocols in place.  The resistance genotyping assay is validated for 
plasma samples containing 500 copies/mL or higher of CMV DNA with a sensitivity cutoff 
of 5% to detect minor variants.  If multiple CMV-positive resistance samples are collected, 
the last on-therapy and follow-up samples will be prioritized for resistance analysis.  
Phenotypic analysis may be performed on any UL56, UL89, or UL51 DNA sequences which 
encode amino acid substitutions that have not been previously characterized for LET
susceptibility.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.  The total amount of blood/tissue to be drawn/collected over the course of the study 
(from pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 10.2 
(Appendix 2).
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
On Day 1 (post-transplant Week 14), a complete physical examination will be conducted by 
an investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard. 
After randomization (Day 1), the physical examination does not need to be performed at 
every visit; a targeted physical examination should be performed only if a participant has any 
complaints.  The timing of physical examinations is indicated in the Study SoA (Section 1.3).
Height and weight will be measured and recorded per the SoA.  
 
 
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8.3.2
Vital Signs
Vital signs will be assessed at the time points indicated in the SoA (Section 1.3) and will 
include the following assessments: 

Body temperature (oral preferred, see below), heart rate respiratory rate, and blood 
pressure will be assessed.  NOTE: Oral temperatures should be taken, but if oral is 
not possible, tympanic, rectal, temporal, or axillary temperatures may be taken. 

Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions.
8.3.3
Electrocardiograms

Single 12-lead electrocardiogram (ECG) will be obtained and reviewed by an 
investigator or medically qualified designee (consistent with local requirements) as 
outlined in the SoA (see Section 1.3) using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  Participants 
should be shaved (if 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.
8.3.4
Child-Pugh Score
The Child-Pugh score will be assessed as indicated in the Study SoA (Section 1.3) according 
to Appendix 8.  At the screening visit, the clinical assessment and the central laboratory 
parameters (total bilirubin, albumin, and PT/INR) obtained at that visit will be used to 
calculate the Child-Pugh score.  Thereafter, at each scheduled assessment of the Child-Pugh 
score, the clinical assessment at the scheduled study visit and the most recently collected and
available local laboratory parameters (total bilirubin, albumin, and INR) obtained at the 
corresponding scheduled study visit, or up to one week prior to the scheduled study visit, will
be used to calculate the Child-Pugh score.  As stated in Section 7.1, a participant must be 
discontinued from study treatment but continue to be monitored in the study if the participant 
develops both moderate hepatic insufficiency (Child-Pugh Class B) and moderate-to-severe 
renal insufficiency (defined as CrCl <50 mL/min as calculated by the Cockcroft-Gault 
equation; see Section 5.2), or develops severe hepatic insufficiency (Child-Pugh Class C). 
8.3.5
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
 
 
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underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol specified laboratory assessments performed at
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
 
 
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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. Thereafter, only SAEs considered to be drug-related or leading to death should 
be reported through Week 48 post-transplant.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting 
Time Period:
Randomizatio
n/ Allocation 
through 14 
days after last 
dose of study 
medication
Reporting Time 
Period:
From 14 days 
after last dose of 
study medication
until study 
completion
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Nonserious
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
Report all
Report only if:
- drug-related. OR
-SAEs leading to 
death, regardless 
of causality 
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously 
reported – Follow 
to 
completion/termi
nation; report 
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:
Randomizatio
n/ Allocation 
through 14 
days after last 
dose of study 
medication
Reporting Time 
Period:
From 14 days 
after last dose of 
study medication
until study 
completion
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
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 all
Not required
Within 5 
calendar days of 
learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (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 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
 
 
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8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. An elevated AST or ALT laboratory value that is ≥3ULN and an elevated total 
bilirubin laboratory value that is ≥2ULN and, at the same time, an alkaline 
phosphatase laboratory value that is <2ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
 
 
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* Note: These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than two times the prescribed dose specified in 
Section 6.6 (Dose Modification [Escalation/Titration/Other]).
Sponsor does not recommend specific treatment for an overdose. Overdose during the study 
will be a reportable safety event (see Section 8.4.1 and Appendix 3 for further details).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
PD parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Biomarkers
CMV-specific T-cell responses will be measured using the QuantiFERON-CMV assay 
[Becke, S., et al 2010] [Goldner, T., et al 2011] at various time points through Week 48 
post-transplant using plasma samples.  The proportion of participants with positive 
QuantiFERON-CMV assay results will be correlated with the incidence of clinically 
significant CMV infection through Week 48 post-transplant and assessed as an exploratory 
endpoint.  The central laboratory based QuantiFERON-CMV assay results will not be shared 
with the respective site investigators.
 
 
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8.11
Health Outcomes Assessment
All-cause mortality, all rehospitalizations and CMV-related rehospitalizations, GVHD, select 
opportunistic infections, IV medication other than LET use, and recurrent CMV infection
will be measured to assess healthcare resource utilization.  The data collected may be used to 
conduct exploratory economic analyses.  Protocol-mandated procedures, tests, and 
encounters are excluded.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Approximately 14 days prior to treatment allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Sections 5.1 and 5.2. Screening procedures may be repeated after consultation with the 
Sponsor.
Human immunodeficiency virus (HIV) antibody test results documented at any time prior to 
screening of the participant will be acceptable; a copy of this HIV report must be available.  
(See Exclusion Criterion #10 in Section 5.2).  If documentation of a previous HIV test is not 
available, the HIV antibody test must be conducted using the central or local laboratory.  
Hepatitis B and hepatitis C screening should only be performed if not previously documented 
within the last 6 months.  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).
8.12.2
Treatment Period
Study medication (LET/Placebo) may begin as early as 14 weeks ± 1 week post-transplant.  
Study medication will be dispensed every 2 weeks and continue through Week 28
(~200 days) post-transplant.  The treatment period is through Week 28 post-transplant 
regardless of when study medication is discontinued. Study visits will occur every 2 weeks 
through Week 28 (~200 days) post-transplant.  
The Day 1 Visit (as shown in the SoA, Section 1.3) will be the day the participant is 
randomized and study medication is initiated.  Study medication will continue for 14 weeks
through the End of Treatment Visit at Week 28 (~200 days) post-transplant.  
All procedures listed under the study visits in the SoA (Section 1.3) will be performed at the 
corresponding visit.  After allocation, the physical examination does not need to be 
performed at every visit; a targeted physical exam should be performed only when clinically 
indicated.
 
 
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8.12.2.1
Day 1 Visit
Day 1 procedures/assessments listed on the SoA (Section 1.3) must be performed prior to 
initiation of study medication.
For female participants of childbearing potential, a urine or serum pregnancy test will be 
performed at the site prior to the initiation of study medication.  If the urine or serum 
pregnancy test result is negative, the participant will be eligible for allocation and the 
remainder of the Day 1 testing/procedures will be performed.  If the urine or serum 
pregnancy result is positive, the participant must not be randomized.
8.12.2.2
Study Medication Administration
The site pharmacist or study coordinator will contact the IRT at all dispensing visits for 
assignment of the study medication to be administered.  Sites should not contact the IRT for 
study medication administration until the participant has met all criteria for the study and is 
ready to receive the first dose of study medication on Day 1.
The first dose of study medication (LET or placebo to LET) will be administered at the trial 
site with monitoring by investigative site personnel at the Day 1 Visit (Visit 2; Week 14
post-transplant).  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, a LET 
IV formulation is available for those participants randomized to LET and IV placebo (saline 
or 5% dextrose) would be administered to those randomized to placebo.  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 who are not on CsA will receive LET 480 mg QD or placebo to LET QD given 
orally.  Participants who are receiving concomitant CsA will receive oral formulation of LET 
240 mg QD or placebo to LET QD.  Participants requiring IV formulation (LET or placebo 
to LET) who are not on CsA will receive 480 mg IV QD (Section 6.1).  Participants requiring
the IV formulation of LET or placebo to LET who are on concomitant CsA will receive 
240 mg QD of IV study medication (ie, participants randomized to placebo who require IV 
administration will be able to receive IV administration of placebo).
If CsA is initiated after starting study medication, the next dose of the study medication
should be decreased to 240 mg once daily.  If CsA is discontinued permanently or for the 
long term in a participant already receiving study medication, the next dose of study 
medication should be increased to 480 mg once daily.  If CsA is temporarily withheld due to 
high levels detected by therapeutic blood monitoring, the dose of study medication need not 
be adjusted (see Section 6.6). 
 
 
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The participant will be trained in the use of the Study Medication Diary.  He/she will be 
instructed to enter the number of tablets of study medication taken during the study treatment
period.  IV study medication will be recorded by the unblinded pharmacist or study personnel 
in the CRF.
8.12.3
Optional Nurse Visit and Telephone Visit (Weeks 32 and 36 Only)
A visiting nurse service may be utilized (if locally available and approved for use) at Visit 11 
(Week 32) and Visit 13 (Week 36) in coordination with an investigator CMV assessment by 
phone.  If a visiting nurse service is utilized, the investigator phone call should occur on the 
same day as the nurse visit, or as soon as possible.  Refer to the nursing manual for additional 
details.
8.12.4
Follow-up Period/Visits
As stated in Section 8.12.2, participants will receive study medication for 14 weeks through 
Week 28 (~200 days) post-transplant.  After the last day of study medication, participants 
will be followed via study visits from Week 30 to Week 48 post-transplant.  These visits will 
occur every 2 weeks from Week 30 to Week 40 and every 4 weeks from Week 40 to 
Week 48 and all procedures listed in the SoA (Section 1.3) corresponding to the visits will be 
performed.  
All participants will continue to be assessed for CMV infection/disease through Week 48
post-transplant and CMV DNA PCR should be tested at the central laboratory as per the SoA 
(Section 1.3).  
Adverse event monitoring should include the collection of all AEs while on study medication
and for 14 days following completion of study medication in all participants.  Thereafter, 
only drug-related SAEs and SAEs leading to death will be collected through Week 48
post-transplant.  
8.12.5
Discontinued Participants Continuing to be Monitored in the Study
8.12.5.1
Discontinuation of Study Medication due to CMV Infection
For participants who develop CS-CMVi through Week 28 post-transplant, the participant 
should have a CMV Infection Visit.  At this visit, study medication should be discontinued 
(if applicable) and all procedures as outlined in the Schedule of Activities (Section 1.3), 
including collection of a blood sample, should be performed immediately prior to the 
initiation PET or treatment of CMV disease.  Additionally, a repeat plasma sample for CMV 
viral resistance testing should be collected at the next scheduled visit after the CMV Infection
Visit (Section 8.2.2).
Such participants will continue to be followed in the study (despite discontinuing study 
medication and initiating anti-CMV therapy) and complete all remaining study visits 
(including all subsequent treatment period visits). 
 
 
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8.12.5.2
Discontinuation for Reasons Other Than CMV Infection
Study Medication Discontinuation
Participants who discontinue study medication prior to the last scheduled treatment visit for 
reasons other than CS-CMVi will continue to be followed in the study and complete all 
remaining study visits regardless of when cessation of study medication occurs.  All specified 
procedures will be completed for these participants through Week 28 post-transplant during 
the treatment period (with the exception of study medication administration, and Study 
Medication Diary review); and through Week 48 post-transplant in the follow-up period as 
outlined in the SoA (Section 1.3).
Early Study Discontinuation
The Early Discontinuation Visit will also be performed for all participants who prematurely 
discontinue the study (ie, withdraw consent) prior to the Week 48 post-transplant visit.  It is 
very important to ensure that all procedures, as outlined in the Study SoA (Sections 1.3), are 
performed for such participants at this visit prior to discontinuing from the study.  A plasma 
sample for CMV DNA PCR testing should be collected at this visit.
8.12.6
Survival Status
Updated survival status may be requested at any time, both during study conduct or after 
study completion, or after a subject discontinues from the study.  All participants or their 
contacts may be contacted for their survival status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12. 
Study Design Overview
A Phase 3 randomized, double-blind, placebo-controlled clinical trial to 
evaluate the safety and efficacy of letermovir (LET) prophylaxis when 
extended from 100 days to 200 days post-transplant in cytomegalovirus 
(CMV) seropositive recipients (R+) of an allogeneic hematopoietic stem 
cell transplant (HSCT)
Treatment Assignment
Approximately 216 participants who have already received ~100 days of 
LET will be randomized in a 2:1 ratio with 144 receiving LET prophylaxis
for an additional 100 days (200-day arm) and 72 receiving placebo (100-day 
arm). Treatment allocation / randomization will be stratified by study center 
and haploidentical donor (yes/no).
 
 
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Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
Proportion of participants with clinically significant CMV infection from
Week 14 (~100 days) post-transplant through Week 28 (~200 days)
post-transplant
Key Secondary Endpoints
1.
Safety and tolerability of LET 
2.
Proportion of participants with clinically significant CMV infection 
from Week 14 post-transplant through Week 38 post-transplant and 
from Week 14 post-transplant through Week 48 post-transplant
3.
Time to clinically significant CMV infection from Week 14 
post-transplant through Week 28 post-transplant and from Week 14 
post-transplant through Week 48 post-transplant
4.
Proportion of participants with PET for documented CMV viremia
from Week 14 post-transplant through Week 28 post-transplant and 
from Week 14 post-transplant through Week 48 post-transplant
5.
Proportion of participants with of all-cause mortality from Week 14 
post-transplant through Week 28 post-transplant and from Week 14 
post-transplant through Week 48 post-transplant
6.
Time to all-cause mortality from Week 14 post-transplant through
Week 28 post-transplant and from Week 14 post-transplant through
Week 48 post-transplant
Statistical Methods for 
Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis will be evaluated by comparing LET to placebo with
respect to the proportion of participants with clinically significant CMV 
infection from Week 14 post-transplant through Week 28 post-transplant
using the stratified Mantel-Haenszel method [Koch, G. G., et al 1990] when 
LET prophylaxis is extended from 100 to 200 days post-transplant.
Statistical Methods for 
Key Safety Analyses
95% CIs (Tier 2 endpoints) 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 [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
Periodic safety analyses will be conducted for the accruing data and
will be reviewed by an external Data Monitoring Committee (DMC) at 
regular intervals as outlined in the DMC charter. This will supplement 
routine in-house medical monitoring. No formal interim analyses for 
efficacy are planned for this study. However, efficacy data will be included 
as part of the periodic safety reviews when at least 40% of the participants 
have completed treatment or discontinued prior to completing treatment to 
allow for an assessment of benefit-risk.
Multiplicity
No formal efficacy analyses will be provided and there is no intention of 
stopping the trial due to overwhelming efficacy at any of these safety
reviews. Nevertheless, since unblinded efficacy data are being periodically 
reviewed, using a Haybittle-Peto α spending approach, a small amount of 
alpha (α = 0.0001) will be allocated for each of these looks before testing 
the primary efficacy hypothesis at Week 28 post-transplant. An allowance 
will be made such that a total of up to three of these unblinded efficacy 
reports may be presented at these periodic safety reviews. The final analysis 
can still be tested at 2.5% level without inflating Type-I error.
 
 
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Sample Size and Power 
The planned sample size is 216. For the proportion of participants with 
clinically significant CMV infection from Week 14 post-transplant through 
Week 28 post-transplant, the study has 80% power at an overall one-sided 
2.5% alpha-level to demonstrate that LET is superior to placebo in the 
prevention of clinically significant CMV infection when LET prophylaxis is 
extended from 100 to 200 days post-transplant, if the incidence rates of CS-
CMVi are 8% for LET (200-day arm) and 22% for placebo (100-day arm).
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.  This study 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 schedule for 
study treatment assignment.  Randomization will be implemented in the IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.2.1.1.
The primary efficacy endpoint will be the proportion of participants with clinically 
significant CMV infection from Week 14 (~100 days) post-transplant through Week 28 
(~200 days) post-transplant, defined as the occurrence of either one of the following 
outcomes: 

onset of CMV end-organ disease (proven or probable)
OR

initiation of anti-CMV PET with approved anti-CMV agents (ganciclovir, 
valganciclovir, foscarnet, and/or cidofovir) based on documented CMV viremia and 
the clinical condition of the participant
 
 
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CMV end-organ disease will be determined using the definitions in Appendix 7 and 
confirmed by an independent, blinded CAC.  The adjudication of cases by the CAC (ie, the 
final CAC assessment) will take precedence over the investigator’s assessment for the 
purpose of analysis.  Only the CAC-confirmed (proven or probable) cases of CMV end-organ 
disease will be included in the CMV end-organ disease category.  However, investigator-
assessed CMV end-organ disease cases that were not confirmed by the CAC but in whom 
anti-CMV therapy was initiated (in the setting of documented CMV viremia at a central 
laboratory) will be included in the initiation of PET category and, therefore, qualify as having 
clinically significant CMV infection.  Concordance/discordance between CAC and 
investigator assessment will be summarized.
Documented viremia is defined as any quantifiable CMV viral DNA on a confirmatory 
sample obtained immediately prior to (ie, on the day of) the initiation of treatment for CMV 
disease or PET, as measured by the Roche COBAS® AmpliPrep/COBAS TaqMan®
(CAP/CTM) System in the central laboratory.  In the event that the confirmatory result is not 
available, a subsequent central laboratory result collected from a sample obtained within 
7 days will be used.  Initiation of anti-CMV therapy without documented CMV viremia 
(using the central laboratory) will not be considered as a case for clinically significant CMV 
infection.  Similarly, quantifiable CMV viral DNA alone without initiation of anti-CMV 
therapy will not be considered as a case for clinically significant CMV infection.  If there are 
cases where anti-CMV therapy is initiated with no quantifiable CMV viral DNA using the 
central laboratory data, a sensitivity analysis will be provided using the local laboratory 
results.
The secondary efficacy endpoints are: 
1. Proportion of participants with clinically significant CMV infection from Week 14 
post-transplant through Week 38 post-transplant and from Week 14 post-transplant
Week 48 post-transplant.  This endpoint will use the same definition of clinically 
significant CMV infection as in the primary efficacy endpoint.
2. Time to onset of clinically significant CMV infection from Week 14 post-transplant
through Week 28 post-transplant and from Week 14 post-transplant through Week 48 
post-transplant. 
The time to onset of clinically significant CMV infection will be calculated in days, 
from the day of transplant to the day of onset of CMV end-organ disease or to the day 
of initiation of anti-CMV PET.  For cases where CMV end-organ disease is 
confirmed by the CAC, date of the first diagnostic test (including, but not limited to, 
radiology tests, viral culture, histopathology, immunohistochemical analysis, in situ 
hybridization, and CMV DNA PCR) will be identified by the CAC as part of their 
medical review and used as the time of onset of CMV end-organ disease.  For cases 
where anti-CMV PET is initiated in the setting of documented viremia (including 
those applicable cases where CMV end-organ disease was not confirmed by the 
CAC), the start date of anti-CMV therapy will be used.  If both criteria for clinically 
significant CMV infection are met, the time to onset will be calculated from the day 
of transplant to the earlier day on which one of the criteria is met.  
 
 
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3. Proportion of participants with initiation of PET for documented CMV viremia from 
Week 14 post-transplant through Week 28 post-transplant, and from Week 14 
post-transplant through Week 48 post-transplant. This endpoint will use the same 
definition for initiation of PET for documented CMV viremia as in the primary 
efficacy endpoint.
4. Proportion of participants with all-cause mortality from Week 14 post-transplant
through post-Week 28 post-transplant, and from Week 14 post-transplant through 
Week 48 post-transplant.
5. Time to all-cause mortality from Week 14 post-transplant through Week 28 
post-transplant, and from Week 14 post-transplant through Week 48 post-transplant. 
The time to all-cause mortality will be calculated in days, from the day of transplant 
to the day of death. 
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Sections 8.3 and 8.4. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values and vital signs.  All AEs will be collected through 14 days after 
completion of treatment period.  Thereafter, all drug-related SAEs and SAEs leading to death 
will be collected through Week 48 post-transplant.   
9.4.3
Exploratory Endpoints
1. Proportion of participants with CMV end-organ disease from Week 14 post-transplant
through Week 28 post-transplant, and from Week 14 post-transplant through Week 48 
post-transplant
2. Time to CMV end-organ disease from Week 14 post-transplant through Week 28 
post-transplant, and from Week 14 post-transplant through Week 48 post-transplant. 
The time to CMV end-organ disease will be calculated in days, from the day of 
transplant to the day of CMV end-organ disease.
3. Proportion of participants with documented CMV viremia ≥300 copies/mL from 
Week 14 post-transplant through Week 28 post-transplant, and from Week 14 
post-transplant through Week 48 post-transplant.
4. The time to documented CMV viremia ≥300 copies/mL from Week 14 
post-transplant through Week 48 post-transplant.
5. Proportion of participants with select opportunistic infections other than CMV 
infection from Week 14 post-transplant through Week 28 post-transplant, and from 
Week 14 post-transplant through Week 48 post-transplant.
 
 
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6. Proportion of participants with GVHD from Week 14 post-transplant through 
Week 28 post-transplant, and from Week 14 post-transplant through Week 48 
post-transplant.
7. Proportion of participants with all rehospitalizations and rehospitalizations for CMV 
infection/end-organ disease from Week 14 post-transplant through Week 28 
post-transplant, and from Week 14 post-transplant through Week 48 post-transplant.
8. Days on intravenous medications other than LET from Week 14 post-transplant
through Week 28 post-transplant, and from Week 14 post-transplant through Week 48 
post-transplant.
9. Proportion of participants with recurrent CMV infection from Week 14 
post-transplant through Week 28 post-transplant, and from Week 14 post-transplant
through Week 48 post-transplant.
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.
11. Antiviral resistance to LET in prophylaxis failures.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized participants 
who received at least one dose of study treatment.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least one dose of study 
treatment.  Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population.  
This will be the treatment group to which they are randomized except for participants who 
take incorrect study treatment for the entire treatment period; such participants will be 
included in the treatment group 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 the respective safety parameter.  
To assess change from baseline, a baseline measurement is also required.
 
 
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9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values may 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=0.025 (1-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the supplemental 
SAP.
Missing Data Handling
There are three types of missing values:

Intermittent missing values due to a missed or skipped visit.  

Monotone (non-intermittent) missing due to premature discontinuation from the 
study: viremia at study discontinuation.

Monotone missing due to premature discontinuation from the study: no viremia at 
study discontinuation.
Table 4 provides a summary of approaches to handle missing values.
Table 4
Summary of Approaches to Handle Missing Values
Approach
Intermittent Missing
Monotone Missing 
No Viremia at Study 
Discontinuation
Viremia at Study 
Discontinuation
OF
No failure
No failure
Failure
NC=F
Failure
Failure
Failure
DAO
Excluded
Excluded
Excluded
F = failure; NC = Non-Completer; OF = Observed Failure; DAO = Data-As-Observed
 
 
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The primary missing data approach will be the Observed Failure (OF) approach in order to 
obtain an estimate of the proportion of clinically significant CMV infection in participants 
who receive prophylaxis study treatment.  Using this approach, participants who develop 
clinically significant CMV infection or participants who discontinue prematurely from the 
study with viremia will be counted as failures, and participants who discontinue prematurely 
from the study for any reason without viremia or those who are missing data at the time
points of interest are not considered failures.  Imputing all participants who discontinue from 
the study prematurely without viremia as failures is likely to substantially overestimate the 
proportion of participants with clinically significant CMV infection.
Two secondary missing data approaches will be used for supportive analyses.  The first is the 
Data-As-Observed (DAO) approach.  In the DAO approach, any participant with missing 
value for a particular endpoint, either because they discontinued from the study without the 
endpoint or are missing data at the key time point (eg, missed visit, missing lab value), will 
be excluded from the analysis.  The second approach is the Non-Completer = Failure (NC=F) 
approach, which provides the worse-case scenario estimate of the proportion of clinically 
significant CMV infection.  Non-completers refer to participants who prematurely 
discontinue from the study for any reason without having developed CMV infection or 
participants who are missing data at the time points of interest. These participants will be 
considered failures using the NC=F approach.
Primary Efficacy Analysis
To test the primary hypothesis that LET is superior to placebo in the prevention of clinically 
significant CMV infection when LET prophylaxis is extended from 100 to 200 days
post-transplant, the stratum-adjusted Mantel-Haenszel method (with continuity correction)
will be used to compare the proportion of subjects with clinically significant CMV infection
from Week 14 (~100 days) post-transplant through Week 28 (~200 days) post-transplant
between the two treatment groups [Koch, G. G., et al 1990].  The stratification factor of
haploidentical donor (yes/no) will be included in the primary efficacy analysis.  Cochran 
Mantel-Haenszel weights will be used to calculate the overall between-group differences 
across strata.  LET is concluded superior to placebo if 1-sided p-value is less than or equal to 
0.0249 (see Section 9.8 for alpha adjustment).  Due to the anticipated large number of study 
centers, study center will not be included as a stratification factor in the primary efficacy 
analysis but may be explored as a sensitivity analysis.  The primary efficacy analysis will be 
performed on the FAS population.  A sensitivity analysis excluding those subjects who had 
quantifiable CMV viral DNA on Day 1 will be provided. The primary missing data approach 
will be the OF approach; supportive analyses using different missing data approaches will 
also be conducted (see Table 5).
Two additional sensitivity analyses for the primary endpoint will be performed to assess 
1) the proportion of participants with either CMV disease or PET initiation based on CMV 
viremia ≥300 copies/mL (ie, participants who initiated PET without meeting the threshold 
will not be considered a case of CS-CMVi), and 2) the proportion of participants with either 
CMV disease or CMV viremia of ≥300 copies/mL regardless of whether PET was initiated.
 
 
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Since the use of a therapy with anti-CMV activity may confound the results of this study, an 
additional sensitivity analysis will be conducted in which participants who start a therapy 
with anti-CMV activity will be censored at the time they begin such therapy.  Subjects with 
CS-CMVi prior to taking a therapy with anti-CMV activity will be classified as having 
CS-CMVi.  Those who did not have CS-CMVi prior to taking a therapy with anti-CMV 
activity (including subjects who subsequently develop CS-CMVi) will be classified as not 
having CS-CMVi and censored at the time they started taking the anti-CMV therapy. 
Secondary Efficacy Analyses
To assess the difference in the proportion of participants with the following secondary 
endpoints: 

clinically significant CMV infection from Week 14 post-transplant through Week 38
post-transplant

clinically significant CMV infection from Week 14 post-transplant through Week 48
post-transplant

initiation of PET for documented CMV viremia from Week 14 post-transplant
through Week 28 post-transplant

initiation of PET for documented CMV viremia from Week 14 post-transplant
through Week 48 post-transplant

all-cause mortality from Week 14 post-transplant through Week 28 post-transplant

all-cause mortality from Week 14 post-transplant through Week 48 post-transplant
Similar to the primary endpoint, 95% confidence interval for the difference in proportion 
between treatment groups will be calculated using the stratum-adjusted Mantel-Haenszel 
method with stratification by haploidentical donor (yes/no) [Koch, G. G., et al 1990].  A 
nominal p-value will be provided to assess the strength of evidence of the effect.
Time to onset of clinically significant CMV infection from Week 14 post-transplant through 
28 weeks post-transplant and from Week 14 post-transplant through Week 48 post-transplant
will be estimated using the nonparametric Kaplan-Meier method.  The Kaplan-Meier curve 
will be plotted by treatment arm and a nominal p-value for the between-arm difference in 
time to onset of clinically significant CMV infection will be provided using the stratified log-
rank test stratified by haploidentical donor (yes/no). Observations will be censored at last 
assessment. Time to all-cause mortality from Week 14 post-transplant through 28 weeks
post-transplant and from Week 14 post-transplant through Week 48 post-transplant will be 
estimated similarly.
 
 
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Table 5
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach† Statistical Method
Analysis 
Population
Missing Data 
Approach*
Primary Endpoint
Proportion of participants with clinically 
significant CMV infection from Week 14 
post-transplant through Week 28 
post-transplant
P
Stratified M&H‡
FAS
OF
S
Stratified M&H‡
FAS
DAO 
S
Stratified M&H‡
FAS
NC=F
Secondary Endpoints
Proportion of participants with clinically 
significant CMV infection from Week 14 
post-transplant through Week 38 
post-transplant and from Week 14 
post-transplant through Week 48
post-transplant
P
Stratified M&H‡
FAS
OF
S
Stratified M&H‡
FAS
DAO
S
Stratified M&H‡
FAS
NC=F
Time to onset of clinically significant CMV 
infection from Week 14 post-transplant
through Week 28 post-transplant, and 
from Week 14 post-transplant through 
Week 48 post-transplant
P
Kaplan-Meier 
FAS
Censored at last 
assessment
Proportion of participants with initiation of 
anti-CMV PET for CMV viremia from 
Week 14 post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant weeks
P
Stratified M&H‡
FAS
OF
S
Stratified M&H‡
FAS
DAO
S
Stratified M&H‡
FAS
NC=F
Proportion of participants with all-cause 
mortality from Week 14 post-transplant
through Week 28 post-transplant, and 
from Week 14 post-transplant through 
Week 48 post-transplant weeks
P
Stratified M&H‡
FAS
OF
Time to all-cause mortality from Week 14 
post-transplant through Week 28 
post-transplant, and from Week 14 
post-transplant through Week 48 
post-transplant
P
Kaplan-Meier 
FAS
Censored at last 
assessment
  †
P=Primary approach; S=Supportive approach.
  ‡ Stratum-adjusted Mantel-Haenszel method with stratification by haploidentical donor (yes/no)   
*  OF=observed failure; DAO=data-as-observed; NC=F = non-completers equal failure 
 
 
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs measurements.
The analysis of safety results will follow a tiered approach (Table 6).  The tiers differ with 
respect to the analyses that will be performed.  Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change (PDLCs) in 
laboratory, and vital signs parameters are either prespecified as “Tier 1” endpoints, or will be 
classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.  
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance.  There 
are no Tier 1 events for this protocol as LET has not been associated with any significant 
AEs that need to be characterized compared to placebo.  
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the proportion of participants with events (Miettinen and 
Nurminen [M&N] method) [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 8 participants in the 200-day arm or 2 participants 
in the 100-day arm exhibit the event; all other AEs and predefined limits of change will 
belong to Tier 3.
The thresholds of events were chosen because the 95% confidence interval for the between-
group difference in percent incidence will always include zero when fewer participants per 
group, respectively, experience events and thus would add little to the interpretation of 
potentially meaningful differences.  Because many 95% confidence intervals may be 
provided without adjustment for multiplicity, the confidence intervals 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-group differences in AEs and safety parameters that 
meet predefined limits of change.
In addition to individual events that occur in 8 or more participants in the 200-day arm or 
2 participants in the 100-day arm, the broad AE categories consisting of the proportion of 
participants with any AE, a drug-related AE, a serious AE, an AE which is both drug-related 
and serious, and discontinuation due to an AE will be considered Tier 2 endpoints. 
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events.  Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
 
 
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for Treatment 
Comparison
Descriptive 
Statistics
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 
≥8 participants in the 200-day arm or ≥2 
participants in the 100-day arm)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence 
≥1 participant in either arm)
X
Change from Baseline Results (Labs, Vital Signs)
X
95% CIs will be based on the method of Miettinen and Nurminen (1985).
† Indicates broad AE category of the number of participants reporting any adverse event
Note:
AE=adverse event; CI =confidence interval; SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; 
X = results will be provided.
9.7
Interim Analyses
Study enrollment is likely to be ongoing at the time of any interim analyses.  Blinding to 
treatment assignment will be maintained at all investigational sites.  The results of interim 
analyses will not be shared with the investigators prior to the completion of the study.  
To supplement the routine safety monitoring outlined in this protocol, an external DMC will 
serve as the primary reviewer of the results of the interim analyses of the study and will make 
recommendations for discontinuation of the study or protocol modifications to the EOC (see 
Appendix 1; Section 10.1.4 [Committees Structure – Executive Oversight Committee]).  No 
formal interim analyses for efficacy are planned for this study.  However, to allow for an 
assessment of benefit-risk, efficacy data will be included as part of the periodic safety
reviews when at least 40% of the participants have completed treatment or discontinued prior 
to completing treatment.  The DMC will monitor the trial with suggested periodic reviews 
occurring approximately every 6 months.  If the DMC recommends modifications to the 
design of the protocol or discontinuation of the study, this EOC may be unblinded to results 
at the treatment level in order to act on these recommendations.  The extent to which 
 
 
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individuals are unblinded with respect to results of interim analyses will be documented by 
the unblinded statistician.  Additional logistical details will be provided in the DMC charter.  
Treatment-level results from the interim analysis will be provided to the DMC by the 
unblinded statistician.  Prior to final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
9.8
Multiplicity
The DMC will be provided with unblinded descriptive summaries of the efficacy data at their 
periodic safety reviews when at least 40% of the participants have completed treatment or 
discontinued prior to completing treatment for an assessment of benefit-risk.  No formal 
efficacy analyses will be provided and there is no intention of stopping the trial due to 
overwhelming efficacy at any of these safety reviews.  Nevertheless, since unblinded efficacy 
data are being periodically reviewed, using a Haybittle-Peto α-spending approach, a small 
amount of alpha (α = 0.0001) will be allocated for each of these looks before testing the 
primary efficacy hypothesis at Week 28 post-transplant.  An allowance will be made such 
that a total of up to three of these unblinded efficacy reports may be presented at these 
periodic safety reviews.  The final analysis can still be tested at 2.5% level without inflating 
Type-I error.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analysis
Data from P001 in participants who were in the high-risk stratum as defined in P001 were 
used to estimate the clinically significant CMV infection rates for this study, since these 
populations are similar between the two studies.  The 100-day arm in this study is similar to 
those in the high-risk stratum on LET who completed treatment without any clinically 
significant CMV infection in P001, in which 20.5% had clinically significant CMV infection
after completing treatment and through Week 24 post-transplant.  This would be expected to 
be slightly higher through Week 28 post-transplant leading to an estimate of 22% for through 
Week 28 post-transplant in this study.  The event rate for the 200-day arm is expected to be 
similar to the event rate at the end of LET treatment at Week 14 post-transplant for
participants in the P001-defined high-risk stratum, which was 10.8% (11/102, including 
4 participants who had discontinued LET due to AEs and then developed CS-CMVi).  Since 
this study will enroll participants who will have already tolerated LET for 100 days, it is 
expected that a lower percentage of patients will discontinue treatment due to AEs, thus 
lowering the overall failure rate in the 200-day arm to ~8%.
This study will randomize a total of 216 participants (in a 2:1 ratio) with 144 in the LET
(200-day) arm and 72 in the placebo (100-day) arm which will have 80% power at an overall 
one-sided, 2.5% alpha-level, to demonstrate the primary hypothesis that extending LET 
prophylaxis to 200 days post-transplant is superior to 100 days of LET prophylaxis 
post-transplant in the prevention of clinically significant CMV infection.  This assumes 
incidence rates of CS-CMVi of 8% for LET (200-day arm) and 22% for placebo (100-day 
 
 
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arm). The calculation is based on normal approximation by Pearson Chi-square test for 
proportion difference without continuity correction and is carried out using (SAS v9.4). The 
minimum criterion for success is that the upper bound of 95% CI of difference < 0. Given the 
assumed response rate in 200-day arm, this may occur when the observed difference between 
treatment groups is approximately -10% or smaller.  Table 7 presents the power under 
various assumptions of rates in the two arms using the OF approach for missing data.
Table 7
Power(%) Under Various Assumptions (With 144 Participants Randomized in 
200-day Arm and 72 in 100-day Arm)
Rate in Placebo 
(100-day) Arm
Rate in LET (200-day) Arm
6
7
8
9
10
11
18
76
67
58
49
39
31
20
85
78
70
62
53
44
22
91
86
80
73
65
57
24
95
92
88
82
76
69
26
97
65
93
89
84
79
28
99
98
96
94
90
86
9.9.2
Sample Size and Power for Safety Analysis
The probability of observing at least one of a particular AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population.  If the underlying incidence of a particular AE is 1% (1 of every 
100 participants receiving the drug), there is a 52% chance of observing at least one of that 
particular AE among 72 participants in the placebo (100-day) arm or a 76% chance of 
observing at least one of that particular AE among 144 participants in the LET (200-day)
arm.  If no AE of that particular type are observed among the 144 participants in the LET 
(200-day) arm, this study will provide 95% confidence that the underlying percentage of 
participants with that particular AE is <2.5% (one in every 40 participants).  
The estimate of and the upper bound of the 95% confidence interval for the underlying 
percentage of participants with a particular AE given various hypothetical observed number 
of participants with the AE are provided in Table 8.  The calculation is based on the exact 
binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 
1934] and is carried out using SAS v9.4.
 
 
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Table 8
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on
Hypothetical Numbers of Participants with AEs
Hypothetical Number of Participants with 
an AE (Estimate of Incidence, %)
95% Upper Confidence Bound†
N=72
0 (0)
5.0
2 (2.8)
9.7
4 (5.6)
13.6
6 (8.3)
17.3
N=144
0 (0)
2.5
4 (2.8)
7.0
8 (5.6)
10.7
12 (8.3)
14.1
† Based on the two-sided exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
9.10
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, black, Asian, other)

Systemic steroid exposure within 6 weeks prior to randomization (yes, no)

Donor type (mismatched related, matched unrelated, mismatched unrelated)

Haploidentical donor (yes, no)

Cord blood (yes, no)

T-cell depleted grafts (yes, no)

Receipt of anti-thymocyte globulin (yes, no)
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.  Other clinically relevant variables 
may be identified for which additional subgroup analyses may be performed.  Subgroup 
analyses will not be conducted in categories that have less than 10% of the participants in 
either LET or placebo group (ie, no estimate of treatment difference and confidence intervals 
will be provided).
 
 
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9.11
Compliance (Medication Adherence)
Study medication data for LET (200-day arm) and placebo (100-day arm) will be collected 
during the study.  A day within the study will be considered an “On-Therapy” day if the 
participant takes at least 1 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:
Summary statistics will be provided on percent compliance by treatment group for the APaT
population.
9.12
Extent of Exposure
The Extent of Exposure to study treatment will be evaluated by summary for the “Number 
of days on Therapy” by treatment group.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input 
with respect to study design, interpretation of study results, and subsequent peer-reviewed 
scientific publications.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
DMC regarding the study.
 
 
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10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study 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 study 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.
10.1.4.4
Clinical Adjudication Committee (CAC)  
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 9, as well as evaluating the 
presence of confounding factors.
The CAC will review clinical, virological, and histopathological data as well as the 
investigator’s assessment for adjudicating all potential cases of CMV end-organ disease.  
CMV end-organ disease will be determined using the definitions in Appendix 7
(Section 10.7).
All personnel involved in the adjudication process will remain blinded to study intervention
allocation throughout the study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7
Compliance with Law, Audit, and Debarmen
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
 
 
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
 
 
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
Laboratory tests are detailed in Table 9.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study medication administration and/or 
response evaluation.  If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time.  Additionally, if the local laboratory 
results are used to make either a study medication decision or response evaluation, the 
results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
 
 
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Table 9
Laboratory Assessments 
Laboratory 
Assessments
Parameters
Central Laboratory
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
[Indicate if 
fasting, or 
nonfasting]
Calcium
Alkaline 
phosphatase
Other Tests

CMV DNA Sequence Analysis to be performed only in participants 
who have both a clinically significant CMV infection and detectable 
CMV DNA 

CMV DNA PCR 

QuantiFERON-CMV
Tests Performed 
at Screening

Coagulation:  PT/INR (using central laboratory at Screening; local 
laboratory testing to be used at other visits)

Creatinine Clearance (calculated using the Cockcroft-Gault equation 
for participants)
Central or Local 
Laboratory
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, and microscopic examination
Tests Performed 
at Screening

Serum β human chorionic gonadotropin (β hCG) pregnancy test (for 
WOCBP)

Serology: HIV antibody, hepatitis B surface antigen (HBsAg), and 
hepatitis C virus (HCV) antibody  

HCV RNA PCR:  to be done only in participants who test positive for 
HCV antibody
 
 
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.  The central laboratory 
based QuantiFERON-CMV assay results will not be shared with the respective site 
investigators.
Table 10 summarizes the approximate blood volumes collected by study visit and sample 
types.
 
 
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Table 10
Approximate Blood/Tissue Volumes Drawn/Collected by Study Visit and by Sample Types
Study Period
Treatment Period
Follow-up
CMVi or 
Early D/C a
Visit No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Post-transplant (TP) Week
SCR 
14
(D1)
16
18
20
22
24
26
28
30
32
34
36
38
40
44
48
Blood Parameter
Hematology
2
2
2
2
2
2
2
2
2
2
2
Chemistry
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
Coagulation PT/INR
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
Serum (β-hCG)
(WOCBP only)
3.5
HIV, Hepatitis B and C screen b
16
CMV DNA PCR c
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
QuantiFERON-CMV assay
3
3
3
3
CMV DNA sequence analysis d
10
Expected Total (mL)
38.5
16
16
16
16
16
16
16
19
11.5
6
6
6
6
6
6
9
29
β-hCG = β-Human Chorionic Gonadotropin; CMV = cytomegalovirus; DNA = deoxyribonucleic acid; D = day; FU = follow-up; HIV = human immunodeficiency virus; HSCT 
= hematopoietic stem cell transplant; IV = intravenous; LET = letermovir; PCR = polymerase chain reaction; PET = pre-emptive therapy; SCR = screening; TP = Transplant; 
WOCBP = woman of childbearing potential.
a.
The visit will be a CMV Infection Visit for all participants who meet the endpoint of CS-CMVi (defined as the occurrence of CMV disease or the initiation of PET)
through Week 48 post-transplant.  The visit can also be an Early Discontinuation Visit for those participants who are prematurely discontinued from the trial up to 
Week 48 post-transplant.  All procedures should be performed at this visit immediately prior to the initiation of treatment of CMV diseases or initiation of PET (ie, on the 
day anti-CMV therapy is initiated).  Most importantly, a plasma sample for CMV PCR testing at the central laboratory should be collected at this visit. 
b.
If not documented within the previous 6 months.  If hepatitis C virus antibody is positive, RNA PCR results should be provided.
c.
Protocol-specified CMV DNA testing will be performed by the central laboratory using the Roche COBAS® AmpliPrep/COBAS TaqMan® [CAP/CTM] System.
d.
To be performed only in participants with clinically significant CMV infection; For participants with clinically significant CMV infection, a sample for CMV DNA 
sequence analysis for LET resistance should be collected at the CMVi visit and a second, confirmatory sample should be collected at the next scheduled visit
following the CMVi visit
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as 
Sponsor’s product) includes any pharmaceutical product, biological product, vaccine, 
device, diagnostic agent, or protocol specified procedure whether investigational 
(including placebo or active comparator product) or marketed, manufactured by, 
licensed by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported 
using the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.

Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
 
 
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
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality

Did the Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. 
The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test product and the AE based 
upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
 
 
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-
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 studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
 
 
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
The assessment of relationship will be reported on the case report forms/worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
 
 
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10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.

Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.

Reference Section 8.4.1  for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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 hormone replacement therapy (HRT).  However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
10.5.2
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to start 
contraception when initiating sexual activity and they agree to use 1 of the contraception 
methods described in Table 11 consistently and correctly during the protocol-defined time 
frame in Section 5.1.
 
 
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Table 11
Contraceptive Methods
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
●Male or female condom with or without spermicide
●Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen-containing) hormonal contraception b,c
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen-only hormonal contraception b,c
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen-only contraceptive implant b,c 
●Intrauterine hormone-releasing system (IUS) b
●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 medication. 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
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
b
If locally required, in accordance with Clinical Trial Facilitation Group guidelines [Heads of Medicines 
Agencies 2014], acceptable hormonal contraceptives are limited to those which inhibit ovulation.
 
 
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10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of study medication, additional pregnancy testing will be performed at 
monthly intervals during the treatment period, for participants who complete the treatment 
period, at the CMV disease/early discontinuation visit, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Country-specific Requirements
Not applicable.
 
 
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Appendix 7 Definition of CMV Disease in Hematopoietic Stem Cell Transplant 
(HSCT) Recipients
CMV Disease
Type
Probable
Proven
Notes
Pneumonia
Signs and/or symptoms of
pneumonia
AND
Detection of CMV by
viral isolation, rapid
culture of BAL fluid, or
the quantitation of CMV
DNA in BAL fluid
Signs and/or symptoms of
pulmonarydisease
AND
Detection of CMV in lung
tissue by virus isolation,
rapid culture,
histopathology,
immunohistochemistry,or
DNAhybridization
techniques

PCR may be too
sensitive, so detection of
CMV by PCR alone is
insufficient for the
diagnosis of CMV
pneumonia.

Superinfectionor
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
macroscopicmucosal
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
DNAhybridization

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
DNAhybridization 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
conventionalhistologic
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
conventionalhistologic
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
conventionalhistologic
features of CMV infection
N/A
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BAL = bronchoalveolar lavage;
CMV = cytomegalovirus; CNS = central nervous system; CSF = cerebrospinal fluid; DNA =
deoxyribonucleic acid; GI = gastrointestinal; HCV = hepatitis C virus; N/A = not applicable; PCR =
polymerase chain reaction; ULN = upper limit of normal
 
 
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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 encephalopathy1
absent 
Grade 1 or Grade 2 
Grade 3 or Grade 4 
Ascites 
absent 
mild
moderate 
Bilirubin (μmol/L) 
< 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
Prothrombin time (INR) 
< 1.7 
1.7 – 2.3 
> 2.3 
1Hepatic 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
Child-Pugh Score Interpretation
5 – 6 points
Child-Pugh stage A (mild hepatic insufficiency)
7 – 9 points
Child-Pugh stage B (moderate hepatic insufficiency*)
≥10 points
Child-Pugh stage C (severe hepatic insufficiency)
*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.
Note:  Central laboratory test results will be used to determine Child-Pugh score at the 
Screening Visit.  Thereafter, local laboratory test results will be used for Child-Pugh scoring.
 
 
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Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living  
AE
adverse event 
BDS
blood drug screen
CAC
Clinical Adjudication Committee
CMV
cytomegalovirus
CNS
central nervous system 
CRF
Case Report Form 
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTCAE
Common Terminology Criteria for Adverse Events
DEHP
diethylhexyl phthalate
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GVHD
graft-versus-host disease
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MTD
maximum tolerated dose 
NA
Not Applicable
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
PCR
polymerase chain reaction
PES
polyethersulfone
PET
preemptive therapy
PK
pharmacokinetic
PT/INR
prothrombin time / international normalized ratio
QP2
department of quantitative pharmacology and pharmacometrics
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
siDMC
Standing Internal Data Monitoring Committee
 
 
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Abbreviation
Expanded Term
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
UDS
urine drug screen
WOCBP
woman/women of childbearing potential 
 
 
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