Clinical trial NCT03940586
Conditions: Cytomegalovirus (CMV) Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-08-08; Completion date: 2023-08-25
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the pharmacokinetics (PK) of letermovir (LET) in pediatric participants. Participants will be enrolled in the following 3 age groups: Age Group 1: From 12 to \<18 years of age (adolescents); Age Group 2: From 2 to \<12 years of age (children); and Age Group 3: From birth to \<2 years of age (neonates, infants and toddlers). All participants will receive open label LET for 14 weeks (\~100 days) post-transplant, with doses based on body weight and age.

Detailed description:

Arms: arm 1: Letermovir administered either orally or intravenously within 28 days post-transplant, once daily through week 14 (approximately 100 days). Dosing will vary based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.
Interventions: intervention 1: Letermovir oral granules intervention 2: Letermovir tablet intervention 3: Letermovir intravenous
Intervention descriptions: intervention 1: Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication. intervention 2: Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication. intervention 3: Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT03940586
Document Date:            21-Oct-2022
A Phase 2b open-label, single-arm study to evaluate 
pharmacokinetics, efficacy, safety and tolerability of 
letermovir in pediatric participants from birth to less 
than 18 years of age at risk of developing CMV 
infection and/or disease following allogeneic 
haematopoietic stem cell


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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 LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2b open-label, single-arm study to evaluate pharmacokinetics, 
efficacy, safety and tolerability of letermovir in pediatric participants from birth to less than 
18 years of age at risk of developing CMV infection and/or disease following allogeneic 
haematopoietic stem cell transplantation (HSCT)
Protocol Number: 030-08
Compound Number: MK-8228
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
EudraCT
2018-001326-25
IND
104,706 (tablet) 
118,361 (intravenous)
Approval Date: 21 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 08
(global, including 
for Spain)
21-OCT-2022
The primary reason for Amendment 08 was Sponsor underwent entity name change and 
update to the address.
Amendment 07
(global including
for Spain)
31-AUG-2021
The primary rationale for the changes in Amendment 07 are as follows:
To provide the initial dose of oral and intravenous (IV) letermovir (LET) for Age Group 3, 
which has been determined by interim pharmacokinetics (PK) analyses using data from 
participants in Age Group 1 and Age Group 2 of this study. To add a requirement for PK 
sampling of hydroxypropyl-beta-cyclodextrin (HPCD), an excipient in the IV LET 
formulation, for Age Group 3 participants receiving the IV formulation for at least 4 
consecutive days.
In addition, the 10-mg oral capsule of LET is now available for use in Spain.
This amendment is intended to merge Amendment 06, a country-specific amendment for 
Spain, with global Amendment 03, which has been used for all other participating countries, 
to date. Thus, Amendment 07 will be used globally, including for Spain.
Amendment 06 
(country-specific 
for Spain)
22-NOV-2019
To add information regarding the 30-mg oral capsules of LET granules, which have now been 
manufactured and made available for use in Spain.
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Document
Date of Issue
Overall Rationale
Amendment 05 
(country-specific 
for Spain)
16-OCT-2019
To include all changes from Amendment 02 made in both Amendment 03 (addition of in-line
filter and related requirements for administration of the IV formulation of LET and 
Amendment 04 (removal of the 10-mg and 30-mg oral capsules from the protocol until they 
become available) in the Summary of Changes table. This country-specific amendment is 
being released to Spain in lieu of Amendment 03, which was released to the rest of the world. 
Amendment 04 was not released because the Amendment 04 Summary of Changes 
inadvertently omitted the changes made in Amendment 03.
Amendment 04 
(country-specific 
for Spain)
17-SEP-2019
The Spanish health authority has required that the protocol be amended to remove the 10-mg
and 30-mg oral capsules from the protocol until these capsule potencies have been
manufactured and the corresponding quality information has been submitted and authorized.
The overall design of the protocol has not changed. Age groups requiring dosing with the
10-mg or 30-mg oral capsules will not be enrolled until a subsequent protocol amendment
including these lower potency capsules has been authorized.
Amendment 03
23-AUG-2019
To add the requirement that the IV formulation of LET supplied by the Sponsor to sites as 
study medication must be administered through a sterile 0.2-micron or 0.22-micron 
polyethersulfone (PES) in-line filter and using diethylhexyl phthalate (DEHP)-free IV bags 
and infusion set materials. This requirement is being added to prevent the possible 
administration of product-related particulate matter. The presence of visible product-related 
particulate matter is an expected characteristic of new clinical supplies of the IV formulation 
of LET. This requirement is being implemented to allow for the release of new clinical 
supplies of IV LET, and, as a precaution, it must be applied regardless of whether the clinical 
site considers its current clinical supply to be impacted.
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Document
Date of Issue
Overall Rationale
Amendment 02
15-MAR-2019
The description of the coating of the oral granule formulation to be used in this study 
provided in Section 2.2.4 was incorrect in the original protocol. This amendment provides the 
correct description of the coating of the oral granule formulation being used (Opadry coating 
without Surelease) and provides the rationale for selection of this oral granule formulation. 
Additional minor changes have been made to incorporate changes communicated in prior 
protocol clarification letters.
Amendment 01
24-JAN-2019
Testicular toxicity testing was removed, and creatinine clearance monitoring every 2 weeks 
was added to the protocol.
Original Protocol 
(Version 00)
08-OCT-2018
Original protocol
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendments:
The primary reason for Amendment 08 was Sponsor underwent entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary Reason for the Amendment
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp and Dohme Corp. underwent an entity 
name and address change to Merck Sharp and Dohme 
LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
Other Changes in the Amendment
1.1 Synopsis
4.3.1 Starting Dose for This 
Study
6.1 Study Intervention(s) 
Administered 
Adjusted oral and IV doses of LET to be 
administered in Age Group 3 participants.
To update dosing recommendations based on results of
the third interim PK analysis.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.1 Schedule of Activities 
Screening/Treatment Period
4.3.1.6 Dosing in Age Group 
3
5.5 Participant Replacement 
Strategy
8.6.1 Blood Collection for 
Letermovir Pharmacokinetic 
Sampling
9.1 Statistical Analysis Plan 
Summary
9.5.1 PK Analysis 
Population
9.6.1 Statistical Methods for 
Pharmacokinetic Analyses
9.7 Interim Analyses
Aligned details for the collection of 
intensive PK in participants on oral and IV 
formulations throughout the protocol.
To clarify that all Age Group 3 participants will have 
intensive PK, regardless of formulation used; those on 
oral formulation will have intensive PK on the 7th
consecutive day of oral LET while those on IV 
formulation will have intensive PK on the 5th
consecutive day of LET administration.
2.2.5 Ongoing Clinical 
Studies
Deleted text of ongoing studies and added 
statement to refer to the Investigator’s 
Brochure (IB).
To align with the most current version of the IB.
4.4 Beginning and End of 
Study Definition
Included a reference to Section 7.3 instead 
of a definition that is provided in Section 
7.3.
To clarify definition of lost to follow-up by referring to 
the appropriate section.
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Section # and Name
Description of Change 
Brief Rationale 
4.4.1 Clinical Criteria for 
Early Study Termination
Revised language about early termination 
based on changing benefit/risk ratio.
To correct grammar and ensure clarity and intent of the 
section.
5 Study Population
Added statement about the collection of 
demographic data and participant 
confidentiality.
To clarify the collection, use, and confidentiality of 
demographic data provided by the participants to align 
with the EU CTR.
6.1 Study Intervention(s) 
Administered
Added a cross-reference to Appendix 7.
To align with recent PMDA regulation changes.
6.1 Study Intervention Table
Revised column heading and footnotes to 
include AxMP.
Changed ‘Experimental’ in the ‘Use’ 
column to ‘Test Product.
To align with EU CTR.
7.3 Lost to follow-up
Deleted note describing loss to follow-up.
To allow individual studies to select language related 
to "lost to follow-up" that is appropriate for the study.
8.1.9 Study Intervention 
Administration
Added parenthetical to allow a qualified 
designee to prepare IV study intervention.
To clarify who is responsible for preparing IV study 
intervention.
8.4.7 Events of Clinical 
Interest (ECIs)
Revised language defining potential DILI.
To clarify for the investigator/site to define what a 
potential DILI is and to align with this acronym being 
used in the reporting table.
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Section # and Name
Description of Change 
Brief Rationale 
8.6.2.1 Additional Creatinine 
Clearance Measurements for 
Participants in Age Group 3 
Receiving Intravenous 
Letermovir Formulation
Consolidated rows in Table 15.
To clarify when samples for creatinine clearance in 
participants receiving IV LET should be collected.
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
10.3 Adverse Events: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting
Added details on the definition and 
recording of medication error, misuse, and 
abuse.
To align with EU CTR.
Throughout
Minor administrative formatting, 
grammatical, and typographical changes 
were made throughout the document.
The ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................6
1
PROTOCOL SUMMARY ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities (SoA)................................................................................25
1.3.1
Schedule of Activities Screening/Treatment Period....................................25
1.3.2
Schedule of Activities Follow-up Period.....................................................32
2
INTRODUCTION..........................................................................................................34
2.1
Study Rationale....................................................................................................34
2.2
Background ..........................................................................................................34
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.2.2
Cytomegalovirus in HSCT Recipients.........................................................35
2.2.3
Pharmacokinetic Background of LET .........................................................38
2.2.3.1
LET, Absorption, Metabolism, and Disposition................................38
2.2.3.2
Drug Interactions Between LET and Immunosuppressant Agents....38
2.2.3.3
Pharmacokinetic Modeling and Simulation in Adults.......................39
2.2.4
Preclinical and Clinical Studies ...................................................................40
2.2.5
Ongoing Clinical Studies.............................................................................42
2.3
Benefit/Risk Assessment......................................................................................42
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................43
4
STUDY DESIGN............................................................................................................43
4.1
Overall Design......................................................................................................43
4.2
Scientific Rationale for Study Design.................................................................51
4.2.1
Rationale for Endpoints ...............................................................................51
4.2.1.1
Pharmacokinetic Endpoints ...............................................................51
4.2.1.2
Safety Endpoints................................................................................51
4.2.1.3
Efficacy Endpoints.............................................................................52
4.2.1.4
Palatability and Acceptance Assessment Endpoint ...........................53
4.2.1.5
Planned Exploratory Biomarker Research.........................................53
4.2.1.5.1
Planned Genetic Analysis ........................................................53
4.2.1.6
Future Biomedical Research..............................................................54
4.3
Justification for Dose...........................................................................................54
4.3.1
Starting Dose for This Study........................................................................54
4.3.1.1
Dose Justifications .............................................................................56
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4.3.1.2
Dose in Age Group 1 (12 to <18 years), Panel A..............................60
4.3.1.3
Dose in Age Group 2 (2 to <12 years), Panel A................................60
4.3.1.4
Dose in Age Groups 1 and 2, Panel B ...............................................61
4.3.1.5
Age Groups 1 and 2 Pharmacokinetic Experience Through 
Interim Analysis 2..............................................................................61
4.3.1.6
Dose in Age Group 3 .........................................................................63
4.3.2
Maximum Dose/Exposure for This Study ...................................................63
4.4
Beginning and End of Study Definition .............................................................63
4.4.1
Clinical Criteria for Early Study Termination .............................................63
5
STUDY POPULATION ................................................................................................63
5.1
Inclusion Criteria.................................................................................................64
5.2
Exclusion Criteria................................................................................................65
5.3
Lifestyle Considerations......................................................................................68
5.3.1
Meals and Dietary Restrictions....................................................................68
5.4
Screen Failures.....................................................................................................68
5.5
Participant Replacement Strategy......................................................................69
6
STUDY INTERVENTION............................................................................................69
6.1
Study Intervention(s) Administered...................................................................69
6.2
Preparation/Handling/Storage/Accountability .................................................73
6.2.1
Dose Preparation..........................................................................................73
6.2.2
Handling, Storage, and Accountability........................................................73
6.3
Measures to Minimize Bias: Randomization and Blinding..............................73
6.3.1
Intervention Assignment..............................................................................73
6.3.2
Stratification.................................................................................................74
6.3.3
Blinding........................................................................................................74
6.4
Study Intervention Compliance..........................................................................74
6.5
Concomitant Therapy..........................................................................................74
6.5.1
Allowed Medications/Therapies ..................................................................74
6.5.1.1
Allowed Medications/Therapies That Can be Administered 
Without Monitoring ...........................................................................74
6.5.1.2
Allowed Medications/Therapies to be Administered with Clinical 
and/or Drug-level Monitoring............................................................75
6.5.2
Prohibited Medications................................................................................76
6.5.2.1
Medications Prohibited with LET......................................................77
6.5.2.2
Additional Medications Prohibited when LET is Coadministered 
with CsA ............................................................................................78
6.5.3
Rescue Medications and Supportive Care ...................................................79
6.6
Dose Modification (Escalation/Titration/Other)...............................................79
6.7
Intervention After the End of the Study............................................................79
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6.8
Clinical Supplies Disclosure................................................................................80
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................80
7.1
Discontinuation of Study Intervention...............................................................80
7.2
Participant Withdrawal From the Study...........................................................82
7.3
Lost to Follow-up .................................................................................................82
8
STUDY ASSESSMENTS AND PROCEDURES........................................................83
8.1
Administrative and General Procedures ...........................................................83
8.1.1
Informed Consent/Assent.............................................................................83
8.1.1.1
General Informed Consent/Assent.....................................................84
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................84
8.1.2
Inclusion/Exclusion Criteria ........................................................................84
8.1.3
Participant Identification Card.....................................................................84
8.1.4
Medical History ...........................................................................................85
8.1.5
Prior and Concomitant Medications Review...............................................85
8.1.5.1
Prior Medications...............................................................................85
8.1.5.2
Concomitant Medications..................................................................85
8.1.6
HSCT Details Review..................................................................................85
8.1.7
Assignment of Screening Number...............................................................86
8.1.8
Assignment of Treatment/Randomization Number.....................................86
8.1.9
Study Intervention Administration ..............................................................86
8.1.9.1
Timing of Dose Administration.........................................................86
8.1.9.2
Study Medication Diary.....................................................................87
8.1.10
Discontinuation and Withdrawal .................................................................88
8.1.10.1
Withdrawal From Future Biomedical Research ................................88
8.1.11
Participant Blinding/Unblinding..................................................................88
8.1.12
Domiciling ...................................................................................................89
8.1.13
Calibration of Equipment.............................................................................89
8.2
Efficacy Assessments ...........................................................................................89
8.2.1
CMV DNA PCR Testing .............................................................................89
8.2.2
CMV DNA Sequence Analysis ...................................................................90
8.3
Safety Assessments...............................................................................................91
8.3.1
Physical Examinations.................................................................................91
8.3.2
Vital Signs....................................................................................................91
8.3.3
Electrocardiograms ......................................................................................92
8.3.4
Clinical Safety Laboratory Assessments .....................................................92
8.3.5
Date of Menarche.........................................................................................92
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8.3.6
Confirmation of Contraception (WOCBP Only).........................................93
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................93
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................93
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......95
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...95
8.4.4
Regulatory Reporting Requirements for SAE .............................................95
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................96
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................96
8.4.7
Events of Clinical Interest (ECIs)................................................................96
8.5
Treatment of Overdose........................................................................................96
8.6
Pharmacokinetics.................................................................................................97
8.6.1
Blood Collection for Letermovir Pharmacokinetic Sampling .....................97
8.6.2
Blood Collection for HPCD Pharmacokinetic Sampling.............................99
8.6.2.1
Additional Creatinine Clearance Measurements for Participants in 
Age Group 3 Receiving Intravenous Letermovir Formulation..........99
8.7
Pharmacodynamics............................................................................................100
8.8
Future Biomedical Research Sample Collection.............................................100
8.9
Planned Genetic Analysis Sample Collection..................................................100
8.10
Palatability and Acceptance Assessment .........................................................100
8.11
Visit Requirements.............................................................................................101
8.11.1
Screening....................................................................................................101
8.11.2
Treatment Period Visits .............................................................................101
8.11.2.1
Day 1 Visit.......................................................................................102
8.11.2.2
Study Intervention Administration Visit..........................................102
8.11.2.3
Additional Treatment Period Visits .................................................103
8.11.3
Follow-up Period/Visits.............................................................................103
8.11.4
Participants Discontinuing Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................104
8.11.4.1
Discontinuation of Study Intervention Due to CS-CMVi ...............104
8.11.4.2
Discontinuation of Study Intervention for Reasons Other Than 
CS-CMVi.........................................................................................104
8.11.5
Discontinuation from Study.......................................................................105
8.11.5.1
Study Discontinuation Prior to Week 24 Post-transplant:...............105
8.11.5.2
Study Discontinuation After Week 24 Post-transplant....................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................105
9.1
Statistical Analysis Plan Summary...................................................................105
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9.2
Responsibility for Analyses/In-house Blinding ...............................................106
9.3
Hypotheses/Estimation ......................................................................................107
9.4
Analysis Endpoints.............................................................................................107
9.4.1
Pharmacokinetics Endpoints......................................................................107
9.4.2
Safety Endpoints........................................................................................107
9.4.3
Efficacy Endpoints.....................................................................................107
9.5
Analysis Populations..........................................................................................108
9.5.1
PK Analysis Population.............................................................................108
9.5.2
Safety Analysis Population........................................................................108
9.5.3
Efficacy Analysis Population.....................................................................109
9.6
Statistical Methods.............................................................................................109
9.6.1
Statistical Methods for Pharmacokinetic Analyses....................................109
9.6.2
Pharmacokinetic Modeling and Simulation for Dose Selection................109
9.6.3
Statistical Methods for Safety Analyses ....................................................110
9.6.4
Statistical Methods for Efficacy Analyses.................................................111
9.6.5
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................112
9.6.5.1
Demographic and Baseline Characteristics .....................................112
9.6.5.2
Palatability and Acceptance Assessment.........................................113
9.7
Interim Analyses ................................................................................................113
9.8
Multiplicity .........................................................................................................114
9.9
Sample Size and Power Calculations ...............................................................114
9.9.1
Sample Size and Power for PK Analysis...................................................114
9.9.2
Sample Size and Power for Safety Analysis..............................................114
9.9.3
Sample Size and Power for Efficacy Analysis ..........................................115
9.10
Subgroup Analyses.............................................................................................116
9.11
Compliance (Medication Adherence)...............................................................117
9.12
Extent of Exposure.............................................................................................117
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................118
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......118
10.1.1
Code of Conduct for Clinical Trials...........................................................118
10.1.2
Financial Disclosure...................................................................................120
10.1.3
Data Protection...........................................................................................120
10.1.3.1
Confidentiality of Data ....................................................................121
10.1.3.2
Confidentiality of Participant Records.............................................121
10.1.3.3
Confidentiality of IRB/IEC Information..........................................121
10.1.4
Committees Structure.................................................................................121
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10.1.4.1
Executive Oversight Committee......................................................121
10.1.4.2
External Data Monitoring Committee .............................................121
10.1.4.3
Clinical Adjudication Committee (CAC) ........................................122
10.1.5
Publication Policy......................................................................................122
10.1.6
Compliance with Study Registration and Results Posting Requirements .122
10.1.7
Compliance with Law, Audit, and Debarment ..........................................123
10.1.8
Data Quality Assurance .............................................................................123
10.1.9
Source Documents .....................................................................................124
10.1.10
Study and Site Closure...............................................................................124
10.2
Appendix 2: Clinical Laboratory Tests............................................................125
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................130
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................130
10.3.2
Definition of AE ........................................................................................130
10.3.3
Definition of SAE ......................................................................................131
10.3.4
Additional Events Reported.......................................................................132
10.3.5
Recording AE and SAE .............................................................................133
10.3.6
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................136
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................138
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................139
10.5.1
Definitions..................................................................................................139
10.5.2
Contraception Requirements......................................................................139
10.5.3
Pregnancy Testing......................................................................................141
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................142
10.7
Appendix 7: Country-specific Requirements..................................................147
10.8
Appendix 8 Definition of CMV Disease in Hematopoietic Stem Cell 
Transplant (HSCT) Recipients.........................................................................148
10.9
Appendix 9 Child-Pugh Classification for Severity of Liver Disease............151
10.10 Appendix 10: Medications Allowed for HSV/VZV Prophylaxis ...................152
10.10.1
Acyclovir....................................................................................................152
10.10.1.1
HSV Prophylaxis .............................................................................152
10.10.1.2
Varicella (Chickenpox) or Herpes Zoster (Shingles), Prophylaxis .152
10.10.2
Valacyclovir...............................................................................................153
10.10.2.1
Herpes Simplex Virus (HSV), Prophylaxis .....................................153
10.10.2.2
Varicella (Chickenpox), Prophylaxis...............................................153
10.11 Appendix 11: Palatability and Acceptance Assessment Form.......................155
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10.12 Appendix 12: Calculation of Creatinine Clearance by Age of Study 
Participant ..........................................................................................................156
10.13 Appendix 13: Abbreviations .............................................................................157
11
REFERENCES.............................................................................................................160
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LIST OF TABLES
Table 1
Number of Haematopoietic Stem Cell Transplantation by Age Group...........35
Table 2
Distribution of Allogeneic Haematopoietic Stem Cell 
Transplantations in 2014 in the United States .................................................35
Table 3
Cytomegalovirus Seroprevalence in General Population, United 
States................................................................................................................36
Table 4
Predicted Letermovir AUC (ng.hr/mL) Values in Adult HSCT 
Recipients.........................................................................................................40
Table 5
Summary of the Geometric Mean Ratios and 90% Confidence 
Intervals for MK-8228 Plasma PK of AUC0-inf and Cmax Following 
Administration of a Single Oral Dose of 240 mg (2x120 mg) MK-
8228 Coated Granule Formulations Administered Alone, in 
Applesauce, or in Vanilla Pudding Compared With 240 mg Tablet in 
Healthy Adult Participants...............................................................................42
Table 6
Enrollment Requirements and Pharmacokinetic Sampling by Age 
Group ...............................................................................................................48
Table 7
Oral Letermovir Dosing Table.........................................................................55
Table 8
Intravenous Letermovir Dosing Table.............................................................55
Table 9
Study Intervention............................................................................................70
Table 10
Dosing for Oral Formulations of LET .............................................................71
Table 11
Dosing for Intravenous Formulation LET .......................................................72
Table 12 Lower Bound of Creatinine Clearance by Age................................................82
Table 13
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.......................................................................94
Table 14
Pharmacokinetic Sampling for Protocol 030 ...................................................98
Table 15
Creatinine Clearance Timepoints for Age Group 3 Participants 
Receiving Intravenous Letermovir ................................................................100
Table 16
Analysis Strategy for Safety Parameters........................................................111
Table 17
Analysis Strategy for key Efficacy Variables................................................112
Table 18
Estimate of Incidence of AEs and 95% Upper Confidence Bound 
Based on Hypothetical Numbers of Participants With AEs ..........................115
Table 19
Two-sided 95% Confidence Intervals for the Proportion of 
Participants With Clinically Significant CMV Infection Through 
Week 24 (~6 Months) Post-transplant (FAS Population)..............................116
Table 20
Protocol-required Laboratory Assessments (Local Laboratory)....................125
Table 21
Protocol-required Laboratory Assessments (Central Laboratory).................126
Table 22
Approximate Blood Volumes Drawn/Collected by Study Visit and by 
Sample Types – Research Testing (Age Group 1).........................................127
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Table 23
Approximate Blood Volumes Drawn/Collected by Study Visit and by 
Sample Types – Research Testing (Age Group 2).........................................128
Table 24
Approximate Blood Volumes Drawn/Collected by Study Visit and by 
Sample Types – Research Testing (Age Group 3).........................................129
Table 25
Contraceptive Methods ..................................................................................140
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LIST OF FIGURES
Figure 1
Study Design....................................................................................................24
Figure 2
Sequential Evaluation of Age Groups..............................................................46
Figure 3
LET Median AUC (With 5th and 95th Percentile Prediction Intervals) 
by age Group and Weight, Based on the Phase 3 Population PK 
Model With Allometric Scaling. Age Group 1 (12 to <18 yrs) and 
Age Group 2 (2 to <7 yrs and 7 to <12 yrs), Without 
Coadministration of CsA, are Given LET IV at the Same Dose as 
Oral ..................................................................................................................57
Figure 4
LET Exposure Predictions Corresponding to the Dosing Paradigm 
for This Study, Showing LET Median AUC (With 5th and 95th
Percentile Prediction Intervals) by Age Group and Weight, Based on 
the Phase 3 Population PK Model With Allometric Scaling. Age 
Group 2 (2 to <7 yrs and 7 to <12 yrs), Without Coadministration of 
CsA, has a 50% Reduction in LET IV Dose Relative to Oral .........................58
Figure 5
Age Group 3 LET Exposure Predictions Corresponding to the Initial 
Dosing Paradigm, Showing LET Median AUC (With 5th and 95th
Percentile Prediction Intervals) by Weight, Based on the Phase 3 
Population PK Model With Allometric Scaling. .............................................59
Figure 6
Letermovir Exposure (AUC24) in All Participants From Age Groups 
1 and 2 who had Intensive PK (N=20).............................................................62
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b open-label, single-arm study to evaluate pharmacokinetics, 
efficacy, safety and tolerability of letermovir in pediatric participants from birth to less than 
18 years of age at risk of developing CMV infection and/or disease following allogeneic 
haematopoietic stem cell transplantation (HSCT)
Short Title: LET for the prevention of CMV infection/disease in pediatric HSCT recipients
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses to be tested in this study. 
In pediatric (birth to <18 years of age) participants who received an allogeneic HSCT and are 
at risk for CMV infection and/or disease:
Objectives
Endpoints
Primary
Objective: To evaluate letermovir PK in 
pediatric participants grouped by age.
AUC0-24, Cmax (for participants 
receiving oral formulation), Ceoi (for 
participants receiving IV formulation), and 
Ctrough
Secondary
To evaluate the safety and tolerability of 
treatment with letermovir through Week 48 
post-transplant based on the proportion of 
participants with adverse events.
Adverse Events (AEs)
AEs Resulting in Study Medication 
Discontinuation
To evaluate the efficacy of letermovir in 
prevention of clinically significant CMV 
infection through Week 14 (~100 days) 
post-transplant and through Week 24 
(~6 months) post-transplant. 
Clinically significant CMV infection (CS-
CMVi, defined as initiation of preemptive 
therapy [PET] for documented CMV 
viremia and/or CMV disease).
To evaluate the palatability and acceptability 
of treatment with letermovir oral granules.
Score on a palatability scale.
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Prevention
Indication
Prevention of clinically significant CMV infection in 
pediatric allogeneic HSCT recipients
Population
Pediatric participants receiving HSCT at risk for CMV 
infection and/or disease
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 44 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent/assent until the 
last participant’s last study-related contact.
Number of Participants:
Approximately 60 participants will be allocated/enrolled.
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Intervention Groups and Duration:
Intervention 
Groups
The study will enroll participants in 3 Age Groups:

Age Group 1: From 12 to <18 years of age (adolescents)

Age Group 2: From 2 to <12 years of age (children)

Age Group 3: From birth to <2 years of age (neonates, infants and 
toddlers)
All participants will receive open-label LET for 14 weeks (~100 days) 
post-transplant. The following tables show estimated starting oral and 
intravenous (IV) doses of LET for participants in Age Groups 1 (12 to <18 
years) and 2 (2 to <12 years). The starting doses are based on available PK 
data from adult HSCT recipients and will be confirmed or modified based 
upon a review of interim PK, safety and tolerability results in the dose-
finding panels of Age Groups 1 and 2 (Panel A). Doses for Age Group 3
(birth to <2 years) are based on the accumulated PK, safety, and tolerability 
data from Age Group 1 (Panels A and B) and Age Group 2 Panel A.
Oral Letermovir Dosing Table
Age 
Group
Age Range
BW limits (kg)
Oral dose LET
(mg)
Oral dose LET
(mg) with CsA
1
12 to
<18 years
Any weight
480
240
2 
2 to 
<12 years
≥30
480
240
18 to <30
240
120
10 to <18
120
60
3
birth to 
<2 years
10 to ≤15
120
60
7.5 to <10
120
60
5.0 to <7.5
60
40
2.5 to <5.0
40
20
BW=body weight; CsA=Cyclosporin A; LET=letermovir; PK=pharmacokinetics.
Intravenous Letermovir Dosing Table
Age 
Group
Age Range
BW limits (kg)
IV dose LET (mg)
IV dose LET (mg) 
with CsA
1
12 to 
<18 years
Any weight
480
240
2 
2 to 
<12 years
≥30
240a
240b
18 to <30
120a
120b
10 to <18
60a
60b
3
birth to 
<2 years
10 to ≤15
60a
60b
7.5 to <10
60c
60b,c
5.0 to <7.5
40c
40b,c
2.5 to <5.0
20c
20b,c
BW=body weight; CsA=Cyclosporin A; IV=intravenous; LET=letermovir; 
PK=pharmacokinetics.
a Based on modeling, for Age Group 2 and Age Group 3, the IV dose of LET without CsA is 
reduced by 50% compared with oral LET in order to maintain target exposures.
b No further reduction of IV LET is necessary when coadministered with CsA.
c Based on interim analyses results, doses are increased for participants weighing <10 kg in Group 
3. 
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Total 
Number
1 (single-arm study)
Duration of 
Participation
Each participant will participate in the study for approximately 50 weeks 
from the time the participant or the participant’s legal representative
provides documented informed consent/assent through the final contact. 
Participants can be screened from up to 15 days prior to receipt of HSCT to 
28 days post-HSCT. Enrollment/allocation can be initiated as early as the 
day of transplant, but must be completed by Day 28 post-transplant. All 
participants will receive treatment until Week 14 post-transplant. After the 
end of treatment, each participant will be followed until Week 48 
post-transplant.
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 13.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
PK=pharmacokinetics.
Refer to Figure 2 (Section 4.1) for further details of study design (sequential enrollment).
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities Screening/Treatment Period
Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
Administrative Procedures
Informed 
Consent/Assent
X
Informed Consent 
for FBR (optional)
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
X
Medical History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Varies by study period (Section 
8.1.5)
Treatment 
Allocation
X
Study intervention
dispensing
X
X
X
X
X
X
X
Contact IRT at all dispensing visits 
(Section 8.11.2.2).
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Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
Study intervention
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Participants discharged on oral 
granules to be taken in the 
outpatient setting must be trained 
on correct procedure for preparing 
and administering the formulation 
(Section 8.11.2.2).
HSCT Details 
Review
X
Study Medication 
Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant/caregiver will be 
trained in the use of the paper 
study medication diary prior to 
discharge from hospital
(Section 8.1.9.2).
Safety Procedures
Full Physical 
Examination
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Weight recorded at enrollment 
(Day 1) will be used to determine
initial dosing. Thereafter, the dose 
must be adjusted according to the 
most recent body weight (Section 
8.3.1).
Targeted Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performed only when clinically 
indicated (Section 8.11.2).
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
12-Lead 
Electrocardiogram
(ECG)
X
X
X
X
Performed locally; ECG only 
required at CMV infection visit or 
the Early Study Discontinuation 
visit if the participant was on study 
therapy at the time of the visit
(Section 8.3.3).
Child-Pugh Score
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Varies by study period 
(Section 8.4)
Hematology
X
X
X
X
X
X
X
X
X
X
X
Performed locally.
Section 8.3.4 & Appendix 2.
Creatinine clearance and liver 
function tests must also be 
evaluated in all participants within 
5 days prior to enrollment.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Creatinine 
Clearance
X
X
X
X
X
X
X
X
X
X
X
Calculated per equations provided 
in Appendix 12. See Section 7.1
for criteria for discontinuation 
from study intervention. See 
Section 8.6.2.1 for additional 
monitoring requirements for Age 
Group 3 participants on IV LET.
Coagulation 
PT/INR
X
X
X
X
X
X
X
X
X
X
X
Performed locally (Appendix 2)
Urinalysis
X
X
X
X
X
Performed locally
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Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
Date of menarche 
(females only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review at each visit as appropriate 
in prepubescent female 
participants. Once a date of 
menarche has been confirmed, 
participant is considered to be a 
WOCBP.
Pregnancy Test 
(urine or serum 
tests for WOCBP 
only)
X
X
X
X
X
X
X
Performed locally (Appendices 2 
and 5)
Participant 
Confirmation of 
Birth Control 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV and Hepatitis 
B and C Screen
X
Performed locally (Appendix 2)
Patient Reported Outcome
Palatability and 
Acceptability 
Assessment 
(pediatric oral 
granules only)
-------------------------X--------------------------
Palatability assessment should 
occur on the first day of oral 
granule administration by mouth 
and be repeated 1 week later. Not 
required for participants 
receiving oral granules via 
G tube/NG tube (Section 8.10).
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Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
CMV Procedures/Assessments
CMV DNA PCR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performed locally (Section 8.2.1)
CMV DNA PCR must also be 
performed within 5 days prior to 
enrollment in all participants.
CMV Disease 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CMV DNA 
Sequence Analysis
X
Plasma sample required 
(Section 8.2.2)
PET Initiation/ 
Treatment of CMV 
Disease 
X
CMV DNA PCR must be collected 
on the same day as PET 
initiation/treatment of CMV 
disease.
PK/Biomarkers
Buccal Swab for 
Planned Genetic 
Analysis 
X
Buccal swab should be obtained 
prior to transplant when possible 
(Sections 8.8 and 8.9).
Sparse PK
X
X
X
X
X
X
X
X
X
Collected within 2 hours predose
for all study participants on study 
intervention (Section 8.6.1)
Intensive PK on 
oral formulation at 
Day 7 visit 
(Panel A)
X
All participants in Panel A of Age 
Groups 1 and 2 who receive oral 
formulation of LET from D1 until 
D7 visit will have intensive PK. 
Section 8.6.1 for PK time points.
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Study Period
Treatment Period a
End of 
Treat-
ment 
Visit
CMV 
Infection
Visitb
Early 
Study 
Discon 
Visitc
Notes (Protocol Section 
Reference for further details)
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
25
26
Visit Name
SCRd
D1d
D7
W2
W3
W4
W5
W6
W7
W8
W9
W
10e
W
11e
W
12e
W
13e
W14e
Days and Weeks correspond to 
the time since enrollment
(Day 1)e
Visit Window
+2
days
+/-3 days
Intensive PK on 
oral formulation
(Age Group 3)
-------------------------X-------------------------
All participants in Age Group 3 
will have intensive PK sampling 
done (starting on the 7th
consecutive day of oral LET, only 
in participants who did not 
previously have intensive PK on 
IV formulation) (Section 8.6.1).
Intensive PK on IV 
formulation
-------------------------X-------------------------
Start on the 5th consecutive day of 
IV dosing and only in 
participants who did not 
previously have intensive PK on 
oral formulation (Section 8.6.1).
HPCD PK sampling 
(for Age Group 3 
participants on IV 
formulation only)
-------------------------X-------------------------
Start on the 4th consecutive day of 
IV dosing. See Sections 8.6.2 & 
8.6.2.1 for timepoints and 
additional requirements for 
creatinine clearance monitoring.
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ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = β-Human Chorionic Gonadotropin; CMV = cytomegalovirus; CS-CMVi = 
clinically significant CMV infection; Discon = discontinuation; DNA = deoxyribonucleic acid; D = day; EOT = end of treatment; FBR = Future Biomedical 
Research; FSH = follicle- stimulating hormone; FU = follow-up; HPCD = hydroxypropyl-beta-cyclodextrin; HIV = human immunodeficiency virus; h = hour; 
HSCT = hematopoietic stem cell transplant; IRT = interactive response technology; IV = intravenous; LET = letermovir; LH = luteinizing hormone; 
PCR = polymerase chain reaction; PET = preemptive therapy; PK = pharmacokinetics; PT/INR = prothrombin time/international normalized ratio; SCR = 
screening; W = week; WOCBP = woman of childbearing potential.
a The “treatment period” is defined as the period from Day 1 through Week 14 post-transplant, regardless of when a participant stops taking LET. Day 1 will 
be the day of enrollment when LET will be initiated. Study intervention may begin as early as the day of transplant and no later than 28 days post-transplant. 
Study intervention will continue through Week 14 (~100 days) post-transplant. Day 1 procedures/assessments must be performed prior to first dose of study 
intervention. 
b 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. During the treatment period, LET must be discontinued (if the participant is still on LET). All procedures indicated in the SoA should be completed
prior to initiating PET for CMV infection or treatment for CMV disease at this visit. 
c The visit will be an Early Study Discontinuation Visit for those participants who are prematurely discontinued from the study (not study intervention alone) 
through Week 24 post-transplant. All procedures indicated in the SoA should be performed at this visit prior to discontinuing the participant from the study.
d Participants may be screened during a period starting from 15 days prior to transplantation until no later than 28 days post-transplant. Participants will have 
CMV viremia assessed using a CMV DNA PCR assay. After establishing absence of CMV viremia, participants should be tested once a week until 
enrollment (Day 1). The following are to be assessed within 5 days prior to enrollment: CMV DNA, Child-Pugh Score; serum AST, ALT, and total bilirubin; 
and creatinine clearance. Note: Screening and enrollment (Day 1) Visits will occur on separate days. 
e All participants will receive treatment until Week 14 post-transplant. The EOT Visit will coincide with Week 10, Week 11, Week 12, Week 13 or Week 14
depending on the day the participant was enrolled relative to the day of transplant as follows:
For participants enrolled from the day of transplant to 6 days post-transplant, participants attend Day 1 to Week 13 (Visits 1-15) and Week 14 (Visit 16) will 
be the EOT Visit.
For participants enrolled from Day 7 to Day 13 post-transplant, participants attend Day 1 to Week 12 (Visits 1-14) and Week 13 (Visit 15) will be the EOT 
Visit.
For participants enrolled from Day 14 to Day 20 post-transplant, participants attend Day 1 to Week 11 (Visits 1-13) and Week 12 (Visit 14) will be the EOT 
Visit.
For participants enrolled from Day 21 to Day 27 post-transplant, participants attend Day 1 to Week 10 (Visit 1-12) and Week 11 (Visit 13) will be the EOT 
Visit.
For participants enrolled on Day 28 post-transplant, participants attend Day 1 to Week 9 (Visits 1-11) and Week 10 (Visit 12) will be the EOT Visit.
All procedures listed under Visit No. 16, EOT Visit, should be performed at the true end of treatment.
After the EOT Visit, all study participants should enter follow-up (Visit No. 17). Refer to SoA Follow-up Period Section 1.3.2.
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1.3.2
Schedule of Activities Follow-up Period
Study Period
Follow-up Period
(through Week 24 
post-transplant)
Follow-up Period
(through Week 48 
post-transplant)
CMV 
Infection 
Visita
Early 
Study 
Discon 
Visit
(follow-
up)b
Notes (Protocol Reference Section for further details)
Visit Number
17
18
19
20
21
22
23
24
25
26
Visit Name
W16
W18
W20
W22
W24
W32
W40
W48
Weeks correspond to weeks post-transplant.
Visit Window
+/-4 Days
Administrative Procedures
Contact
X
X
X
Virtual Visit, not a site visit
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
Varies by study period (Section 8.1.5)
Safety Procedures
Height
X
X
X
Weight
X
X
X
Targeted Physical 
Examination
X
X
X
X
X
X
X
Performed only when clinically indicated (Section 8.3.1)
Vital Signs
X
X
X
X
X
X
X
Heart rate, blood pressure, respiratory rate, and body 
temperature (Section 8.3.2)
Adverse Events 
Monitoring
X
X
X
X
X
X
X
X
X
X
Varies by study period (Section 8.4)
Hematology
X
X
X
Performed locally (Section 8.3.4)
Chemistry
X
X
X
Performed locally (Section 8.3.4)
Creatinine Clearance
X
X
X
Calculated per equations provided in Appendix 12. See Section 
7.1 for discontinuation criteria for study intervention.
Urinalysis
X
X
X
Performed locally (Section 8.3.4)
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Study Period
Follow-up Period
(through Week 24 
post-transplant)
Follow-up Period
(through Week 48 
post-transplant)
CMV 
Infection 
Visita
Early 
Study 
Discon 
Visit
(follow-
up)b
Notes (Protocol Reference Section for further details)
Visit Number
17
18
19
20
21
22
23
24
25
26
Visit Name
W16
W18
W20
W22
W24
W32
W40
W48
Weeks correspond to weeks post-transplant.
Visit Window
+/-4 Days
Date of menarche 
(females only)
X
X
Review at specified visits as appropriate in prepubescent 
female participants. Once a date of menarche has been 
confirmed, participant is considered to be a WOCBP.
Pregnancy Test (urine or 
serum for WOCBP only)
X
X
Performed locally (Appendices 2 and 5)
Participant Confirmation 
of Birth Control 
(WOCBP only)
X
X
Acceptable methods of contraception to be used from the time 
of consent/assent through 28 days after the last dose of study 
intervention (Appendix 5).
CMV Procedures/Assessments
CMV DNA PCR
X
X
X
X
X
X
X
Performed locally (Section 8.2.1)
CMV Disease 
Assessment
X
X
X
X
X
X
X
CMV DNA Sequence 
Analysis
X
Plasma sample required. Performed only in participants with 
CS-CMVi
PET Initiation/Treatment 
of CMV Disease
X
AE = adverse event; CMV = cytomegalovirus; CS-CMVi = clinically significant CMV infection; Discon = discontinuation; DNA = deoxyribonucleic acid; FU 
= follow-up; LET = letermovir; PCR = polymerase chain reaction; PET = preemptive therapy; W = week; WOCBP = women 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 24 post-transplant. During the treatment period, LET must be discontinued (if the participant is still on LET). All 
procedures indicated in the SoA should be completed prior to initiating PET for CMV infection or treatment for CMV disease at this visit.
b
The visit will be an Early Study Discontinuation Visit for those participants who are prematurely discontinued from the study through Week 24 post-
transplant. All procedures indicated in the SoA should be performed at this visit prior to discontinuing the participant from the study.
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2
INTRODUCTION
Letermovir (LET, also known as MK-8228, AIC246, AIC001) is an inhibitor of the CMV 
viral terminase inhibitor and has been approved for prophylaxis of CMV infection or disease 
in adult CMV-seropositive recipients (R+) of an allogeneic HSCT.
2.1
Study Rationale
In a pivotal, global, Phase 3 study (P001), LET was demonstrated to be effective in the 
prevention of CMV infection and disease in adult R+ allogeneic HSCT recipients. LET has 
been developed and approved for adult CMV-seropositive allogeneic HSCT recipients (R+). 
The purpose of this study is to assess PK, safety, tolerability, and efficacy of LET in pediatric 
allogeneic HSCT recipients aged birth to <18 years. 
The pathogenesis and manifestations of CMV disease are similar in adults and in pediatric 
patients [Castagnola, E., et al 2004]. Therefore, LET is anticipated to have a similar safety 
and efficacy profile in pediatric patients when given at doses that achieve a similar exposure 
to that observed in adult patients. The PK data obtained in this study will be used to update 
currently available population PK and physiologically based pharmacokinetics (PBPK)
models based on adult PK data to support dosing recommendations in the pediatric 
population. 
2.2
Background
Refer to the IB 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, which cleaves newly 
synthesized CMV DNA into individual viral genomes and guides them into empty viral 
capsids. The mechanism of action of LET is highly specific, suggesting a limited potential 
for mechanism-based toxicity. 
LET is currently available as an oral formulation (tablets) and an intravenous (IV) 
formulation for use in adult allogeneic HSCT recipients. Participants in this study will either 
receive the currently marketed oral adult tablets (240-mg strength or multiples thereof) or the 
newly developed age-appropriate pediatric oral formulation (consisting of encapsulated
coated granules of LET; henceforth referred to as “oral granules”) for oral administration
(see Section 2.2.4 for the bioavailability evaluation of the oral granules). During the course 
of the study, participants may use the IV formulation when a transient condition (such as
vomiting) precludes oral intake. The IV formulation that will be used in P030 will be the 
same IV formulation previously used in adult participants in P001 and currently marketed for 
adult administration.
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2.2.2
Cytomegalovirus in HSCT Recipients
CMV infection is common. It is generally acquired early in life, with the majority of the adult 
population being CMV-seropositive in most countries. Similar to other herpes viruses, acute 
infection is generally followed by latent (dormant) infection. Among individuals with intact 
immune systems, reactivation of CMV infection is uncommon and generally asymptomatic. 
However, CMV reactivation in immunocompromised patients, such as transplant recipients, 
can cause significant morbidity and mortality. 
Data on the number of HSCTs by age group in pediatric patients are limited. Preliminary data 
on allogeneic HSCTs (unpublished) from 358 centers in Europe across 46 countries for the 
years 2008 to 2012 provided by the European Group for Blood and Marrow Transplantation 
(EBMT) are summarized in Table 1. During this period 62,940 HSCT transplants took place,
of which 13,513 (21.4%) were performed in children up to 18 years of age. 
Table 1
Number of Haematopoietic Stem Cell Transplantation by Age Group
Age Groupa
Number (%)
0-23 months
2,280 (3.6% of 62940)
2-11 years
7,277 (11.5% of 62940)
12- <18 years
3,956 (6.2% of 62940)
All children (0- <18 years)
13,513 (21.4% of 62940)
≥18 years 
49,427 (78.6% of 62940)
a EBMT Data from 358 centers in 46 countries in the EU, 2008-2012
Table 2 shows the distribution of allogeneic HSCTs in the US by age group in 2014 [Center 
for International Blood and Marrow Transplant Research 2017]. As seen in the European 
database, approximately 20% of HSCTs performed in United Stated were performed in the 
pediatric subpopulation.
Table 2
Distribution of Allogeneic Haematopoietic Stem Cell Transplantations in 2014 in 
the United States
Age at Transplant (Years)
Number (%)
0-10
908 (10.7%)
11-20
703 (8.3%)
21+
6,859 (81.0%)
Total
8,470 (100%)
[Center for International Blood and Marrow Transplant Research 2017]
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CMV seropositivity in either transplant recipients or donors is associated with increased 
mortality post-transplant [Emery V, Zuckerman M, Jackson G, Aitken C, Osman H 2013] 
[Tomonari, A., et al 2007]. In HSCT recipients, the risk of CMV reactivation and progression 
to disease is greatest in CMV-seropositive recipients, where up to 80% of recipients are 
likely to reactivate CMV, regardless of the serostatus of the donor (D-/R+ or D+/R+)
[Ljungman, P., et al 2011] [Ljungman, P. 2014] [Razonable, R. R. 2005] [Zhou, W., et al 
2009]. The highest risk period for developing CMV infection (as defined by detectable CMV 
DNA) is during the first 100 days post-transplant [Özdemir, E., et al 2007]. 
Worldwide, CMV seroprevalence increases with increasing age (Table 3). In the US, 
seroprevalence is between 5% to 20% in children between 0 to 5 years of age [Cannon, M. J., 
et al 2010] and increases to around 42.7% for children 12 to 19 years of age [Bate, S. L., et al 
2010]. A similar trend in increasing CMV seroprevalence with increasing age was also 
reported in studies from the European Union (EU) [Just-Nubling, G., et al 2003] [Ludwig, A. 
2009] [Lopo, S., et al 2011].
Table 3
Cytomegalovirus Seroprevalence in General Population, United States
Age Group
Seroprevalence (%)
0-5 yearsa
5-20
6-11 yearsb
34-41
12-19 yearsb
40-46
20-29 yearsb
46-53
30-39 yearsb
53-60
40-49 yearsb
55-61
>50 yearsa
65-90
a Cannon, 2010
b Bate, 2010
[Cannon, M. J., et al 2010] [Bate, S. L., et al 2010]
Given the relatively small number of HSCTs performed in pediatric patients and the lower 
CMV seroprevalence in younger individuals, enrollment in the current study may be 
challenging, particularly in the youngest age group. These considerations have been taken 
into account when designing the study to enable broad enrollment across the subpopulation 
of HSCT recipients. 
The clinical effects of CMV infection can be divided into direct and indirect effects 
[Ljungman, P., et al 2002] [Boeckh, M. 2011]. The direct effects include the spectrum of 
CMV disease manifestations, including pneumonia, hepatitis, retinitis, and encephalitis; these
are associated with considerable morbidity and mortality [Boeckh, M. and Geballe, A. P. 
2011] [Ljungman, P., et al 2002] [Boeckh, M. 2011]. 
The indirect effects of CMV infection include increased risk of opportunistic bacterial and 
invasive fungal infections, graft-versus-host disease (GVHD), and nonrelapse mortality 
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[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]. Since the introduction of PET for the management of 
CMV reactivation in allogeneic HSCT recipients, the incidence of CMV disease has been 
dramatically reduced. However, allogeneic HSCT patients have a high likelihood of 
developing CMV viremia [Ariza-Heredia, E. J., et al 2014], which is associated with an 
increased risk of overall mortality [Green, M. L., et al 2016].
CMV Prevention in HSCT recipients
There are 2 approaches to preventing CMV disease in HSCT recipients: 1) prophylaxis with 
antivirals, and 2) PET, defined as the practice of active surveillance for viral replication and 
initiating treatment with anti-CMV agents when CMV viremia is detected [Ljungman, P., et 
al 2002].
With the exception of LET, all other available anti-CMV agents are nucleoside analogues 
with associated toxicities including myelosuppression and nephrotoxicity that limit their 
clinical utility in the HSCT setting. 
Due to the concerns for toxicities associated with the nucleoside analogue anti-CMV agents, 
PET is generally preferred to prophylaxis, and has been the preferred approach for preventing 
CMV disease in the majority of HSCT transplant centers worldwide, especially during the 
first 100 days post-transplant. However, PET is suboptimal for several reasons: 

PET is initiated after patients develop CMV viremia. A recent study concluded that CMV 
viremia is associated with an increased risk of overall mortality regardless of the 
initiation of PET [Green, M. L., et al 2016].

Given the toxicities associated with anti-CMV agents, it is important not to initiate PET 
unless it is clear that the benefit outweighs the risks. However, there is no universally 
accepted viral load threshold for the initiation of PET to guide clinicians when to initiate 
PET [Romkens, T. E., et al 2016].
Based on these considerations, a safe and efficacious prophylaxis strategy offers advantages 
over PET. LET, an anti-CMV agent with a novel mechanism of action, has recently been 
shown to be generally well tolerated and efficacious in a pivotal Phase 3 study (P001) when 
used for CMV prophylaxis in adult CMV-seropositive HSCT recipients (refer to 
accompanying the IB for further details). It has recently been approved and is available in 
several regions of the world for CMV prophylaxis in adult HSCT recipients. CMV 
prophylaxis with LET will likely represent a paradigm shift from the practice of PET with 
nucleoside analogues for CMV prevention currently employed by most transplant centers 
worldwide. The current study will evaluate the PK, safety, and efficacy of LET in this 
subpopulation of HSCT recipients. 
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2.2.3
Pharmacokinetic Background of LET
In the clinical development program for LET, population pharmacokinetics, exposure-
response models and PBPK modeling supported the characterization of LET
pharmacokinetics in healthy adult participants and HSCT recipients. 
2.2.3.1
LET, Absorption, Metabolism, and Disposition
Based on population PK analyses, LET bioavailability in HSCT patients is approximately 
35%, while coadministration with CsA increases bioavailability to approximately 85%
(Table 4). The population mean total volume of distribution is estimated to be 45.5 L in 
HSCT recipients. LET is extensively bound (98.7%) to human plasma protein in vitro and 
there was no dependence on concentration over the range from 0.2 to 50 mg/L. Biliary 
excretion is the major route of elimination and LET is primarily eliminated as parent drug 
(~70% of dose) and an acyl-glucuronide (~6% of dose) in human feces. In vitro studies 
indicated that LET is a substrate of UGT1A1 and UGT1A3 and the hepatic uptake 
transporters OATP1B1 and OATP1B3. Drug interaction studies with the OATP1B inhibitor 
CsA increased LET exposure suggesting that OATP1B plays a central role in the elimination 
of LET. Although LET is a substrate of CYP3A, CYP2D6, and CYP2J2 in vitro, oxidative 
metabolism of LET is a minor pathway in vivo.
2.2.3.2
Drug Interactions Between LET and Immunosuppressant Agents
The Effect of Immunosuppressant Agents on LET:
CsA is an inhibitor of CYP3A, P-gp, OATP1B1/3, and several other transporters. In Phase 1 
drug-drug interaction (DDI) studies, coadministration of LET with 50- or 200-mg CsA
resulted in approximately 1.9- to 3.4-fold increase in AUC and 1.5- to 2.7-fold increase in 
Cmax of LET. These results in the presence of CsA are consistent with the Phase 3 
population PK analyses in adult HSCT recipients (Table 1). Therefore, the adult LET dose of 
480 mg is reduced to 240 mg QD when coadministered with CsA. Tacrolimus and 
mycophenolate mofetil do not affect LET plasma concentrations and sirolimus is not 
anticipated to affect LET plasma concentrations.
The Effect of LET on Immunosuppressant Agents:
Coadministration of 240-mg QD oral LET with a single dose of 50-mg CsA resulted in 66% 
and 8% increase in CsA AUC and Cmax, respectively. Coadministration of 480-mg QD oral 
LET with a single dose of 5-mg tacrolimus resulted in 2.42- and 1.57-fold increase in 
tacrolimus AUC and Cmax, respectively. In the case of sirolimus, 3.40- and 2.76-fold 
increases in sirolimus AUC and Cmax, respectively, were observed following 
coadministration of 480-mg QD oral LET with 2-mg sirolimus. However, there was no 
clinically relevant effect of LET on mycophenolate mofetil. Coadministration of LET
increases the exposures of the immunosuppressants (CsA, sirolimus, and tacrolimus). 
Frequent monitoring of CsA, sirolimus, or tacrolimus whole blood concentrations should be 
performed during and at discontinuation of LET and the dose of immunosuppressant should 
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be adjusted accordingly. The dose of LET is not adjusted when LET is given with tacrolimus, 
sirolimus, or mycophenolate mofetil.
For the full description of other DDI studies with LET, refer to the IB or the local prescribing 
information (if available) for LET.
2.2.3.3
Pharmacokinetic Modeling and Simulation in Adults
There are currently no PK data for LET in pediatric patients. In order to guide dose selection 
for the proposed clinical study in pediatric participants, the Phase 3 population PK model, as 
well as a PBPK model based on adult data, will be used.
A Phase 1 population PK model was developed to characterize the nonlinear and time-
varying LET PK in healthy adult participants, and to evaluate the effects of selected intrinsic 
factors [Prohn M, Dykstra K, Cho C, et al. 2017]. The final PK model is a 4-compartment 
open model with first-order elimination and nonlinearity on clearance (CL) and 
intercompartmental clearance (Q1). The Phase 1 population PK model identified a 
statistically significant increase in both the maximum CL and volume of distribution (Vd)
with an increase in body weight, and a race effect (Asian) on Vd.
A Phase 3 population PK model was developed using data pooled from the Phase 3 study
(P001), one Phase 2b study, and 3 Phase 1 studies, to characterize LET steady-state PK in 
adult HSCT recipients at the clinical dose, and to evaluate the effects of selected intrinsic and 
extrinsic factors on the PK of LET [Viberg A, Prohn M, Dykstra K, et al. 2017]. The final 
PK model is two-compartment with linear absorption and clearance (dose proportional). The 
only significant covariates identified were a race effect (Asian) that decreased peripheral 
volume, and CsA coadministration that increased bioavailability and decreased clearance. 
Overall, oral bioavailability of LET was approximately 35%, increasing to approximately 
85% with CsA coadministration. LET clearance was 4.84 L/h, decreasing to 3.38 L/h with 
CsA coadministration. 
The Phase 3 population PK model was used to estimate LET exposures in HSCT recipients 
given LET 480 mg QD oral or IV, or 240 mg when coadministered with CsA (Table 4). LET
exposures in HSCT recipients given 480 mg IV LET were similar to healthy participants
given the same regimen. However, exposures in HSCT recipients following oral dosing of 
LET was lower than healthy participants given the same regimen, which may be attributed to 
gastrointestinal mucosal injury, reported as a common side-effect of chemotherapy in HSCT 
recipients, and a similar effect is also anticipated in pediatric HSCT recipients.
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Table 4
Predicted Letermovir AUC (ng.hr/mL) Values in Adult HSCT Recipients
Group/Subgroup
Median
AUC a (ng.hr/mL)
90% Prediction Interval
480 mg Oral, no CsA
34,400
(16,900-73,700)
480 mg IV, no CsA
100,000
(65,300-148,000)
240 mg Oral, with CsA
60,800
(28,700-122,000)
240 mg IV, with CsA
70,300
(46,200-106,000)
AUC=area under the concentration-time curve; CI=confidence interval: CsA=cyclosporin A; 
HSCT=haematopoietic stem cell transplantation; IV=intravenous.
Overall Median AUC (90% CI) = 49,200 (26,900 – 87,400) ng.hr/mL.
a
Values are rounded to 3 significant digits.
Exposure-response analyses for efficacy indicated that the entire range of exposures achieved 
with LET 480 mg QD, adjusted to 240 mg QD LET with CsA coadministration, in the Phase 
3 study (P001) is efficacious. There was no significant dependence of the efficacy endpoint 
(proportion of participants with CS-CMVi) on LET exposures over the range of exposures 
assessed using exposure quartiles. The exposure-safety analyses showed that there was no 
exposure dependency for the selected AEs over the exposure ranges achieved in the Phase 3 
study. 
A PBPK model was developed for exploring the basis of differences in LET PK between 
populations, including adult and pediatric. The PBPK model incorporated key absorption, 
distribution, metabolism, and excretion (ADME) and PK properties of LET such as biliary 
excretion as the major route of elimination, saturable UGT-mediated metabolism, and 
CYP3A-mediated metabolism as a minor pathway.
A full PBPK model with first-order absorption and a permeability-limited liver model were 
applied to describe the distribution of LET. The final model successfully described the key 
plasma disposition properties of LET including the nonlinear PK and the magnitude of 
greater-than-dose-proportional increase in exposure in white healthy volunteers. The 
mechanism of nonlinear PK was best described by the saturation of OATP1B-mediated 
hepatic uptake transporter and was most sensitive towards changes in Michaelis-Menten 
parameters of OATP1B transporter.
Both the adult Phase 3 population PK model and adult PBPK model with pediatric module 
were used to predict exposures to support initial dose selection in the pediatric population, as 
described in Section 4.3.
2.2.4
Preclinical and Clinical Studies
In animal studies, LET was not shown to be genotoxic. Complete details of additional 
preclinical studies (including repeat dose-toxicity studies in rats [Barrow, P. C., et al 2011]
and monkeys [Barrow, P. C., et al 2011] and fertility and embryo-fetal development study in 
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rats [Barrow, P. C., et al 2011]) can be found in the accompanying IB. These studies support 
the evaluation of LET in the pediatric population.
LET has been shown to be generally well tolerated in 29 Phase 1 studies, 1 biopharmaceutic 
study evaluating the oral granule formulation (P031, described below), 2 Phase 2 clinical 
studies (P019 and P020) and a single, pivotal Phase 3 study (P001) conducted in adult HSCT 
recipients. Proof-of-concept (antiviral activity) was established in the Phase 2a study (P019), 
while the safety and efficacy of LET for CMV prophylaxis in HSCT recipients was 
demonstrated in a dose-dependent manner in the Phase 2b study (P020). The results of the 
pivotal Phase 3 study (P001) established the safety and efficacy of LET for CMV 
prophylaxis in adult CMV-seropositive recipients (R+) of an allogeneic HSCT. These studies
are described in greater detail in the accompanying IB.
Comparative Bioavailability Study of LET Oral Pediatric Formulations (P031)
P031 evaluated the comparative bioavailability of 2 different LET pediatric oral granule 
formulations (2 x 120 mg; an Opadry® coating, and an Opadry + Surelease® coating), 
compared with the currently marketed adult tablet (240 mg) (in n=24 healthy adults). For 
each pediatric formulation, a subset of 6 participants was randomized to coadministration 
with either applesauce or vanilla pudding. The PK profiles of both pediatric formulations 
were bioequivalent to the adult tablet. The geometric mean ratios (GMR) and 90% 
confidence intervals (CI) for AUC0-inf and Cmax of the formulation comparisons are 
summarized in Table 5. The Opadry-coated granules were selected for the current study 
following evaluation both of the PK profile of this formulation and of manufacturing 
considerations. The effect of food on the PK profile of the Opadry-coated granules was 
assessed as not clinically significant as the 90% CI of the LET AUC GMR (fed / fasted) fell 
within the clinical comparability range (0.5 to 3.0). Applesauce resulted in a 20% increase in 
LET AUC and 33% increase in Cmax, while vanilla pudding resulted in a 13% increase in 
AUC and 25% increase in Cmax. The Opadry coating was also considered to provide 
advantages in stability and manufacturing. Furthermore, in a palatability assessment, the 
majority of participants indicated that the oral granules (Opadry coating) mixed in vanilla 
pudding or applesauce were neutral to very easy to swallow, had a neutral or pleasant taste 
and texture, and had a neutral or pleasant aftertaste (10 minutes after administration). No 
safety concerns were observed with LET administration.
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Table 5
Summary of the Geometric Mean Ratios and 90% Confidence Intervals for 
MK-8228 Plasma PK of AUC0-inf and Cmax Following Administration of a Single Oral 
Dose of 240 mg (2x120 mg) MK-8228 Coated Granule Formulations Administered Alone, in 
Applesauce, or in Vanilla Pudding Compared With 240 mg Tablet in Healthy Adult 
Participants
GMR and 90% CI
Oral Granule Comparisons
AUC0-infa
Cmaxa
Granules (2 x 120 mg) vs Tablet (240 mg) fasting
MK-8228 Granules (Opadry)/MK-8228 Tablet
1.00
(0.95, 1.06)
1.05
(0.97, 1.14)
MK-8228 Granules (Opadry+Surelease)/ MK-8228 Tablet
0.97
(0.90, 1.03)
0.94
(0.86, 1.04)
Granules (2 x 120 mg) mixed with soft food vs Granules alone (2 x 120 mg)
MK-8228 Granules (Opadry) in vanilla pudding/ 
MK-8228 Granules (Opadry)
1.13
(1.04, 1.22)
1.25
(1.13, 1.39)
MK-8228 Granules (Opadry) in applesauce/ 
MK-8228 Granules (Opadry)
1.20
(1.00, 1.43)
1.33
(1.09, 1.63)
MK-8228 Granules (Opadry+Surelease) in vanilla pudding/ MK-8228 
Granules (Opadry+Surelease)
1.15
(1.04, 1.28)
1.42
(1.26, 1.61)
MK-8228 Granules (Opadry+Surelease) in applesauce/
MK-8228 Granules (Opadry+Surelease)
1.10
(0.99, 1.23)
1.15
(1.01, 1.31)
CI=Confidence interval; GMR=Least-squares Geometric Mean Ratio between treatments; 
MK-8228=letermovir (LET).
a
Back-transformed least-squares mean and confidence interval from linear mixed-effects model performed 
on natural log-transformed values.
2.2.5
Ongoing Clinical Studies
Refer to the IB for further details on the ongoing studies.
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.
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this study. 
In pediatric (birth to <18 years of age) participants who received an allogeneic HSCT and are 
at risk for CMV infection and/or disease:
Objectives
Endpoints
Primary
•
Objective: To evaluate letermovir PK in 
pediatric participants grouped by age.
•
AUC0-24, Cmax (for participants 
receiving oral formulation), Ceoi (for 
participants receiving IV formulation),
and Ctrough
Secondary
•
To evaluate the safety and tolerability of 
treatment with letermovir through Week 
48 post-transplant based on the proportion 
of participants with adverse events.
•
Adverse Events (AEs)
•
AEs Resulting in Study Medication 
Discontinuation
•
To evaluate the efficacy of letermovir in 
prevention of clinically significant CMV 
infection through Week 14 (~100 days) 
post-transplant and through Week 24 (~6 
months) post-transplant. 
•
Clinically significant CMV infection 
(CS-CMVi, defined as initiation of 
preemptive therapy [PET] for 
documented CMV viremia and/or 
CMV disease)
•
To evaluate the palatability and 
acceptability of treatment with letermovir
oral granules.
•
Score on a palatability scale
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2b, open-label, single-arm study to evaluate PK, safety, tolerability, and 
efficacy of LET when used for CMV prophylaxis in pediatric participants from birth to less 
than 18 years of age who are at risk of developing CS-CMVi following an allogeneic HSCT. 
Clinically significant CMV infection is defined as the occurrence of either one of the 
following outcomes:

onset of CMV end-organ disease,
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and/or

initiation of anti-CMV PET based on documented CMV viremia and the clinical 
condition of the participant.
Approximately 60 HSCT recipients will be enrolled in this study. Only R+ participants will 
be enrolled in the oldest age group (Age Group 1, see below). CMV seroprevalence 
decreases with decreasing age. Therefore, enrollment criteria for Age Groups 2 and 3 have
been broadened to include participants with any risk for CMV reactivation (ie, R+ and/or D+;
Section 5.1).
Screening of participants may begin 15 days prior to transplantation, but enrollment must 
occur no later than 28 days post-transplant (Figure 1). Participants will be tested for CMV 
viremia using a CMV DNA PCR assay. After establishing absence of CMV viremia, 
participants will be tested once a week in order to minimize enrollment of those with active 
CMV replication in the study. Any participant who tests positive for CMV viremia prior to 
enrollment will be excluded from the study. 
On the day of enrollment, eligibility criteria should be confirmed. Participants should have 
no documented CMV viremia as confirmed from a sample collected within 5 days prior to 
enrollment. Creatinine clearance and liver function test results within 5 days prior to 
enrollment should be within the range allowable as outlined in Section 5.2. Once enrolled, 
CMV viremia will be monitored at the time intervals detailed in the Schedule of Activities
(SoA; Section 1.3). LET prophylaxis (study intervention) may begin as early as the day of 
transplant and will continue through Week 14 (~100 days) post-transplant. 
The study will enroll (allocate to receive LET) participants in 3 Age Groups:

Age Group 1: From 12 to <18 years of age (adolescents)

Age Group 2: From 2 to <12 years of age (children)

Age Group 3: From birth to <2 years of age (neonates, infants, and toddlers)
See Figure 2 and Table 6 for distribution of study participants by age groups and panels.
Enrollment will begin with Age Group 1 and move sequentially to younger age groups based 
on evaluation of PK in Panel A of the preceding age group (Figure 2). For Age Group 1 and 
Age Group 2, an initial small cohort of participants (Panel A, n=6 participants) will be 
evaluated prior to enrolling more participants in the same age group (Panel B, n=20). 
For Age Group 2, approximately half of the enrolled participants will be 7 to <12 years of 
age; the remainder will be from 2 to <7 years of age. This will allow for the assessment of 
maturation effects on the PK disposition of LET, ensure a wide age and weight distribution 
representative of the entire age group, and will provide continuity of the age and weight 
distributions with Age Groups 1 and 3.
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Age group assignment is based on the age at the time of documented informed 
consent/assent.
Panel A will examine the PK to identify the correct dosing for an age group.
Non-compartmental analysis of PK parameters will be performed, population PK and PBPK 
models will be updated as necessary, and optimal doses confirmed for further study. The 
final dose selected in Panel A will trigger initiation of Panel B in the same age group, and 
Panel A in the younger age group, simultaneously. In the event that the PK exposure results 
from Panel A suggest the dose should be modified, any participant remaining on LET in 
Panel A will have their dose adjusted for the remainder of the treatment period. All 
participants that enroll in Panel B will receive the modified dose. Recommendations for dose 
modifications will be communicated to sites via a Protocol Clarification Letter (PCL) as soon 
as they are available.
Due to anticipated enrollment challenges (few HSCTs performed and low CMV 
seroprevalence), there will be only 1 panel (n=8) for the youngest age group (Age Group 3). 
Enrollment in this panel will be temporarily held after 3 participants are enrolled for further 
PK analysis to confirm dosing prior to continuing enrollment in this age group. The dose for 
the remaining participants (n=5) will be confirmed or modified by the Sponsor once the 
results of this PK analyses are available. The recommended dosing for each age group will be 
confirmed or modified by the Sponsor after each PK analysis.
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Figure 2
Sequential Evaluation of Age Groups
PK=pharmacokinetics; yr=year.
† n represents number of PK-evaluable participants.
* PK analysis will occur at 3 intervals: when all evaluable participants have completed intensive PK in Age Group 1 Panel A, when all evaluable participants 
have completed intensive PK in Age Group 2 Panel A, and when the first 3 evaluable participants have completed intensive PK in Age Group 3.
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LET formulations: Oral and IV formulations of LET will be available (Section 6.1). LET 
should preferably be initiated as an oral formulation (tablets or oral granules), as long as the 
participant is able to swallow or receives oral granules via a gastric (G) tube or a nasogastric 
(NG) tube and does not have a condition that may interfere with the absorption of oral 
medication (eg, vomiting, diarrhea, or a malabsorptive condition). Age Group 1 participants 
preferably should be administered the tablet formulation; participants unwilling to or unable 
to swallow the tablet should receive the oral granules by mouth, instead. Instructions for 
preparation and administration of all LET formulations are provided in the Pharmacy 
Manual.
As the primary objective of this study is to obtain PK data to support dosing 
recommendations for the pediatric oral granule formulation, all participants in Panel A of 
Age Groups 1 and 2 (and preferably all participants in Age Group 3) must receive an
oral formulation from Day 1 through the Day 7 visit when intensive PK sampling is 
completed. Panel A participants who need to be switched to the IV formulation during the 
first 7 days may be switched; they will continue in the study, but will not have intensive PK 
samples drawn on the Day 7 visit. The Sponsor should be notified immediately, as an 
additional participant may subsequently be enrolled in the corresponding panel, at the 
Sponsor’s discretion (Section 8.11.2.2). 
The IV formulation should only be used when participants are either unable to 
swallow/cannot use a G tube/NG tube or have a condition that may interfere with the 
absorption of an oral formulation. Use of the IV formulation should generally be limited to 4 
weeks or less in duration. However, it will be left to the investigator’s discretion to continue 
IV administration beyond 4 weeks if the benefit/risk ratio supports continued administration. 
Simultaneous use of IV and oral LET is not allowed. The IV formulation should be switched 
to oral LET as soon as the condition necessitating the use of the IV formulation resolves.
Cyclosporin A coadministration: In clinical DDI studies in adult participants, 
coadministration of CsA results in an approximately 2 to 3-fold increase in LET exposures,
necessitating lower doses of LET when coadministered with CsA (Section 2.2.3.2). The
appropriate dosage of LET for pediatric participants will be first assessed in the absence of 
CsA (Panel A) to build upon the PK model used for dose selection prior to adding an 
additional covariate. Table 6 summarizes the enrollment requirements for LET formulation 
and CsA use as well as the PK sampling requirements by age group and panel.
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Table 6
Enrollment Requirements and Pharmacokinetic Sampling by Age Group
Age
Group
Age
Range
Panel A
Panel B
1
12 to 18 
years
N=6 (PK evaluable)
Participants must receive oral 
formulation of LET (tablets 
preferably, or oral granules a) 
from Day 1 through Day 7 
visit.
Participants cannot receive 
concomitant CsA.
Sparse and intensive PK 
sampling in all participants

N=20 participants

Participants may receive 
tablets or oral granules 
and/or IV formulations of 
LET.

Participants may receive 
concomitant CsA

Sparse PK sampling in all 
participants. Additionally,
intensive PK if participant 
receives at least 5 
consecutive days of IV 
LETb.
2
2 to 12 
years
N=6 (PK evaluable)
- N=3 participants 2 years to 
<7 years
- N=3 participants 7 years to 
<12 years
Participants must receive 
Oral granules of LET a from 
Day 1 through Day 7 visit.
Participants cannot receive 
concomitant CsA.
Sparse and Intensive PK 
sampling in all participants

N=20 participants
-
N=10 participants 2 
years to <7 years
-
N=10 participants 7 
years to <12 years

Participants may receive 
oral granules and/or IV 
formulation of LET.

Participants may receive 
concomitant CsA. 

Sparse PK sampling in all 
participants. 

Intensive PK, if participant 
receives at least 5 
consecutive days of IV 
LET.
3
birth to <2 
years

N=8 (PK evaluable)

Participants can receive oral granules (preferably) and/or IV 
formulation of LET.

Participants may receive concomitant CsA.

Sparse PK sampling in all participants 

Intensive PK sampling in all participants, regardless of whether 
on oral or IV LET formulationb

HPCD PK samplingc
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Age
Group
Age
Range
Panel A
Panel B
CsA=cyclosporin A; IV=intravenous; HPCD=hydroxypropyl-beta-cyclodextrin; LET=letermovir; n=number 
of participants; PK=pharmacokinetics.
a For Age Group 1, tablets should be preferably administered unless the participant is unable or unwilling to 
swallow the tablet, in which case, the participant may receive oral granules. The oral granules may be 
administered either by mouth or via a G tube/NG tube, provided the participant does not have a condition 
that may interfere with the absorption of oral medication (eg, vomiting, diarrhea, or a malabsorptive 
condition)
b Intensive PK on IV formulation will be collected from participants who have not had intensive PK on the 
oral formulations (oral granules/oral tablet); sample collection will start on the 5th consecutive day of IV 
dosing.
c HPCD PK sampling will start on the 4th consecutive day of IV dosing. HPCD PK sampling timepoints and 
additional creatinine clearance monitoring requirements are detailed in Sections 8.6.2 and 8.6.2.1.
PK sampling: Intensive PK sampling for LET will be done at the Day 7 visit in all Panel A 
participants who received an oral formulation from Day 1 through Day 7. Panel B 
participants, and participants who are not on the oral formulation through Day 7 (ie, switch to
IV during this period) will not undergo intensive PK sampling on Day 7. 
Any participant who receives IV LET for 5 or more consecutive days will have intensive PK 
sampling performed on the fifth day of IV LET administration, except for those who have 
already had intensive PK sampling done on the oral formulation. No participant will have 
intensive PK draws more than once. 
All participants in Age Group 3 will have intensive PK sampling done regardless of the 
formulation received (starting on either the fifth consecutive day of IV LET or the seventh 
consecutive day of oral LET, whichever comes first).
The Sponsor should be notified if intensive PK cannot be done in a participant in Panels A of 
Age Groups 1 and 2, and all of Age Group 3. Enrollment of participants in these panels will 
continue until the minimum number of evaluable participants for the interim PK analyses are 
enrolled in each panel. After a pause in enrollment for each interim PK analysis, enrollment 
of additional study participants will be resumed.
Sparse PK sampling will be done in all study participants at the designated visits 
(Section 1.3–SoA). 
HPCD PK sampling: Whole blood will be collected from Age Group 3 participants starting 
on the fourth consecutive day of IV LET administration. Sections 8.6.2 and 8.6.2.1 contain 
details on timepoints for HPCD PK sampling and the additional creatinine clearance
monitoring requirements for Age Group 3 participants for whom HPCD PK sampling will be 
obtained.
Monitoring for CS-CMVi: All participants will receive LET from the day of enrollment
(Day 1) through Week 14 (~100 days) post-transplant, the period of highest risk for CMV 
reactivation, with the intent of preventing CS-CMVi. Participants will have study visits 
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scheduled at weekly intervals during the treatment period. Thereafter, CMV viremia will be 
monitored every 2 weeks through Week 24 post-transplant, as the risk for CMV reactivation 
is considerably reduced during this interval. The incidence of CS-CMVi will also be assessed 
through Week 24 (~6 months) post-transplant to evaluate the occurrence of late CS-CMVi
(between Weeks 14 and 24 post-transplant). 
For participants who develop CS-CMVi through Week 24 post-transplant, the 
participant should have a CMV Infection Visit. At this visit, LET should be discontinued (if 
applicable) and all procedures as outlined in the SoA (Section 1.3), including collection of a 
CMV DNA PCR sample, should be performed immediately prior to the initiation PET or 
treatment of CMV disease. Such participants will continue to be followed in the study and 
complete all remaining study visits). 
Participants who discontinue the study prior to Week 24 post-transplant should 
complete an Early Study Discontinuation Visit and complete all procedures as per the SoA 
(Section 1.3).
Following completion of the study period at Week 24 (~6 months) post-transplant, all study 
participants will remain in the study for an additional 24 weeks through Week 48 
post-transplant for long-term follow-up to continue collecting safety information 
(Section 8.4). Mortality data will be collected throughout the participants’ enrollment in the 
study.
Following the conclusion of this study and the Clinical Study Report (CSR) for the study, a 
final PK model will be developed that includes all PK data from participants from birth to 
18 years, in addition to relevant adult data previously collected in the program. The final 
model and proposed pediatric dosing regimen will be summarized in a separate modeling 
report.
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 detailed in the DMC charter), 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. Some analyses may be combined at the request of the DMC. The DMC may 
review safety data at other time points (including after the last scheduled safety check) as 
needed.
An independent, Clinical Adjudication Committee (CAC) will be established for adjudicating 
all potential investigator-reported cases of CMV end-organ disease, as defined in Appendix 
8, throughout the study. For analysis purposes, the adjudication of cases by the CAC will 
take precedence over the investigator’s assessment.
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.
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4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Pharmacokinetic Endpoints
The primary objective of this study is to evaluate the PK of LET in pediatric participants to 
support LET dose selection for use in prevention of clinically significant CMV infection in 
pediatric patients receiving an allogeneic HSCT. For the noncompartmental analysis (NCA), 
the primary PK endpoints for LET are: area under the concentration-time curve for the 
dosing period (AUC0-24), maximum concentration observed (Cmax, for participants 
receiving oral formulations), minimum concentration observed before next dose (Ctrough), 
and concentration at the end of infusion (Ceoi, for participants receiving IV formulation). 
Additional PK parameters for participants receiving oral formulations are time to maximum 
observed plasma drug concentration (Tmax), half-life (t1/2), apparent clearance (CL/F), and 
apparent volume of distribution (Vd/F). Additional PK parameters for participants receiving 
IV formulation are half-life (t1/2), clearance (CL), and volume of distribution (Vd). Plasma 
samples for PK evaluations will be collected at the time points described in the SoA 
(Section 1.3). Refer to Section 8.6.1 for the PK sampling scheme.
4.2.1.2
Safety Endpoints
Safety and tolerability are key secondary objectives of this study. 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, 12-lead ECGs, and 
standard laboratory safety tests at appropriate time points as specified in the SoA 
(Section 1.3). 
Rationale for Specific Safety Endpoint Analyses: 
Renal function
The IV formulation of LET contains the excipient HPCD, which can accumulate in patients 
with renal insufficiency. In this regard, cyclodextrin is also an excipient in other approved IV 
agents, including IV voriconazole (given with the excipient, sulfobutylether-β-cyclodextrin). 
Recent data suggest that, despite accumulation of cyclodextrin in patients with reduced renal 
function, baseline renal function is not a predictor of worsening renal function in patients 
receiving IV voriconazole [Neofytos, Dionissios, et al 2012]. Additionally, the quantity of 
cyclodextrin in the IV formulation of LET is less than that in the IV voriconazole 
formulation (1800 mg of cyclodextrin/vial for a 240-mg dose of LET as compared with
3200 mg of cyclodextrin/vial for a 200-mg dose of voriconazole, which is administered twice 
a day). 
The IV formulation of LET was used in a total of 99 participants (27%) in the pivotal Phase 3 
study (P001). The extent of exposure to IV LET was similar to IV placebo in P001. The 
incidence of AEs reported in recipients of the IV formulation was comparable in the 2
treatment groups. Further assessments of trends in blood urea nitrogen (BUN) and serum 
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creatinine confirm that the use of the LET IV formulation had a similar renal safety profile 
compared with placebo, suggesting that the use of the cyclodextrin formulation in P001 was 
not associated with renal toxicity.
Renal function will be closely monitored in this study (reported AEs as well as laboratory 
parameters of renal function including BUN, serum creatinine levels and creatinine 
clearance) to confirm the cyclodextrin-containing IV formulation is not associated with renal 
toxicity in the pediatric population. Additionally, HPCD PK sampling will be done in Age 
Group 3 participants who receive the IV formulation for at least 4 consecutive days. See 
Section 8.6.2 and Section 8.6.2.1 for sampling timepoints and additional creatinine clearance 
monitoring requirements in these Age Group 3 study participants receiving the IV 
formulation. 
Based on the above, the use of IV LET is permitted in participants in this study with renal 
insufficiency, provided creatinine clearance is >10 mL/min as calculated by the Cockcroft-
Gault equation (for participants ≥12 years of age) or >10 mL/min/1.73 m2 by the modified 
Schwartz equation (for participant <12 years of age) or the participant is not on hemodialysis
(Appendix 12). However, the IV formulation should only be used when participants are 
either unable to swallow or have a condition (eg, vomiting, diarrhea, or malabsorptive 
condition) that may interfere with the absorption of the oral formulation. Participants on IV 
LET should be switched to the oral formulation as soon as they are able to swallow and/or 
the condition that warranted the use of the IV formulation has resolved.
4.2.1.3
Efficacy Endpoints
The efficacy endpoints of the study will be the proportion of participants with CS-CMVi
through Week 14 (~100 days) and Week 24 (~6 months) post-transplant, defined as the 
occurrence of either one of the following outcomes: 

onset of CMV end-organ disease 
OR

initiation of anti-CMV PET based on documented CMV viremia and the clinical 
condition of the participant. Initiation of PET in this study refers to the practice of 
initiating therapy with the following anti-CMV agents when active CMV viral 
replication is documented: ganciclovir, valganciclovir, foscarnet, and/or cidofovir.
Note: Documented viremia is defined as any detectable CMV viral DNA (including PCR 
results above or below the lower limit of quantification).
CMV infection, as measured by CMV viremia, is associated with considerable morbidity and 
mortality in HSCT recipients due to an increased incidence of CMV disease (the “direct” 
effects) and the “indirect” effects secondary to the effects of CMV on the immune system as 
described in Section 2.2.
Currently, with most centers using PET for prevention of CMV disease, the overall incidence 
of CMV disease in HSCT recipients has declined to around 5% in the first 3 months 
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post-transplant, the period of highest risk, from 20% to 30% prior to the routine use of 
preventive measures [Boeckh, M. 2011] [Boeckh, M. and Nichols, W. G. 2004] [Marty, F. 
M., et al 2011] [Craddock, C., et al 2001] [Boeckh, M., et al 1992] [Winston, D. J., et al 
2008] [Ljungman, P., et al 1998] [Snydman, D. R. 2011]. Therefore, the efficacy endpoint 
selected for this study – CS-CMVi – will be a composite endpoint of CMV infection 
warranting initiation of PET and/or CMV disease.
Assessment of Efficacy Endpoint
Detection of CMV in plasma or blood is associated with an increased risk of CMV disease 
[Gerna, G., et al 2011] [Lowance, D., et al 1999] [Gor, D., et al 1998] [Atkinson, C. and 
Emery, V. C. 2011]. CMV viral DNA as a measure of CMV infection is already used 
routinely in clinical practice to initiate and monitor PET [Boeckh, M. 2011] [Boeckh, M. and 
Ljungman, P. 2009] [Winston, D. J., et al 2008] [Härter, G. and Michel, D. 2012] [Emery, V. 
C., et al 2000]. The decision to initiate PET should be guided by detection of viral DNA and 
the clinical condition of the participant. 
Investigators will report all “probable” and “proven” cases of CMV disease using the 
definitions in Appendix 8. All investigator-reported disease will be confirmed by an 
independent CAC. The CAC will review clinical, virological, and histopathological data as 
well as the investigator’s assessment for adjudicating all potential cases of end-organ CMV 
disease. For analysis purposes, the adjudication of cases by the CAC will take precedence 
over the investigator’s assessment.
4.2.1.4
Palatability and Acceptance Assessment Endpoint
Palatability may play an important role in adherence to treatment in the pediatric population. 
Palatability is an important element in the determination of acceptability, and encompasses a 
product’s smell, taste, aftertaste, and texture. Acceptability, including palatability, of the oral 
granule formulation will be assessed in all participants using the Palatability Acceptance 
Assessment (PAA). In previous studies, the most commonly reported assessment measured 
palatability preference using a visual analog scale that was modified by including a facial 
hedonic scale (FHS; facial expression scale depicting various degrees of pleasure)
[Thompson, C., et al 2015]. The 5-point FHS for taste is one of the most frequently reported 
types of palatability assessments used in pediatric clinical studies and will be used in this 
study.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
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DNA samples will be used for research related to the study intervention(s), the disease under 
study, and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases, and study intervention(s). 
Genetic research may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR. 
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
(Appendix 6).
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
Table 7 and Table 8 show doses for initiating LET prophylaxis with the oral or IV 
formulations of LET, respectively, when LET is administered with or without CsA, for 
Age Groups 1 to 3. Age Group 1 (age 12 to <18 years), Panel A started with the adult dose of 
480 mg once daily. For Age Group 2 (age 2 to <12 years), the LET doses shown are the 
starting doses. The starting doses for Age Groups 1 and 2  were confirmed based on the 
review of interim analyses of PK, safety, and tolerability from Age Group 1, Panel A. Doses 
for Age Group 3 (birth to <2 years) are based on the accumulated PK, safety, and tolerability
data from Age Group 1 (Panels A and B) and Age Group 2 Panel A. The LET doses shown 
for Age Group 3 in Table 7 and Table 8 are the starting doses and will be confirmed or 
modified based on the review of an interim analysis of PK, safety, and tolerability from the 
first 3 participants from Age Group 3. (Note: for weight-based dosing, weight recorded at 
enrollment [Day 1] will be used to determine initial dosing. Dose may need to be 
adjusted according to the most recent body weight taken per the SoA). In the event the 
starting doses listed here need to be modified, this information will be communicated to 
investigators and sites via a PCL. The rationale for these starting doses is described below in 
Section 4.3.1.1. See Section 6.1 for full dosing instructions.
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Participants requiring IV administration or coadministration with CsA within the first 7 days
of the study will not be enrolled in Age Groups 1 or 2 of Panel A in order to first establish 
the oral LET pediatric PK profile and subsequent model predictions. However, participants 
initially enrolled in Panel A, but requiring a switch to IV administration after the Day 7 visit 
will still be included in the population PK analysis.
Table 7
Oral Letermovir Dosing Table
Age 
Group
Age Range
BW limits 
(kg)
Oral dose LET
(mg)
Oral dose LET (mg) 
with CsA
1
12 to <18 years
Any weight
480
240
2 
2 to <12 years
≥30
480
240
18 to <30
240
120
10 to <18
120
60
3
birth to <2 years
10 to ≤15
120
60
7.5 to <10
120
60
5.0 to <7.5
60
40
2.5 to <5.0
40
20
BW = body weight recorded at enrollment (Day 1) will be used to determine the initial dosing. Dose may be 
adjusted according to the most recent body weight taken per the SoA. CsA = Cyclosporin A; IV = intravenous; 
LET = letermovir; PK = pharmacokinetics; SoA=Schedule of Activities.
Table 8
Intravenous Letermovir Dosing Table
Age 
Group
Age Range
BW limits (kg)
IV dose LET (mg)
IV dose LET (mg) 
with CsA
1
12 to <18 years
Any weight
480
240
2 
2 to <12 years
≥30
240a
240b
18 to <30
120a
120b
10 to <18
60a
60b
3
birth to <2 years
10 to ≤15
60a
60b
7.5 to <10
60c
60b,c
5.0 to <7.5
40c
40b,c
2.5 to <5.0
20c
20b,c
BW=body weight recorded at enrollment (Day 1) will be used to determine the initial dosing. Dose may be 
adjusted according to the most recent body weight taken per the SoA; CsA=Cyclosporin A; IV=intravenous; 
LET=letermovir; PK =pharmacokinetics; SoA=Schedule of Activities.
a
Based on modeling, for Age Group 2, the IV dose of LET is reduced by 50% compared with oral LET in 
order to maintain target exposures.
b
No further reduction of IV LET is necessary when coadministered with CsA.
c
Based on interim analyses results, doses are increased for participants weighing  <10 kg in Group 3
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4.3.1.1
Dose Justifications
Using modeling and simulation in the adult clinical program, the relationship between LET
exposure and response (efficacy and safety) in adult HSCT recipients was characterized. In 
addition, the pathogenesis of CMV infection (viremia) and disease, and the mechanism of 
action of LET, are not anticipated to be different in pediatrics compared with adults. Thus, 
achieving LET exposures in pediatric HSCT recipients that are similar to adult HSCT 
recipients is expected to result in similar efficacy and safety in both populations.
Exposure targets:
Exposure targets and bounds for the pediatric HSCT population were established using the 
typical exposures and ranges predicted for the HSCT adult population given the clinical dose. 
The Phase 3 population PK model predicted steady-state median exposures (AUC0-24h) in 
adult HSCT recipients following oral and IV LET 480 mg without CsA (Table 4), 
respectively, were chosen as the target range (34,400 to 100,000 ng.hr/mL) for the pediatric 
median exposures. In addition, the 5th percentile exposure following 480 mg oral LET, and 
the 95th percentile exposure following 480 mg IV LET, respectively, were chosen as the 
(16,900 to 148,000 ng·hr/mL) lower and upper bound for the pediatric exposure range.
Simulations with both the PBPK model combined with the Simcyp pediatric module and the
Phase 3 population PK model with allometric scaling were used to select optimal LET doses 
and weight bounds within each of the 3 age groups, with the goal of keeping both the median
and extreme predicted exposures within the prespecified bounds. The pediatric patients had 
an assumed weight distribution at each age according to CDC (2 to 17 years) and WHO (0 to 
23 months) growth tables. Figure 3 and Figure 4 are based on the adult population PK model 
and depict the predicted pediatric AUC in Age Groups 1 and 2, as a function of Age Group 
and body weight, for the 4 regimens of oral or IV route of LET administration, and with or 
without concomitant CsA. Figure 3 is the dosing paradigm using oral and IV LET (without 
CsA) interchangeably for both Age Groups 1 and 2. 
Figure 4 shows the dosing paradigm for this study, where participants in Age Group 2 (2 to 
<12 years) without coadministration of CsA require a 50% reduction in LET IV dose relative 
to oral.
Figure 5 shows the Age Group 3 LET exposure predictions corresponding to the initial 
dosing paradigm, based on the Phase 3 population PK model with allometric scaling.
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Figure 3
LET Median AUC (With 5th and 95th Percentile Prediction Intervals) by age 
Group and Weight, Based on the Phase 3 Population PK Model With Allometric Scaling. 
Age Group 1 (12 to <18 yrs) and Age Group 2 (2 to <7 yrs and 7 to <12 yrs), Without 
Coadministration of CsA, are Given LET IV at the Same Dose as Oral
AUC=area under the concentration-time curve; CsA=cyclosporin A; LET=letermovir (MK-8228); 
IV=intravenous; po=by mouth; yrs=years.
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Figure 4
LET Exposure Predictions Corresponding to the Dosing Paradigm for This Study, 
Showing LET Median AUC (With 5th and 95th Percentile Prediction Intervals) by Age Group 
and Weight, Based on the Phase 3 Population PK Model With Allometric Scaling. Age 
Group 2 (2 to <7 yrs and 7 to <12 yrs), Without Coadministration of CsA, has a 50% 
Reduction in LET IV Dose Relative to Oral
See Table 7 for initial dosing paradigm (oral) and Table 8 for initial dosing paradigm (IV). Green dotted lines 
are the median exposures (50th percentile) following the 480 mg oral and IV LET dose (without CsA) of 34,400 
to 100,000 ng.hr/mL, respectively, and represent the target exposure range for the pediatric median exposures.
Brown dotted lines are the 5th percentile exposure of 16,900 ng·hr/mL following 480 mg oral LET and the 95th 
percentile exposure of 148,000 ng·hr/mL following 480 mg IV LET, and represent the lower and upper bound 
targets, respectively, for the pediatric exposure range. 
Red dotted line is the maximal AUC exposure achieved in the Phase 1 program. 
AUC=area under the concentration-time curve; CsA=cyclosporin A; LET=letermovir (MK-8228); 
IV=intravenous; po=by mouth; yrs=years.
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Figure 5
Age Group 3 LET Exposure Predictions Corresponding to the Initial Dosing 
Paradigm, Showing LET Median AUC (With 5th and 95th Percentile Prediction Intervals) by
Weight, Based on the Phase 3 Population PK Model With Allometric Scaling. 
Solid lines are medians and shaded regions are 90% prediction intervals.
AUC=area under the concentration-time curve; CsA=cyclosporin; IV=intravenous; Ph=Phase; po=by mouth.
LET is transported by OATP1B1/3, for which limited maturation data are available. In the 
literature, relative protein expression of OATP1B1 was highly variable among individuals, 
and no statistically significant difference was observed among the studied age groups 
[Thomson, M. M., et al 2016] [Prasad, B., et al 2016]. For OATP1B3, protein expression was 
not significantly different between adults and children >1 year, but was significantly different 
for children <1 year [Prasad, B., et al 2016]. However, it is unknown how much of the 
measured protein represents active transporter. Therefore, dose predictions for Age Group 3 
(birth to <2 years) exhibit a higher uncertainty than the older pediatric age groups. As such,
dose predictions for Age Group 3 were determined by the interim analysis following the 
availability of Age Group 2 Panel A PK data, along with all cumulative PK, safety, and 
tolerability data. The resulting oral and IV dose selections for all Age Groups are presented 
in Table 7 and Table 8, respectively.
LET administered without CsA:
The adult clinical program included patients with a body weight range of 35.1 to 141.5 kg 
who demonstrated favorable PK, safety, and efficacy. Based on the comparable body weight 
and OATP1B maturation in participants aged 12 to <18 years (Age Group 1), it is anticipated 
that the PK of LET in this age group will behave similarly to those of adults receiving the 
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adult 480-mg oral dose of LET. The adult clinical program supports that the IV and oral LET 
dose are interchangeable. This approach was modeled for Age Group 1, and although the 
predicted exposures for IV and/or CsA regimens exceeds the median and upper bound
exposure targets for simulated adolescents approaching the lowest 5th percentile weight of 
30 kg, the exposures are generally within the target exposures overall, and are below the 
highest exposure achieved in the entire clinical program (~ 328,000 ng.hr/mL) (Figure 4, 
rows 2-4, column 3). Exposures in the lowest weight adolescents will be carefully monitored, 
and an additional weight band in Age Group 1 may be added in the event actual exposures 
exceed the clinical experience in adults.
During the modeling of the dose selections for Age Group 2, when using interchangeable 
doses for IV and oral LET, the predicted exposures for IV without CsA exceeded both the 
median and upper bound exposure targets (Figure 3, row 2, columns 1-2). In order to 
maintain predicted exposures within target bounds for IV, 2 options for Age Group 2 were 
considered: (1) add additional weight bands with a narrower weight range and maintain 
interchangeable IV and oral doses; or (2) maintain the current weight bands and reduce the 
IV dose by 50%. Given that there is less known about drug disposition in this age group, and 
that the children with the lowest body weight were at the highest risk to exceed the upper 
limit of the exposure target, in order to achieve the target exposure range in Age Group 2, the 
initial IV dose of LET is reduced by 50%. 
LET administered with CsA:
As the PBPK models are not currently validated to predict drug-drug interactions for CsA, 
the Phase 3 population PK model alone was used to estimate LET exposures with CsA, 
suggesting a reduction of oral LET dose by 50% when given with CsA for ages 
2 to <18 years, due to the expected increase in bioavailability and decrease in clearance with 
CsA. No further reduction in the LET IV dose is anticipated when coadministered with CsA
(Figure 3).
4.3.1.2
Dose in Age Group 1 (12 to <18 years), Panel A
For the initial dose for Age Group 1 Panel A, the LET PBPK model simulations assume the 
same OATP1B1/3 abundance for hepatic uptake and effects of physiology as estimated for 
adult patients. The PBPK and the population PK model suggests that the adult dose of LET
of 480 mg oral or IV will result in comparable exposures in ages 12 to <18 years as in adults. 
The adult tablets will be used in this age group, thus establishing continuity with the body of 
adult PK data from the adult studies. For participants unable or unwilling to swallow the 
adult tablets, oral granules may be used (see Section 6.1 for dosing instructions). No dose 
modifications for Age Group 1 were necessary based on the interim PK analysis of all 
evaluable participants in Age Group 1 Panel A.
4.3.1.3
Dose in Age Group 2 (2 to <12 years), Panel A
The doses for Age Group 2 Panel A shown in Table 7 and Table 8 were estimated, as 
described in Section 4.3.1.2. The doses were confirmed by interim analyses of PK, safety, 
and tolerability data. Age Group 2 (2 to <12 years) is subdivided into weight bands. For 
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participants weighing ≥30 kg, an oral dose of 480 mg of LET is estimated to result in 
comparable exposures as the adult HSCT patients. For participants weighing 18 to <30 kg, an 
oral dose of 240 mg of oral granules of LET is estimated to result in comparable exposures as 
the adult HSCT patients. For participants weighing 10 to <18 kg, an oral dose of 120 mg of 
LET is estimated. In the event that a participant is switched to IV LET, the IV dose is 
reduced in this age group and the estimated IV doses are described in Table 8.
A minimum of 3 evaluable participants per age range (2 years to <7 years, and 7 years
<12 years) are required prior to initiating interim PK analysis, in order to assess maturation 
effect on the PK disposition of LET. No dose modifications for Age Group 2 were necessary 
based on the planned interim PK analysis of all evaluable participants in Age Group 2 Panel 
A.
All participants in Age Group 2 Panel A will receive oral granules sprinkled on soft food or 
administered via a G tube/NG tube (see supporting study documentation [eg, Pharmacy 
Manual] for details on preparation and administration of oral granules by mouth or via 
G tube/NG tube).
4.3.1.4
Dose in Age Groups 1 and 2, Panel B
The doses for Panel B were determined from interim analyses of PK, safety and tolerability 
following the completion of intensive PK in all participants of Panel A. The interim PK 
analysis was based on NCA of Panel A intensive PK, and utilized population PK and PBPK 
modeling and simulation based on all cumulative PK data.
The goal of the interim PK analyses was to assess LET PK in each age group and determine
whether exposures are broadly similar to adult HSCT recipients. The Day 7 intensive PK 
data from Age Group 1 or 2 of Panel A was used to estimate exposures using NCA. The 
range of exposures estimated by NCA was largely within the limits of those observed for 
adult therapeutic doses; no adjustments to the doses specified in Table 7 and Table 8 were
made for Panel B. The final determination of doses for Panel B was based on the composite 
assessment of cumulative PK and safety and tolerability results through Panel A.
Recommendations for dose modifications will be communicated to investigators and sites via 
a PCL as soon as they are available. The interim and final analyses will be described in a 
separate Modeling and Simulation Plan, and reported in separate Modeling and Simulation 
Reports.
4.3.1.5
Age Groups 1 and 2 Pharmacokinetic Experience Through Interim 
Analysis 2
The initial dose selections for Age Groups 1 and 2 were evaluated by intensive PK 
measurements for Panel A (n=6 per Age Group) following oral administration of LET 
without CsA for at least 7 days. As of the second interim analysis, 7 participants in Age 
Group 1 Panel B had intensive PK following IV administration of 480 mg LET for at least 
5 consecutive days, with 4 of 7 participants coadministered CsA. In addition, 1 participant in 
Age Group 1 Panel B had intensive PK following oral administration of 240 mg LET with 
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CsA. Exposures that exceeded the adult exposure target range were also compared with the 
upper clinical bound of the highest exposure observed in the LET Phase 1 program (328000 
h.ng/mL). Figure 6 shows the steady-state exposures (AUC24) determined by 
noncompartmental analysis (NCA) for the (n=20) participants who had intensive PK as of 
Interim Analysis 2. Overall, 17/20 participants had exposures in the adult exposure target 
range, comprising 4/6 participants in Age Group 1 Panel A, 7/8 participants in Age Group 1 
Panel B, and 6/6 participants in Age Group 2 Panel A. Of the 3/20 participants who had 
exposures outside the adult exposure target range, one participant receiving oral LET (Age 
Group 1 Panel A) had an exposure below the target range, another receiving oral LET (Age 
Group 1 Panel A) had an exposure above the target range, but 1.46-fold below the upper 
clinical bound, and one participant receiving IV LET (Age Group 1 Panel B) had an exposure 
above the target range, but 2.11-fold below the upper clinical bound. Overall, these results 
support the validity of the method used to determine the doses for Age Groups 1 and 2, and 
the continuation of the same method for Age Group 3.
Figure 6
Letermovir Exposure (AUC24) in All Participants From Age Groups 1 and 2 who 
had Intensive PK (N=20)
AUC24=area under the concentration-time curve for the dosing interval (0 to 24 hours); CsA=cyclosporin; 
IV=intravenous; NG=nasogastric; po=by mouth; y=year.
CsA above the symbol indicates CsA was coadministered with the LET dose. Vertical dotted lines show the 
dosing weight band boundaries for Age Group 2 (there are no dosing weight boundaries for Age Group 1).
a  The relative size of each symbol reflects the dose of LET: small=120 mg; medium=240 mg; large=480 mg.
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4.3.1.6
Dose in Age Group 3
The initial doses in Age Group 3 were determined based on an analysis of the accumulated 
PK data from Age Group 1 (Panels A and B) and Age Group 2 Panel A, as described above
in Section 4.3.1.4. Having validated the dose selection for Age Groups 1 and 2, the method 
of allometric scaling of the adult Phase 3 population PK model was applied to Age Group 3. 
A metabolic maturation adjustment to the allometric scaling coefficient for glucuronidated 
drug clearance was used, as well as a small adjustment to exposure for granules consumed 
with food. The Age Group 3 participants have an assumed weight distribution according to 
WHO (0 to 23 months) growth tables. As for all age groups, doses and weight bands were 
selected to keep the predicted pediatric exposures within the adult target range. The resulting 
simulated exposures in Figure 5 show that nearly all Age Group 3 participants are expected 
to have exposures in the adult target range with the proposed doses in Table 7 and Table 8.
Following the collection of intensive PK in 3 evaluable participants in Age Group 3, 
enrollment was paused until after the analysis of intensive PK and reevaluation of the initial 
dose for this age group. Changes in doses for Age Group 3 was communicated to
investigators and sites via a PCL.
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose of LET in this study will not exceed 480 mg once daily.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent, or is lost to follow-up 
(Section 7.3).
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criterion specified below:
1. The eDMC recommends termination of the study and the Executive Oversight 
Committee (EOC) agrees as stated in the DMC charter.
2. The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole 
is unacceptable. In addition, further recruitment in the study or at (a) particular study 
site(s) may be stopped, as described in Appendix 10.1.10.
5
STUDY POPULATION
Male and female recipients of an allogeneic HSCT between the ages of birth and <18 years 
of age (on the day of documenting informed consent/assent) will be enrolled in this study.
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As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age, race, ethnicity, and sex. The collection and use of these 
demographic data will follow all local laws and participant confidentiality guidelines while 
supporting the study of the disease, its related factors, and the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in this study if the individual meets all of the following 
criteria:
1. All Age Group 1 participants must have documented positive CMV serostatus (CMV IgG 
seropositive) for the recipient (R+) within 90 days prior to enrollment.
Participants in Age Group 2 and 3 must have documented positive CMV serostatus
(CMV IgG seropositive) for the recipient (R+) within 90 days prior to enrollment and/or 
for the donor (D+); the donor serostatus should be documented within 1 year prior to 
enrollment.
2. Be the recipient of a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or 
cord blood transplant).
3. Have undetectable CMV DNA from a plasma or whole blood sample collected within 5 
days prior to enrollment.
4. Be within 28 days post-HSCT at the time of enrollment.
Demographics
1. Participant is aged from birth to <18 years of age at the time of providing documented
informed consent/assent.
Female Participants
2. 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 
intervention.
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Informed Consent/Assent
3. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant or legally acceptable representative may also 
provide consent/assent for FBR. However, the participant may participate in the study 
without participating in FBR.
Additional Categories
4. Study participants in Panel A of Age Groups 1 and 2 must not be on concomitant CsA 
and must be able to take (as assessed by the investigator) LET tablets or the oral granules
(either by mouth or via G tube/NG tube), provided the participant does not have a 
condition that may interfere with the absorption of oral medication (eg, vomiting, 
diarrhea, or a malabsorptive condition) from the day of enrollment until the intensive PK 
sampling is completed in these panels (Day 7 Visit, see SoA, Section 1.3).
5. For Age Group 2, the participant’s weight should be at least 10 kg; and for Age Group 3, 
the participant’s weight should be at least 2.5 kg and less than or equal to 15 kg at the 
time of enrollment.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has received a previous allogeneic HSCT (Note: receipt of a previous autologous HSCT 
is acceptable). 
2. Has a history of CMV end-organ disease within 6 months prior to enrollment.
3. Has evidence of CMV viremia at any time from either providing documented ICF or the 
HSCT procedure, whichever is earlier, until the time of enrollment. (Note: Evidence of 
CMV viremia will include any test result reported as “positive” on a qualitative assay; 
“detectable” including “detectable, not quantifiable,” or “detected” with a numeric value 
provided by a quantitative assay.)
4. Has suspected or known hypersensitivity to active or inactive ingredients of LET
formulations.
5. Has severe hepatic insufficiency (defined as Child-Pugh Class C; see Appendix 9) within 
5 days prior to enrollment.
6. Has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 x the 
upper limit of normal (ULN) or serum total bilirubin >2.5 x ULN within 5 days prior to 
enrollment. 
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have repeat testing done one time prior to enrollment. If the repeat value 
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does not meet this criterion, they may continue in the screening process. Only the specific 
out of range value should be repeated (not the entire panel).
7. Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis)
OR 
b) has end-stage renal impairment with a creatinine clearance ≤10 mL/min, as 
calculated by the Cockcroft-Gault equation (for participants ≥12 years of age) or ≤10 
mL/min/1.73 m2 by the modified Schwartz equation (for participants <12 years of 
age) using serum creatinine within 5 days prior to enrollment (Appendix 12).
Note: Participants who meet this exclusion criterion may, at the discretion of the 
investigator, have repeat testing done one time within 5 days prior to enrollment. If 
the repeat value does not meet this criterion, they may continue in the screening 
process. Only the specific out of range value should be repeated (not the entire panel).
8. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency. 
Note: Moderate hepatic insufficiency is defined as Child-Pugh Class B (Appendix 8); 
moderate-to-severe renal insufficiency is defined as a creatinine clearance <50 mL/min, 
as calculated by the Cockcroft-Gault equation (for participants in Age Group 1) or 
<50 mL/min per 1.73 m2 calculated using the modified Schwartz equation (for 
participants in Age Group 2). Participants in Age Group 3 should not be enrolled if they 
have moderate hepatic insufficiency and creatinine clearance <20 mL/min per 1.73 m2
calculated using the modified Schwartz equation; see Appendix 12 for Cockcroft-Gault 
and modified Schwartz equations).
9. Has an uncontrolled infection on the day of enrollment.
10. Requires mechanical ventilation or is hemodynamically unstable at the time of 
enrollment.
11. Has a documented positive result for a human immunodeficiency virus antibody (HIV-
Ab) test at any time prior to enrollment, or for hepatitis C virus antibody (HCV-Ab) with 
detectable HCV RNA, or hepatitis B surface antigen (HBsAg) within 90 days prior to 
enrollment.
12. Has active solid tumor malignancies with the exception of localized basal cell or 
squamous cell skin cancer or the condition under treatment (eg, lymphomas).
13. Has a preexisting cardiac condition a) for which the patient is currently being treated or 
b) which required hospitalization within the last 6 months or c) that may be expected to 
recur during the course of the trial. Examples of preexisting cardiac conditions that would 
preclude enrollment include atrial fibrillation and atrial flutter.
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Prior/Concomitant Therapy
14. Received within 7 days prior to enrollment any of the following:

ganciclovir

valganciclovir

foscarnet

acyclovir (at doses greater than those recommended for HSV/VZV prophylaxis; see 
Appendix 10)

valacyclovir (at doses greater than those recommended for HSV/VZV prophylaxis: 
see Appendix 10) 

famciclovir
15. Received within 30 days prior to enrollment of any of the following:

cidofovir

CMV immunoglobulin 

any investigational CMV antiviral agent/biologic therapy

Rifampin and other strong inducers (such as phenytoin, carbamazepine, St John’s 
wort (Hypericum perforatum), rifabutin and phenobarbital) and moderate inducers 
such as nafcillin, thioridazine, modafinil and bosentan.
16. Received letermovir at any time prior to enrollment in this study.
Prior/Concurrent Clinical Study Experience 
17. Is currently participating or has participated in a study with an unapproved
investigational compound or device within 28 days, or 5X half-life of the investigational 
compound (excluding monoclonal antibodies), whichever is longer, of initial dosing in 
this study. Participants previously treated with a monoclonal antibody will be eligible to 
participate after a 28-day washout period. 
Note: 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.
18. Has previously participated in this study or any other study involving LET.
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19. Has previously participated or is currently participating in any study involving 
administration of a CMV vaccine or another CMV investigational agent, or is planning to 
participate in a study of a CMV vaccine or another CMV investigational agent during the 
course of this study.
Refer to Section 6.5.2.1 for information on COVID-19 vaccines.
Other Exclusions 
20. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the 
time of consent through 28 days after the last dose of study intervention.
21. Is expecting to donate eggs starting from the time of consent through 28 days after the 
last dose of study intervention.
22. 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.
23. 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.
24. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
When using an allowed concomitant medication, please refer to the pediatric prescribing 
information of each local product circular for meal and dietary restrictions.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy
If a participant enrolled in Panel A of Age Group 1 or 2 or in Age Group 3 discontinues from 
study intervention or withdraws from the study prior to intensive PK sampling, or is 
considered not evaluable for intensive PK, a replacement participant may be enrolled in the 
corresponding panel to ensure n=6 PK-evaluable participants in each Panel A, and n=8
PK-evaluable participants in Age Group 3. Enrollment of replacement participants will be at 
the discretion of the Sponsor and may occur at any active study site. The replacement
participant will be assigned a unique allocation number. 
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 interventions provided by the Sponsor will be packaged to support 
enrollment and replacement participants as required. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 9.  In this study, 
approximately 60 participants will be enrolled in three age groups to receive LET once a day 
from the day of enrollment (Day 1, within 28 days post-transplant) through 14 weeks (~100 
days) post-transplant.  Both oral (adult tablet and capsules containing oral granules) and IV 
formulations of LET will be used in this study.  Simultaneous use of IV and oral study 
therapy is not allowed.
Dosing for all age groups will be based on age and most recent weight (SoA 1.3.1). Dosing 
recommendations for all Age Groups are provided in Table 10 and Table 11.
Country-specific requirements are noted in Appendix 7.
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Table 9
Study Intervention
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
trationa
Regimen/ Treatment 
Period
Use
IMP/
NIMP/
AxMP
Sourcing
1
Experimental
letermovir
Drug
Tablet
240 mg
Age/
weight based 
Oral
QD from Day 1 through 
week 14 (~100 days) 
post-transplant 
Test 
Product
IMP
Sponsor
2
Experimental
letermovir 
Drug
Capsule (oral 
granules)a
120 mg
Age/
Weight based
Oral
QD from Day 1 through 
week 14 (~100 days) 
post-transplant
Test 
Product
IMP
Sponsor
3
Experimental
letermovir
Drug
Capsule (oral 
granules)a
30 mg
Age/
Weight based
Oral
QD from Day 1 through 
week 14 (~100 days) 
post-transplant
Test 
Product
IMP
Sponsor
4
Experimental
letermovir
Drug
Capsule (oral 
granules)a
10 mg
Age/
Weight based
Oral
QD from Day 1 through 
week 14 (~100 days) post 
transplant
Test 
Product
IMP
Sponsor
5
Experimental
letermovir
Drug
Intravenous
20 mg/mL 
vial
Age/
Weight based
Intravenous
QD from Day 1 through 
week 14 (~100 days) post 
transplantb
Test 
Product
IMP
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational medicinal product/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
a
The oral granules may be administered either by mouth or via G tube/NG tube, provided the participant does not have a condition that may interfere with the 
absorption of oral formulation (eg, vomiting, diarrhea, or a malabsorptive condition).
b
Use of IV formulation should generally be limited to 4 weeks or less in duration. The IV formulation should be switched to oral study intervention (ie, at the 
next planned visit) as soon as such participants are able to swallow and/or the condition necessitating the use of IV formulation resolves.
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Dosing of Oral Formulation:
For Age Group 1: Either the currently marketed oral 240-mg tablets (or multiples thereof) for 
adults will be used (preferably) or, the oral granules will be used for participants unable or 
unwilling to swallow the adult tablets. The adult tablets may be taken with or without food.
For Age Groups 2 and 3: The only oral formulation that will be used in these groups will be 
oral granules.
Oral Granule Administration: 
Oral granules are encapsulated and may be administered either by mouth using a soft food 
vehicle, or as a suspension using a G tube/NG tube. Please see Pharmacy Manual for further 
details on preparation and administration of oral granules.
Table 10
Dosing for Oral Formulations of LET
Age 
Group
Age 
Range
BW limits
(kg)
Oral dose 
LET
(mg)
Clinical supplies 
for oral dose a, c
Oral dose 
LET (mg) 
with CsA
Clinical supplies for 
oral dose with CsA
1
12 to <18 
years
Any weight
480
2x240 mg tablets
OR
4x120 mg capsules b
240
1x240 mg tablet
OR
2x120 mg capsules b
2 
2 to <12 
years
≥30
480
4x120 mg capsules
240
2x120 mg capsules
18 to <30
240
2x120 mg capsules
120
1x120 mg capsule
10 to <18
120
1x120 mg capsule
60
2x30 mg capsules
3
Birth to <2 
years
10 to ≤15
120
1x120 mg capsule
60
2x30 mg capsules
7.5 to <10
120
1x120 mg capsules
or 
4x30 mg capsules
60
2x30 mg capsules
5.0 to <7.5
60
2x30 mg capsules
40
4x10 mg capsules
2.5 to <5.0
40
4x10 mg capsules
20
1x10 mg capsule
BW=body weight recorded at enrollment (Day 1) will be used to determine initial dosing. Dose may be 
adjusted according to the most recent body weight taken per the SoA; CsA=cyclosporin A; LET=letermovir.
a
Capsules refer to the capsules containing oral granules for administration with soft food or via G tube/NG
tube.
b
For participants unable to swallow tablets.
c
Alternate combinations may be used to achieve doses, if necessary. These alternate combinations will be 
communicated separately to investigators. 
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Dosing of IV Formulation:
For study participants who cannot swallow and/or have a condition that may interfere with 
the absorption of an oral formulation (eg, vomiting, diarrhea, or a malabsorptive condition), 
study intervention can be initiated with or switched to the IV formulation (Table 11). The IV 
formulation should be administered over a period of 60 minutes. A sterile 0.2-micron or 
0.22-micron polyethersulfone (PES) in-line filter and diethylhexyl phthalate (DEHP)-free IV 
bags and infusion set materials must be used. Use of the IV formulation should generally be 
limited to 4 weeks or less in duration. However, it will be left to the investigator’s discretion 
to continue IV administration beyond 4 weeks.
Administration of IV Formulation:
Please see Pharmacy Manual for details on preparation and administration of the IV 
formulation.
Table 11
Dosing for Intravenous Formulation LET
Age Group
Age Range
BW limits
(kg)
IV dose LETa
(mg)
IV dose LET (mg) with CsAa
1
12 to <18 years
Any weight
480
240
2 
2 to <12 years
≥30
240b
240
18 to <30
120b
120
10 to <18
60b 
60
3
Birth to <2 years
10 to ≤15
60b
60
7.5 to <10
60c
60b,c
5.0 to <7.5
40c
40b,c
2.5 to <5.0
20c
20b,c
BW=body weight recorded at enrollment (Day 1) will be used to determine initial dosing. Dose may be 
adjusted according to the most recent body weight taken per the SoA; CsA=cyclosporin A; 
LET=letermovir.
a
IV formulation concentrate to be diluted per the Pharmacy Manual.
b
Based on modeling for Age Groups 2 and 3, the IV dose of LET is reduced by 50% compared with oral 
LET in order to maintain target exposures and no further reduction of IV LET is necessary when 
coadministered with CsA.
c
Based on interim analysis results for Age Group 3, dose increase for BW limits <10 kg.
As additional PK analyses are performed during the study, the dose proposed for participants 
will be confirmed or modified. Recommendations for dose modifications will be 
communicated to investigators and sites via a PCL.
All supplies indicated in Table 9 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 .
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Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed in order to administer the 
proper dose to each participant are outlined in a separate document provided by the Sponsor.
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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
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6.3.2
Stratification
Participants in this study will be stratified by age group (birth to <2 years, 2 to <12 years, and 
12 to <18 years).
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment plan for >7 consecutive days require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
It is important for investigators to review each medication (prescription and nonprescription) 
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
6.5.1.1
Allowed Medications/Therapies That Can be Administered Without 
Monitoring
The following medications/therapies are allowed in this study without monitoring.

Standard antimicrobial prophylaxis (eg, levofloxacin for bacteria, fluconazole/
posaconazole for fungi; see Section 6.5.1.2 for recommendations on voriconazole use
when coadministered with LET)

acyclovir, or valacyclovir, for prophylaxis of herpes simplex virus (HSV) or varicella 
zoster virus (VZV) infections at doses no greater than prohibited doses of these 
medications (Appendix 10)

All types of prior conditioning regimens (including myeloablative, reduced-intensity, 
or nonmyeloablative regimens)
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
Prior/Ongoing graft manipulation regimens (including various ex-vivo or in vivo
T-cell depletion or selection regimens)

GVHD prophylaxis regimens, other than those outlined below in Section 6.5.1.2.
6.5.1.2
Allowed Medications/Therapies to be Administered with Clinical and/or 
Drug-level Monitoring
The following medications/therapies are allowed when coadministered with LET, but should 
be used with clinical monitoring for adverse events related to these agents and/or drug-level 
monitoring of these agents. 
When using an allowed concomitant medication please refer to the pediatric prescribing 
information of each local product circular. Note that all allowed medications in this section 
have pediatric prescribing information, but not all these agents have prescribing information 
covering the wide age range of participants (from birth to <18 years of age) that will be 
evaluated in this protocol. 
Note: Since the DDIs may be different when LET is coadministered with CsA, the 
combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor, 
please refer to Section 6.5.2.2 for additional recommendations when LET is 
coadministered with CsA.

CYP3A substrates:
o
Coadministration of LET with drugs that are CYP3A substrates may result in 
clinically relevant increases in the plasma concentrations of coadministered CYP3A 
substrates (examples: alfentanil, fentanyl, and midazolam). Therefore, frequent 
monitoring for adverse reactions related to these agents is recommended during 
coadministration. 
o
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 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 and the dose of CsA adjusted 
accordingly.

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 and the dose of sirolimus 
adjusted accordingly. When LET is coadministered with CsA, refer to the 
sirolimus prescribing information for specific dosing recommendations for use of 
sirolimus with CsA.
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
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 and the dose of 
tacrolimus adjusted accordingly.

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 and the dose of everolimus 
adjusted accordingly. (Note: Please see Section 6.5.2.2 for recommendations for
everolimus when LET is coadministered with CsA).
Note: LET dose adjustment is not necessary when coadministered with tacrolimus, sirolimus, 
everolimus or mycophenolate mofetil.

Certain HMG-CoA reductase inhibitors (also referred to as Statins) as substrates of 
organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and/or CYP3A:
o
Atorvastatin: The dose of atorvastatin should not exceed a daily dose of 20 mg.
(Note: Please see Section 6.5.2.2 for recommendations for the administration of 
atorvastatin when LET is coadministered with CsA). 
o
Fluvastatin, rosuvastatin, lovastatin, or pravastatin: The dose of fluvastatin, lovastatin, 
or pravastatin may need to be adjusted when coadministered with LET. Monitoring 
for statin-associated adverse reactions (eg, myalgias, rhabdomyolysis) is 
recommended during coadministration with LET. 

Substrates of CYP2C9 and CYP2C19:
o
Voriconazole: Coadministration of LET with voriconazole decreases the plasma 
concentrations of voriconazole likely due to induction of CYP2C9 and/or 2C19. If 
concomitant administration is necessary, close monitoring for reduced effectiveness 
of voriconazole is recommended.
o
Warfarin: LET may decrease the plasma concentrations of CYP2C9 and/or CYP2C19 
substrates (eg, warfarin). Frequent monitoring of international normalized ratio (INR) 
should be performed while warfarin is coadministered with LET.
o
Proton Pump Inhibitors, such as omeprazole and pantoprazole: LET may decrease the 
plasma concentrations of CYP2C19 substrates. Clinical monitoring and dose 
adjustment may be needed.
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 DDI on coadministered 
drugs may be different when LET is coadministered with CsA than when drugs are 
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coadministered with LET without CsA, additional prohibited medications when LET is 
coadministered with CsA are outlined in Section 6.5.2.2. 
Letermovir 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. While the participant 
is enrolled in the study, only LET provided by the Sponsor as study medication can be 
administered to the participant.
If there is a clinical indication for one of these or other medications specifically prohibited 
during the study, discontinuation from LET may be required. The investigator should 
discuss any questions regarding this with the Clinical Director. The final decision on any 
supportive therapy rests with the investigator and/or the participant's primary physician. 
However, the decision to continue the participant on LET requires the mutual agreement of 
the investigator, the Sponsor, and the participant.
6.5.2.1
Medications Prohibited with LET
A. Prohibited Anti-CMV Medications
The following antiviral drugs or therapies for prevention/treatment of CMV are 
prohibited through Week 24 post-transplant unless required for the initiation of PET or 
treatment of CMV disease at a CMVi visit:
o
Ganciclovir or valganciclovir
o
Foscarnet
o
Cidofovir
Note: these agents may be used for other indications while participants are on study 
therapy (eg, foscarnet for the treatment of human herpes virus 6 [HHV-6]). 
B. Other Prohibited Agents With Anti-CMV Activity
The following antiviral drugs or therapies for prevention/treatment of CMV are prohibited 
through Week 24 post-transplant:
o
Acyclovir, valacyclovir (at doses greater than those recommended for HSV/VZV 
prophylaxis: see Appendix 10), famciclovir, or letermovir (not provided by the 
Sponsor as study medication).
o
CMV hyper-immune globulin or intravenous immune globulin.
o
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, acyclovir for treatment of disseminated zoster). 
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C. Other Medications Prohibited With LET
The following medications/therapies are prohibited during treatment with study 
medication and through 28 days following the last dose of study medication:

Investigational Agents: Unapproved investigational agents or investigational 
regimens involving combinations of approved agents are not permitted except
o
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.
o
Investigational vaccines (ie, those not licensed or approved for emergency use) 
are not allowed. 
Note: any licensed COVID-19 vaccine (including for emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy. 

Herbal Supplements: Herbal supplements are not permitted.

CYP3A substrates with NTR that can lead to SAEs, including but not limited to:
o
pimozide: Concomitant administration of LET may result in increased 
concentrations of pimozide due to inhibition of CYP3A by LET, which may lead 
to QT prolongation and torsade de pointes.
o
ergot alkaloids: Concomitant administration of LET may result in increased 
concentration of ergot alkaloids (ergotamine and dihydroergotamine) due to 
inhibition of CYP3A by LET, which may lead to ergotism.

Certain Statins (Note: See Section 6.5.2.2 for additional statins that are prohibited for 
use when LET is coadministered with CsA):
o
simvastatin and pitavastatin. 
o
Fixed-dose combinations of statins.
• Rifampin and other strong inducers (such as phenytoin, carbamazepine, St John’s 
wort [Hypericum perforatum], rifabutin and phenobarbital) and moderate inducers 
such as nafcillin, thioridazine, modafinil, and bosentan.
6.5.2.2
Additional Medications Prohibited when LET is Coadministered with CsA
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on coadministered 
drugs may be different when LET is coadministered with CsA. Medications listed in this 
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section pertain to coadministration with LET with 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.
When used together, they should be administered in a manner consistent with the local 
product circulars (for CsA and if available, for LET), including the complete list of 
prohibited medications including those that are contraindicated or not recommended. For
example, the SmPC for LET has additional contraindications when LET and CsA are 
administered; the local product circular for LET supersedes this section when the product 
circular is more restrictive.

Certain statins: When LET is coadministered with CsA, the magnitude of the increase 
in statin plasma concentrations is expected to be greater than with LET alone. 
o
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 6.5.1.2 for recommendation for everolimus 
when coadministered with LET alone).

repaglinide 
6.5.3
Rescue Medications and Supportive Care
In the event of CS-CMVi (CMV disease or initiation of PET based on CMV viremia and the 
clinical condition of the participant [see Section 4.2.1.3]) at any time during the 14-week 
post-transplant period, study intervention 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 4.3.1 for the LET dose to be used with or without coadministered CsA.
If CsA is initiated after starting study intervention, the next dose of LET (administered up to 
24 hours later) should be decreased as applicable. If CsA is discontinued permanently or for 
the long term in a participant already receiving LET, the next dose of LET (administered up 
to 24 hours later) should be increased as applicable. If CsA is temporarily withheld due to 
high levels detected by therapeutic blood monitoring, the dose of LET 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.
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6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.10.
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 pregnancy test.

The participant develops CS-CMVi as determined by the investigator (Section 
4.2.1.3).

The participant develops (one or more of the following):
o
An elevated AST or ALT lab value that is ≥3 × ULN and an elevated total 
bilirubin lab value that is ≥2 × ULN and, at the same time, an alkaline 
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phosphatase lab value that is <2 × ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing
o
Both moderate hepatic insufficiency (Child-Pugh Class B; Appendix 9) and 
moderate-to-severe renal insufficiency (defined as creatinine clearance
<50 mL/min as calculated by the Cockcroft-Gault equation (for Age Group 1) 
or <50 mL/min per 1.73 m2 as calculated using the modified Schwartz 
equation (for Age Group 2); Participants in Age Group 3 should be 
discontinued if they have moderate hepatic insufficiency and creatinine 
clearance <20 mL/min per 1.73 m2 calculated using the modified Schwartz 
equation; see Appendix 12 for Cockcroft-Gault and modified Schwartz 
equations.
o
Severe hepatic insufficiency (Child-Pugh Class C; Appendix 9).
o
Either 
a) a need for renal replacement therapy (eg, hemodialysis, peritoneal dialysis)
OR
b) has end-stage renal impairment with creatinine clearance ≤10 mL/min as 
calculated by the Cockcroft-Gault equation (for participants ≥12 years of age) 
or ≤10 mL/min per 1.73 m2 as calculated using the modified Schwartz 
equation (for participants <12 years of age; Appendix 12).

For Age Group 3 participants only, the IV formulation of LET should be 
discontinued when the creatinine clearance (as determined by the using the modified 
Schwartz equation) meets the following criteria:
• decreases by ≥50% from the baseline value (ie, on the day IV LET was 
initiated) 
AND
• is below the lower bound of normal creatinine clearance for the age at the time 
of assessment (Table 12).
•
Note: The decrease in creatinine clearance should be confirmed by repeat testing as 
soon as possible. The confirmatory sample should be obtained no later than 4 days 
following the report of the first test result. If confirmed, the IV formulation should be 
discontinued.
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Table 12
Lower Bound of Creatinine Clearance by Age
Age at time of assessment
Lower bound of normal creatinine clearancea, b
18 months to <2 years
≥76 mL/min/1.73m2
12 to <18 months
≥73 mL/min/1.73m2
8 to <12 months
≥65 mL/min/1.73m2
14 weeks to<8 months
≥57 mL/min/1.73m2
6 to <14 weeks
≥47 mL/min/1.73m2
2 to <6 weeks
≥41 mL/min/1.73m2
1 to <2 weeks
≥35 mL/min/1.73m2
Birth to <1 week
≥20 mL/min/1.73m2
a
Modified Schwartz equation used to calculate creatinine clearance (Appendix 12.1).
b
Lower bound of normal creatine clearance taken from published lower bound standard deviation of age-
appropriate means (Biron, Schwartz).
[Brion, L. P., et al 1986] [Schwartz, G. J. 2009]
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Study 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 used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, 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 vary; see Appendix 2.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this clinical 
study or FBR . If there are changes to the participant’s status during the study (eg, health or 
age of majority requirements), the investigator or medically qualified designee must ensure 
the appropriate documented consent/assent is in place.
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8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the trial protocol 
number, trial protocol title, dated signature, and /agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent discussion. 
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial informed consent/assent form, any subsequent revised consent/assent, and any 
written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use. The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study. 
The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s or their 
legally acceptable representative’s dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. 
The assent, as applicable, will adhere to IRB/IEC requirements, applicable laws and 
regulations and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the FBR consent/assent to the 
participant, or the participants legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent/assent before performing any procedure 
related to FBR. A copy of the informed consent/assent will be given to the participant before 
performing any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee
to ensure that the participant qualifies for the study.
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 utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a participant identification 
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card immediately after the participant provides documented informed consent/assent. At the 
time of intervention allocation/randomization, site personnel will add the 
treatment/randomization number to the participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee 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 medication taken by the participant within 30 
days prior to enrollment will be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All concomitant medications should be reviewed and documented while participants are on 
study intervention.
Anti-CMV medications administered for treatment of CMV disease or for initiation of PET, 
medications used for HSV/VZV prophylaxis, and all drug/biologic therapies used to 
prevent/treat GVHD should be recorded at every visit through Week 48 post-transplant.
During the follow-up period (after Week 14 post-transplant through Week 48 post-transplant
or from the time the participant stops taking the study intervention through Week 48 post-
transplant), concomitant medication review is limited to the above and all antimicrobials 
(antibacterials, antifungals, antiparasitic agents and antivirals), chemotherapy agents, and 
immunosuppressant agents.
8.1.6
HSCT Details Review
All relevant data about the HSCT will be collected on Day 1 (enrollment). This includes 
details regarding the conditioning regimen used, the date and type of transplant, primary 
reason for transplant, the source of stem cells, type of graft manipulation, presence of 
GVHD, and GVHD prophylaxis regimen (if any) used.
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8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to allocation. Each participant will 
be assigned only 1 screening number. Screening numbers must not be re-used for different 
participants.
Those participants who meet laboratory exclusion criteria may have the testing repeated one 
time as described in Section 5.2. Only the exclusionary lab is to be retested. Any individual 
who has more than one screening will retain the original screening number assigned at the 
original screening visit.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
randomization number. The randomization number identifies the participant for all 
procedures occurring after randomization. Once a 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 randomization number.
8.1.9
Study Intervention Administration
The first dose of study intervention will be administered at the study site on Day 1 after 
enrollment/allocation. A sample for CMV DNA PCR must be collected prior to initiating
study intervention.
The oral granules may be administered by mouth (with a soft food vehicle), or via a G
tube/NG tube. Refer to Pharmacy Manual for further details on preparation and 
administration of oral granules. 
For IV formulation, the study pharmacist (or appropriately qualified designee) will be 
responsible solely for the preparation of the IV study intervention. The IV formulation will 
be administered by site personnel through a sterile 0.2-micron or 0.22-micron PES in-line 
filter and using DEHP-free IV bags and infusion set materials. Refer to the Pharmacy Manual 
for further details on preparation and administration of the IV formulation.
Please refer to Section 6.1 for details regarding administration of oral granules.
8.1.9.1
Timing of Dose Administration
Study intervention should be taken at approximately the same time each day for the duration 
of the treatment period of the study (once daily for LET). Treatment compliance is further 
described in Section 6.4.
If a participant misses a dose of LET, the missed dose should be taken as soon as possible 
during the same day. Then, the next dose should be taken at the normally scheduled time. 
However, if more than 12 hours have elapsed after the regular dosing time, then the missed 
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dose should be skipped, and the normal dosing schedule should be resumed. The next dose 
should not be doubled in order to “make up” what has been missed.
If a participant vomits within 2 hours of an administration of tablets or oral granules, the full 
dose can be repeated one time within 6 hours of vomiting. If a participant vomits and it has 
been longer than 2 hours from the time of an administration of tablets or oral granules, the 
dose should not be repeated. Instead, the next dose should be taken at the usual time the 
following day.
8.1.9.2
Study Medication Diary 
For hospitalized participants receiving either LET oral tablets or granules, study intervention 
will be recorded in the participant’s chart; this will serve as the source document. For 
participants receiving oral tablets or granules outside of the hospital setting (ie, receiving oral 
LET at home), study intervention will be recorded in a paper study medication diary (SMD). 
The investigator/study coordinator will review and provide instructions to the 
participant/legally acceptable representative on the use of the SMD, which is to be completed 
during the treatment period of the study. The investigator/study coordinator will be 
responsible for entering the participant’s identification (randomization/allocation number), 
visit weeks, the diary distribution date, and the information to indicate the appropriate dosage 
form and quantity before giving the SMD to the participant/legally acceptable representative. 
The participant/legally acceptable representative will be instructed on proper storage, 
preparation and administration of LET oral granules and to use the SMD to record 
dates/times and the number of tablets/capsules of LET dosed for the entire treatment period;
participants on oral granule formulation given by mouth will also record soft food 
information, whether the entire dose was consumed and the timeframe over which the dose 
was consumed. Participants on oral granules administered via G tube/NG tube will record 
whether the entire dose was given. In addition, the reason for any missed or incorrect doses 
or entire dose not being consumed/given will need to be recorded. Only the 
participant/legally acceptable representative should enter information into the SMD. The 
participant/legally acceptable representative is to return the completed SMD at each 
scheduled visit. 
For all visits during the treatment period, site personnel are required to verify the accuracy of 
the dosing recorded in the SMD by comparing entries with amounts of unused study 
medication. If a discrepancy is noted, the investigator/study coordinator must discuss the 
discrepancy with the participant, and the explanation must be documented. The 
investigator/study coordinator will be responsible for transferring the appropriate information 
from the SMD to the appropriate CRF.
Training participants/legally acceptable representative on administration of oral 
granules
For participants discharged on oral granules to be administered either by mouth or via
G tube/NG tube on an outpatient basis, site personnel must provide training to the 
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participant/legally acceptable representative on preparation and administration of the 
oral granules prior to discharge, preferably during the preceding week (refer to the 
Pharmacy Manual on detailed instructions; instructions are also briefly provided in the 
SMD). Such training also should be provided when the route of administration of oral 
granules changes (eg, from G tube/NG tube to administration by mouth). Documentation of 
such training and that the participant/caregiver has understood the instructions and will be 
able to take the oral granules correctly must be entered in the participant’s chart, which will 
serve as the source document. 
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Study 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 .
8.1.10.1
Withdrawal From Future Biomedical Research
A Participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate). A participant’s consent 
may be withdrawn at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@msd.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
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8.1.12
Domiciling
For participants who will undergo intensive PK sampling, the investigator should make 
arrangements (including local accommodations outside the context of hospitalization, if 
needed/warranted) such that all PK sampling at specified time points can be performed as 
scheduled.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
CMV DNA PCR Testing
CMV DNA PCR testing will be performed using a qualitative or quantitative CMV DNA 
PCR assay at the local laboratory. The same PCR assay method should be used for testing 
throughout the study for each individual participant. When available, quantitative CMV 
DNA PCR is preferable over qualitative testing. After the initial screening visit until 
enrollment, samples must be collected and tested once per week. The test should be repeated 
one more time within 5 days of the planned enrollment date to ensure the result is still 
negative. Thereafter, samples will be collected as indicated in the SoA (Section 1.3). CMV 
DNA PCR testing may be conducted within 3 days prior to a scheduled study visit and no 
later than the day of the scheduled study visit. (This CMV DNA PCR testing window is not 
applicable to a CMV Infection Visit).
For participants who develop CS-CMVi (through 24 weeks post-transplant): When the 
investigator intends to initiate either treatment for CMV disease or PET, the participant 
should have a CMV Infection Visit. It is very important to ensure that all procedures, as 
outlined in the SoA (Section 1.3), are performed at the CMV Infection Visit immediately 
prior to the initiation of treatment of CMV diseases or initiation of PET (ie, on the same day 
anti-CMV therapy or PET is initiated). Thereafter, the participant should be discontinued 
from LET (if applicable) and treated according to the local standard of care (outside the 
context of the study). Such participants will continue to be followed in the study (despite 
discontinuing study intervention and initiating anti-CMV therapy) and complete all 
remaining study visits (including all subsequent treatment period visits). At such subsequent 
visits, all procedures specified in the SoA (Section 1.3) should be completed with the 
exception of study intervention administration, PK assessments and palatability assessments. 
Additional CMVi Visit(s) are also required for every new episode of CS-CMVi following the 
initial episode through Week 24 post-transplant.
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Note on re-initiation of study intervention: There may be instances when lab test results 
for CMV DNA PCR obtained on the day of PET initiation may be negative (CMV DNA 
undetectable) and the investigator may wish to discontinue PET. The decision to stop PET in 
the event of a negative (CMV DNA undetectable) result collected on the day of PET 
initiation resides with the investigator caring for the participant. Therefore, in the event the 
CMV DNA sample at PET initiation is negative for CMV viremia, the Sponsor will allow for 
LET to be restarted at the investigator’s discretion, once PET is discontinued. In such 
instances, study intervention should be restarted within 7 days from the date on which study 
intervention was stopped. It is important to note that the status of the participants’ study 
intervention in IRT should NOT be changed until the investigator is certain that LET 
prophylaxis will be permanently discontinued.
Assessment of CMV Disease
CMV disease will be assessed at every visit from screening through Week 24 post-transplant. 
Diagnostic criteria for the evaluation of CMV disease are outlined in Appendix 8. If CMV 
Disease is suspected, site should perform the CMV Infection Visit instead of the scheduled 
visit assessments (Section 1.3). The investigator will ensure that clinical information, 
radiology results, and specimens for the appropriate diagnostic tests (including, but not 
limited to, viral culture, histopathology, immunohistochemical analysis, in situ hybridization, 
CMV DNA PCR) as outlined in Appendix 8 will be collected. Both “probable” or “proven” 
cases of CMV disease should be reported.
8.2.2
CMV DNA Sequence 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 CS-CMVi at the CMV infection visit. 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 SoA (Section 1.3) with 
detectable CMV viral DNA. Samples will be analyzed by next generation sequencing 
technology through an established contract laboratory with validated protocols in place. In 
participants with multiple CMV-positive samples, the last on-therapy and/or follow-up 
samples will be used for analysis. 
Because plasma volume collection is limited in the pediatric population compared with 
adults, actual sample volume collected may be less than expected. If insufficient plasma is 
available for resistance genotyping of all 3 CMV terminase complex genes, testing of the 
UL56 gene will be prioritized. In vitro studies have confirmed that substitutions in the UL56 
protein are both necessary and sufficient for LET resistance. Mutations in the UL89 and 
UL51 genes alone have little impact on LET activity, but further decrease LET potency in 
combination with UL56 mutations in vitro. Therefore, UL56 gene sequencing will be 
prioritized for participants receiving LET who meet the criteria for CS-CMVi. UL89 and 
UL51 sequencing will also be attempted, provided sufficient plasma is available. 
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Phenotypic analysis may be performed on any UL56, UL89, or UL51 DNA sequences, which 
encode amino acid substitutions that have not been previously characterized via phenotypic 
analysis. 
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study for research testing, including approximate blood/tissue volumes drawn/collected 
by visit and by sample type per participant, can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at visits specified 
in the SoA (Section 1.3). The complete physical examination includes the following 
assessments: general appearance, head, eyes, ears/nose/throat, neck, lymph nodes, skin, 
lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, rectal, and 
genitourinary/pelvic exams should be performed when clinically indicated.
A brief directed physical examination may be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard at any 
other visit when clinically indicated.
Height and weight will be measured and recorded per the SoA. Weight will be used to guide 
LET dosing. Body weight recorded at enrollment (Day 1) will be used to determine the 
initial dosing. Dose may be adjusted according to the most recent body weight taken per 
the SoA. Height and weight will be measured per SoA to monitor creatinine clearance, as 
calculated by the Cockcroft-Gault equation (for participants ≥12 years of age) or by the 
modified Schwartz equation (for participants <12 years of age) using serum creatinine 
(Appendix 12).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be assessed as indicated in the SoA (Section 1.3). 
Vital signs will include heart rate, blood pressure, respiratory rate, and body temperature 
(oral). Participants should be resting for at least 5 minutes prior to measurement of vital 
signs.
Note: Temperatures should be taken orally, but if oral is not possible, tympanic, rectal, and 
axillary temperatures are acceptable.
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Vital signs will be measured after 5 minutes’ rest and will include temperature, systolic and 
diastolic blood pressure, pulse, and respiratory rate.
8.3.3
Electrocardiograms
Single 12-lead electrocardiogram (ECG) will be obtained and reviewed locally by an 
investigator or medically qualified designee (consistent with local requirements) as outlined 
in the SoA (Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. 
Participants should be shaved (if necessary) for proper lead placement. Participants should be 
resting for at least 5 minutes prior to having ECG readings obtained.
8.3.4
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements)
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Date of Menarche
The date of menarche must be recorded for females who have previously experienced 
menarche. Once a date of menarche has been confirmed, the participant is considered to be a 
woman of child bearing potential (WOCBP). For prepubescent females, site staff should 
continue to review and record, as appropriate, at each visit during the treatment period.
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8.3.6
Confirmation of Contraception (WOCBP Only)
Throughout the screening and treatment periods, precaution must be taken to avoid 
pregnancy in WOCBP. Confirmation must be obtained and documented by site personnel 
that WOCBP are using acceptable methods of contraception (Appendix 5). This assessment 
must be documented in the participant's study chart at each specified visit.
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. Investigators need to document if an AE 
and/or SAE was associated with a medication error, misuse, or abuse.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization must be 
reported by the investigator if the participant dies, is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
From the time of treatment allocation/randomization through 28 days following cessation of 
treatment, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Thereafter, only SAEs related to study medication or SAEs leading to death will be collected 
through Week 48 post-transplant.
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 
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death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated Table 13.
Table 13
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/
Allocation through 
Protocol-Specified 
Follow-up Period
(28 days following
last dose of study 
medication)
Reporting Time 
Period:
After the Protocol-
Specified Follow-
up Period (from 28 
days following last 
dose of study 
medication through 
Week 48 post-
transplant)
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Non-Serious 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:
- death due to any 
cause 
- 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/termina
tion; report 
outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (ECI) 
(require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI) 
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/
Allocation
Reporting Time 
Period:
Randomization/
Allocation through 
Protocol-Specified 
Follow-up Period
(28 days following
last dose of study 
medication)
Reporting Time 
Period:
After the Protocol-
Specified Follow-
up Period (from 28 
days following last 
dose of study 
medication through 
Week 48 post-
transplant)
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 
calendar days of 
learning of event
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.
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]).
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Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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:

Potential DILI events defined as an elevated AST or ALT lab value that is greater than or 
equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is 
greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than 2 times the prescribed dose specified in 
Section 6.6 (Dose Modification [Escalation/Titration/Other]).
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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
Plasma samples for sparse PK will be collected in all participants. 
Plasma samples for intensive PK (oral formulation) will be collected from all participants in 
Panel A of Age Groups 1 and 2 who receive oral LET formulation (by mouth or G tube/NG 
tube) from Day 1 until Day 7 visit. Additionally, plasma samples for intensive PK (IV 
formulation) will be collected for any study participant who receives at least 5 consecutive 
days of IV dosing and has not had prior intensive PK collected on the oral formulation. The 
proposed PK sampling scheme for sparse PK and intensive PK across all age groups is 
provided in Table 14.
8.6.1
Blood Collection for Letermovir Pharmacokinetic Sampling
Sample collection, storage, and shipment instructions for PK samples will be provided in the 
laboratory manual. PK samples should not be collected in participants after discontinuation 
of study intervention.
On all PK visits where a predose sample will be collected, the visit should occur prior to the 
participant’s regular time for taking their study intervention and the participant should 
withhold their dose until after the predose sample is drawn. If it is not feasible to schedule the 
visit prior to the participant’s regular time for taking their study intervention, the participant 
should withhold their dose until reporting to the clinic. The predose PK sample will be 
obtained and the next scheduled dose will then be administered at the clinic. The date and 
time of each PK sample as well as the date and time of the last dose of study medication prior 
to the PK sample will be recorded.
For participants receiving oral granules in soft food, the soft food vehicle used to administer 
the last dose of study medication prior to the PK sample as well as the day of the PK sample 
will also be recorded. For participants receiving oral granules via G tube or NG tube, the use 
of these tubes will be recorded.
If a participant vomits following administration of oral LET while intensive PK sampling is 
ongoing, no further samples should be collected, and the Sponsor should be informed to
determine further course of action. 
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Table 14
Pharmacokinetic Sampling for Protocol 030
PK Type
LET Route of 
Administration
Study Visit
PK Sample Timesa
Primary 
PK 
Parameters
Other 
PK 
Parameters
Intensive 
PK for 
LET
Oral 
Formulationsb
Day 7c
(Days 7-9)
Predose (0 to 20 min before 
dose)
1 h (± 10 min)
2.5 h (± 30 min)
8 h (± 2 h)
24 h (0 to 2 h before next 
dose)
AUC0-24h
Cmax
Ctrough
Tmax
t1/2
CL/F
Vd/F
IVd
Any
Predose (0 to 20 min before 
IV infusion begins)
1 h (0 to 10 min after IV 
infusion ends)
2.5 h (± 30 min)
8 h (± 2 h)
24 h (0 to 2 h before next 
dose)
AUC0-24h
Ceoi
Ctrough
t1/2
CL
Vd
Sparse 
PK for 
LET
Oral 
Formulationsb
Weeks 2, 4, 6, 
8, 10, 12, 14, 
CMVie or 
Early Discone
Visits
Predose (0 to 2 h before dose)
Ctrough
IV
Weeks 2, 4, 6, 
8, 10, 12, 14
Predose (0 to 2 h before IV 
infusion begins)
Ctrough
HPCD 
PK
sampling
IV
See notef
1 h after initiating the IV 
infusion (within 10 mins of 
ending a 60 min IV infusion)
on the 4th consecutive day of 
IV infusion
24 h after initiating the IV 
infusion (0 to 2 hours before 
the next dosing) on the 5th
consecutive day of IV LET 
administration
PK
exploratory 
parameters
IV
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PK Type
LET Route of 
Administration
Study Visit
PK Sample Timesa
Primary 
PK 
Parameters
Other 
PK 
Parameters
AUC0-24h=area under the concentration-time curve from time 0 to 24 hours; CEIO=concentration at the end 
of infusion; CL= clearance; Cmax=maximum concentration; CMVi=cytomegalovirus infection; Ctrough= 
trough concentration; Discon=discontinuation; F=bioavailability; h=hour(s); HPCD=hydroxypropyl-beta-
cyclodextrin; IV=intravenous; LET=letermovir: min=minute; min(s)=minute(s); PK=pharmacokinetics; 
t1/2=apparent half-life; Tmax=time to maximum concentration; Vd=apparent volume of distribution.
a Sample collection times for IV formulation are relative to start of IV infusion, with acceptable ranges 
noted.
b The oral formulations may be tablets or oral granules. Oral granules may be administered either by mouth 
or via G tube/NG tube, provided the participant does not have a condition that may interfere with the 
absorption of oral formulation (eg, vomiting, diarrhea, or a malabsorptive condition).
c All participants in Panel A of Age Groups 1 and 2 who receive oral formulation of LET from Day 1 until 
Day 7 visit will have intensive PK on Day 7. All participants in Age Group 3 will have intensive PK 
sampling done regardless of the formulation received (starting on either the fifth day of IV LET or the 
seventh consecutive day of oral LET, whichever comes first).
d Intensive PK on IV formulation will be collected from participants who have NOT had intensive PK on the 
oral formulations (oral granules/oral tablet); sample collection will start on the 5th consecutive day of IV 
dosing.
e Collected only if the participant is still on LET at the CMVi or Early Discontinuation Visit and the visit 
occurs on or before Week 14.
f Start on the 4th consecutive day of IV dosing for participants in Age Group 3.
8.6.2
Blood Collection for HPCD Pharmacokinetic Sampling
Whole blood will be collected from Age Group 3 participants starting on the fourth
consecutive day of IV LET administration, as follows:

The first sample on that day will be taken 1 hour after initiating the IV infusion 
(within 10 minutes of ending the 60 minute infusion). 

The second sample must be taken 24 hours after initiating the IV infusion (0 to 2 
hours before the next dosing) on the fifth consecutive day of IV LET administration. 
The central laboratory manual contains instruction for sample handling and processing.
All Age Group 3 participants, for whom HPCD sampling is collected, will also need 
local laboratory testing for serum creatinine levels to correlate any changes in creatinine 
clearance with HPCD levels as outlined in Section 8.6.2.1.
8.6.2.1
Additional Creatinine Clearance Measurements for Participants in Age 
Group 3 Receiving Intravenous Letermovir Formulation
Timepoints for collection of HPCD PK and creatinine clearance measurements (which would 
require local laboratory testing for serum creatinine) depend on the number of consecutive 
days of IV LET and whether it is the initial or subsequent IV LET dose (Table 15). 
Creatinine clearance measurements should be repeated every time a subsequent course of IV 
formulation is initiated.
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Table 15
Creatinine Clearance Timepoints for Age Group 3 Participants Receiving 
Intravenous Letermovir
Course and Duration 
of IV LET
Collection of 
HPCD PK 
Sampling
(Yes/No)
Collection of 
Creatinine 
for Creatinine Clearance
First course ≥4 days at 
any time during 
treatment
Yes

1st day of IV LET administration (prior to initiating IV LET)

0 to 2 hours before the next dose of LET (at the same time as 
the second HPCD PK sample is collected)

last day of IV LET (immediately after discontinuing the 
infusion, if IV LET continues beyond 5 consecutive days)
All other course(s)
regardless of duration
No

1st day of IV LET administration (prior to initiating LET)

last day of IV LET (immediately after discontinuing the IV)
HPCD=hydroxypropyl-beta-cyclodextrin; IV=intravenous; LET=letermovir.
8.7
Pharmacodynamics
No pharmacodynamic parameters will be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant provides documented informed consent/assent for FBR, the following 
specimens will be obtained as part of future biomedical research:

Residual DNA from buccal swab for future research

Leftover plasma from CMV viral resistance samples stored for future research.
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for buccal swabs will be provided in 
the laboratory manual.
8.10
Palatability and Acceptance Assessment
The PAA (Appendix 11) is to be completed for all participants on the first day of oral granule 
administration and repeated one week later. The PAA should be implemented with the 
following recommendations: 

From Birth to Age 4 years: Completion by an observer (legally acceptable 
representative/caregiver/health care provider).
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
Ages 5 to 13 years: Combined completion where the participant completes the faces 
question, and the observer completes the remaining questions.

Ages 14 to less than 18 years: Completion directly by the participant, preferred when 
possible.
Observer assessments should be based on what the legally acceptable 
representative/caregiver/health care provider has observed directly during and after 
medication administration, including the participant’s facial expressions, behavior, and what 
the participant says. Only individuals who have actually observed the participant taking the 
medication should complete the assessment.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Screening of potentially eligible participants may begin within 15 days prior to 
transplantation, but enrollment/allocation must occur no later than 28 days post-transplant. 
The informed consent and assent (as applicable) must be obtained before any study-specific 
procedure is performed. Potential participants will be evaluated to determine if they fulfill the 
Inclusion/Exclusion entry requirements as described in Sections 5.1 and 5.2. All screening 
procedures listed under Visit 1 of the Study SoA (Section 1.3) will be performed. Laboratory 
tests including chemistry, hematology, urinalysis, prothrombin time (PT)/coagulation, HIV, 
and hepatitis B and C tests will be performed locally. As noted in Section 5.2, participants
who meet laboratory exclusion criterion 6 or 7, at the discretion of the investigator, may have 
repeat testing done one time within 5 days prior to enrollment.
Participants who are WOCBP will be instructed that they are required to use birth control as 
specified in Appendix 5 starting from the time of consent through 28 days after the last dose 
of study intervention (or longer if dictated by local regulations). Participants will also be 
instructed about the restrictions for concomitant medications, as noted in Section 6.5.
Presence of CMV disease in the screening period will be assessed according to Appendix 8.
8.11.2
Treatment Period Visits
Study intervention (LET) may begin as early as the day of transplant and no later than 28 
days post-transplant. Study intervention will continue through Week 14 (~100 days) 
post-transplant. Study visits will occur weekly through Week 14 (~100 days) post-transplant. 
For the purposes of this study, “Treatment Period” refers to the period from Day 1 through 
Week 14 post-transplant, regardless of when a participant may have discontinued treatment 
with LET.
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The Day 1 Visit (as shown in the SoA, Section 1.3.1) will be day the participant is 
enrolled/allocated and LET is initiated. Study intervention will continue through the End of 
Treatment Visit. The End of Treatment Visit may occur at the Week 10, 11, 12, 13, or 14 
Visit depending on when study intervention is started during the 28-day post-transplant 
window. For example, if LET is started on the day of transplant, the End of Treatment Visit 
will be the Week 14 Visit (which corresponds to Week 14 post-transplant). If LET is started 
28 days post-transplant, the End of Treatment Visit will be the Week 10 Visit (which 
corresponds to Week 14 post-transplant).
All procedures listed under the study visits in the SoA (Section 1.3.1) will be performed at 
the corresponding visit. After allocation, a complete physical examination does not need to 
be performed at every visit; a targeted physical examination should be performed only when 
clinically indicated. 
8.11.2.1
Day 1 Visit
Day 1 procedures/assessments listed on the SoA (Section 1.3.1) must be performed prior to 
initiation of study intervention. The weight of the participant on Day 1 will be used to 
determine LET dose (Section 6.1).
For female participants of childbearing potential, a urine or serum pregnancy test will be 
performed at the site prior to the initiation of study intervention. 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 allocated.
8.11.2.2
Study Intervention Administration Visit
Following completion of the Day 1 procedures/assessments and confirmation of eligibility, 
the participant will be allocated/enrolled. Sites should not allocate the participant for study 
intervention (LET) administration until the participant has met all eligibility criteria for the 
study and is ready to receive the first dose of LET on Day 1. The site pharmacist or study 
coordinator will contact the IRT for assignment to allocate the participant to LET. The dose 
of LET will be determined by the participant’s weight at Day 1, the formulation 
administered, and by whether the participant is receiving concomitant CsA (see Section 6.1 
for specific details of dose selection and administration instructions). Dose may be adjusted 
thereafter, according to the most recent body weight taken per the SoA
Participants in Panel A of Age Groups 1 and 2:

Must initiate LET using an oral formulation (either tablets or oral granules; oral 
granules may be administered by mouth or via G tube/NG tube) from the day of 
enrollment through the completion of the intensive PK sampling at the Day 7 visit. 

May not receive concomitant administration of CsA from the day of enrollment 
through the completion of the intensive PK sampling at the Day 7 visit.
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
These restrictions are not applicable to participants enrolled in Age Group 1 (Panel B 
only), Age Group 2 (Panel B only), or for participants in Age Group 3; although all 
participants should preferably be initiated on oral LET formulation. In the event that a 
participant enrolled in Panel A has a need to either (1) switch to IV formulation 
administration or (2) to have CsA coadministered prior to the Day 7 visit, they may 
do so and will be permitted to continue on LET as appropriate. In such an event, the
participant will not have intensive PK samples drawn at the Day 7 visit. If a 
participant switches to IV formulation or has a new requirement for CsA 
coadministration, the site is required to notify the Sponsor immediately. The Sponsor 
will make arrangements for an additional participant to be enrolled in the 
corresponding panel to maintain n=6 PK-evaluable participants.
In the event that participants who were initiated on an oral formulation subsequently develop 
a condition (eg, vomiting, diarrhea, or a malabsorptive condition) that may interfere with the 
absorption of the tablets, these participants can be switched to the IV formulation. For 
participants who are switched to the IV formulation (Panel A or B), or who initiated with the 
IV formulation (Panel B only), these participants should be switched to oral LET as soon this
participant is able to swallow and/or the condition necessitating the use of the IV formulation 
resolves (ie, at the next planned dose). Use of the IV formulation should generally be limited 
to 4 weeks or less in duration; however, it will be left to the investigator’s discretion to 
continue IV administration beyond 4 weeks, if the benefit/risk ratio supports continued 
administration.
LET may be used with or without concomitant CsA. See Section 6.1 for the LET dose to be 
used with or without coadministered CsA and for details of study drug modification if 
concomitant CsA is initiated or discontinued.
8.11.2.3
Additional Treatment Period Visits
Procedures/assessments listed on the SoA (Section 1.3.1) must be performed at all the 
weekly study visits during the treatment period.
Throughout the treatment period precaution must be taken to avoid pregnancy in WOCBP. 
Confirmation must be obtained and documented by site personnel that WOCBP are using 
acceptable methods of contraception (Appendix 5). This assessment must be documented in 
the participant's study chart at each specified visit.
From Day 1, through Week 14 (~100 days) post-transplant participants will be assessed for 
CMV disease and CMV DNA PCR should be tested at the local laboratory as per the SoA 
(Section 1.3.1). 
8.11.3
Follow-up Period/Visits
As stated in Section 8.11.2, participants will receive study intervention with LET for 14 
weeks post-transplant (ie, participants will receive approximately 10 to 14 weeks of LET 
depending on initiation of study intervention in relation to the date of transplant). After the 
last day of study intervention, participants will be followed via study visits at the site from 
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Week 16 to Week 24 post-transplant. These visits will occur every 2 weeks and all 
procedures listed in the SoA (Section 1.3.2) corresponding to the visits will be performed. 
All participants will continue to be assessed for CMV disease through Week 24 post-
transplant and CMV DNA PCR should be tested at the local laboratory as per the SoA 
(Section 1.3). 
Subsequent post treatment follow-up visits will occur at Weeks 32, 40, and 48 post-transplant 
(telephone contact) and all procedures listed in the SoA (Section 1.3.2) corresponding to the 
visits will be performed. 
Adverse event monitoring should include the collection of all adverse events while on study 
intervention and for 28 days following completion of study intervention in all participants. 
Thereafter, only drug-related SAEs and SAEs leading to death will be collected through 
Week 48 post-transplant. 
8.11.4
Participants Discontinuing Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study intervention (LET) for any reason will continue to be 
followed in the study as outlined in the Study SoA (Section 1.3.1), provided informed 
consent has not been withdrawn. 
8.11.4.1
Discontinuation of Study Intervention Due to CS-CMVi
As all participants in the study will receive the study intervention (LET) through Week 14 
post-transplant, LET should be discontinued when the CMV infection Visit occurs prior to 
the End of Treatment Visit. A sample for CMV DNA PCR should be collected 
immediately prior to the initiation of PET or treatment of CMV disease. Such 
participants will continue to be followed in the study (despite discontinuing LET and 
initiating anti-CMV therapy) and complete all remaining study visits (including all 
subsequent treatment period visits). All procedures as outlined in the SoA (Section 1.3.1),
with the exception of study intervention administration, PK sampling, collection of samples 
for PT/INR, Child-Pugh score assessments, and study medication diary review, will be 
performed for the remainder of the study.
8.11.4.2
Discontinuation of Study Intervention for Reasons Other Than CS-CMVi
Participants who discontinue study intervention (LET) prior to the last scheduled treatment 
visit for reasons other than CS-CMVi (eg, for an AE) will continue to be followed in the 
study and complete all remaining study visits regardless of when cessation of study 
intervention occurs. All procedures as outlined in the SoA (Section 1.3.1), with the exception 
of study intervention administration, PK sampling, collection of samples for PT/INR, Child-
Pugh score assessments, and study medication diary review, will be performed for the 
remainder of the study.
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8.11.5
Discontinuation from Study
8.11.5.1
Study Discontinuation Prior to Week 24 Post-transplant:
Participants who prematurely discontinue the study (eg, withdrawal of consent) prior to 
Week 24 post-transplant will have an Early Study Discontinuation Visit. It is important to
ensure that all procedures, as outlined in the Study SoA (Sections 1.3.1 and 1.3.2), are 
performed for such participants at this visit prior to discontinuing the participant from the 
study. A sample for CMV DNA PCR testing should be collected at this visit.
8.11.5.2
Study Discontinuation After Week 24 Post-transplant
All participants who are discontinued from the study after Week 24 post-transplant should 
have all information collected at the last visit (as outlined in the Study SoA, Section 1.3.2), 
prior to discontinuing the participant from the study.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in 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 to 9.12. 
Study Design Overview
A Phase 2b open-label, single-arm study to evaluate pharmacokinetics, 
safety, efficacy and acceptability/palatability of LET in pediatric 
participants from birth to less than 18 years of age at risk of developing 
CMV infection and/or disease following allogeneic haematopoietic 
stem cell transplantation (HSCT).
Treatment Assignment
This will be an open-label, nonrandomized study. 
Analysis Populations
Pharmacokinetics: Per Protocol (PP) 
Safety: All Participants as Treated (APaT)
Efficacy: Full Analysis Set (FAS)
Primary Endpoint(s)
AUC0-24, Cmax, (for participants receiving oral formulation), Ceoi, 
(for participants receiving IV formulation), and Ctrough
Key Secondary Endpoints
Safety: Number of participants experiencing 
• Adverse Events (AEs)
• AEs Resulting in Study Medication Discontinuation
Efficacy: Clinically significant CMV infection (CS-CMVi) through 
Week 14 post-transplant and through Week 24 post-transplant.
Palatability: Score on a palatability scale
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Statistical Methods for Key 
Pharmacokinetic/ Efficacy
Analyses
AUC0-24, Cmax, and Ctrough will be calculated, and geometric means 
and 95% confidence intervals (CIs) will be provided for AUC0-24, 
Cmax, and Ctrough by age group and dose.
The proportion of participants with CS-CMVi through Week 14 
(~100 days) post-transplant and through Week 24 (~6 months) 
post-transplant will be estimated using a 95% CI (via the Clopper-
Pearson method). The missing data approach will be Non-Completer= 
Failure (NC=F) approach.
Statistical Methods for Key 
Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant 
parameters including AEs, laboratory tests, vital signs and ECG 
parameters. Descriptive statistics will be provided for these safety 
parameters.
Interim Analyses
An external DMC will be appointed and will review the safety and 
tolerability data. The DMC will periodically review the safety data at the 
following time points: 1) when 6 PK-evaluable participants in Age 
Group 1, Panel A have completed intensive PK sampling. 2) when 6 
PK-evaluable participants in Age Group 2, Panel A have completed 
intensive PK sampling. 3) when ~10 (which is ~50%) of participants in 
Age Group 1, Panel B have completed the Week 4 visit. 4) when ~10
(which is ~50%) of participants in Age Group 2, Panel B have 
completed the Week 4 visit. 5) when at least 3 participants in Age Group 
3 have completed intensive PK sampling. This will supplement routine 
in-house medical monitoring.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
PK: A sample size of 6 in Age Group 1 and 2 has approximately 95% 
power to show that the 95% confidence interval of the geometric mean 
of AUC0-24 in this age group will be within 60% and 140% of the 
geometric mean estimates of the AUC0-24 of LET. A sample size of 8 in 
Age Group 3 has approximately 99% power to show that the 95% 
confidence interval of the geometric mean of AUC0-24 in this age group 
will be within 60% and 140% of the geometric mean estimates of the 
AUC0-24 of LET.
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. The statistical analyses of the PK data will 
be conducted in collaboration with the Pharmacokinetics, Pharmacodynamic and Drug 
Metabolism and Clinical Research departments of the Sponsor.
This study is being conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule for study 
intervention assignment. Allocation number will be assigned via an IRT.
Planned interim analyses for ongoing safety monitoring are described in Section 9.7. 
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9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are stated in 
Section 3.
9.4
Analysis Endpoints
Pharmacokinetics, safety, and efficacy endpoints that will be evaluated are listed below.
9.4.1
Pharmacokinetics Endpoints
An initial description of PK endpoints is provided in Section 4.2.1.1. The primary PK 
endpoints for LET are: AUC0-24, Cmax (for participants receiving oral formulation), Ceoi 
(for participants receiving IV formulation), and Ctrough. Additional PK parameters for 
participants receiving oral formulations are time to maximum observed plasma drug 
concentration (Tmax), half-life (t1/2), apparent clearance (CL/F), and apparent volume of 
distribution (Vd/F). Additional PK parameters for participants receiving IV formulation are 
half-life (t1/2), clearance (CL), and volume of distribution (Vd).
9.4.2
Safety Endpoints
An initial description of safety endpoints is provided in Section 4.2.1.2. 
All AEs will be collected through 28 days following the last dose of study medication in all 
participants. Thereafter, only drug-related serious adverse events (SAEs) and SAEs leading 
to death will be collected through Week 48 post-transplant. 
Safety endpoints will be analyzed using a 3-tiered approach (Section 9.6.3).
9.4.3
Efficacy Endpoints
An initial description of efficacy endpoints is provided in Section 4.2.1.3. 
The key efficacy endpoints will be the proportion of participants with CS-CMVi through 
Week 14 (~100 days) post-transplant and through Week 24 (~6 months) post-transplant, 
defined as the occurrence of either one of the following outcomes: 
•
onset of CMV end-organ disease 
OR
•
initiation of anti-CMV PET based on documented CMV viremia and the clinical 
condition of the participant.
CMV end-organ disease will be determined using the definitions in Appendix 8 and 
confirmed by an independent CAC. For analysis purposes, the adjudication of cases by the 
CAC (ie, the final CAC assessment) will take precedence over the investigator’s assessment. 
Only the CAC-confirmed cases of CMV end-organ disease will be included in the CMV end-
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organ disease category. However, investigator-assessed CMV end-organ disease cases, which 
were not confirmed by the CAC but in whom anti-CMV therapy was initiated (in the setting 
of documented CMV viremia) will be included in the initiation of PET category and, 
therefore, qualify as having CS-CMVi. Concordance/discordance between CAC and 
investigator assessment will be summarized.
In this study, any detectable CMV viral DNA result using a local CMV PCR assay is 
acceptable for documenting viremia as a component of the efficacy endpoint. Documented 
viremia is defined as any detectable CMV viral DNA obtained immediately prior to (ie, on 
the day of) the initiation of treatment for CMV disease or PET. In the event that the 
confirmatory result is not available, a subsequent laboratory result collected from a sample 
obtained within 7 days will be used. Initiation of anti-CMV therapy without documented 
CMV viremia will not be considered as a case of CS-CMVi. Similarly, detectable CMV viral 
DNA alone without initiation of anti-CMV therapy will not be considered as a case of CS-
CMVi.
The proportion of participants with CMV disease through Week 14 post-transplant and 
through Week 24 post-transplant and the proportion of participants with initiation of PET for 
documented CMV viremia through Week 14 post-transplant and Week 24 post-transplant
will also be presented separately. 
9.5
Analysis Populations
9.5.1
PK Analysis Population
Per Protocol (PP): The Per-Protocol Population will serve as the primary population for the 
analyses of PK data in the study. The PP population consists of the subset of participants who 
comply with the protocol sufficiently to ensure that these data will be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
Compliance covers such considerations as exposure to treatment (participants’ dosing 
compliance should be such that their PK is expected to be approaching steady state at the 
time of intensive PK sampling, availability of measurements and absence of major protocol 
deviations that may affect the PK assessment. Major protocol deviations will be identified 
prior to final database lock. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data will be included in the Per-Protocol dataset. This population will be used for 
the PK analyses.
9.5.2
Safety Analysis Population
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all allocated participants who received at least one dose of study 
intervention. The safety analyses will include all participants who receive any dose of study 
intervention, but participants who receive different doses in Panels A and B will also be 
reported separately.
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At least one laboratory, vital sign, or ECG measurement obtained after at least one dose of 
study intervention is required for inclusion in the analysis of the respective safety parameter. 
To assess change from baseline, a baseline measurement is also required.
9.5.3
Efficacy Analysis Population
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population consists of all allocated participants who 
receive at least one dose of study intervention and had no detectable CMV viral DNA on 
Day 1 (when study intervention is initiated). Participants who receive different doses in 
Panels A and B will also be reported separately.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary
objectives. Methods related to exploratory objectives will be described in the sSAP.
9.6.1
Statistical Methods for Pharmacokinetic Analyses
The PK parameters of interest (AUC0-24, Cmax, Ctrough, Ceoi) will be summarized by Age 
Group and dose level, with geometric means (GMs) and 95% CIs based on natural log-
transformed values and the t distribution. Individual AUC0-24, Cmax, Ctrough, and Ceoi 
values will be plotted by Age Group and dose level as appropriate. 
Individual values will also be listed for each PK parameter by Age Group and dose level as 
appropriate, and the following (nonmodel-based) descriptive statistics will be provided: N 
(number of participants with non-missing data), arithmetic mean, standard deviation, 
arithmetic percent coefficient of variation (CV) (calculated as 100 × standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV
(calculated as 100 × sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log 
scale). Descriptive statistics will also be provided for concentrations/PK parameters obtained
at other time points, as appropriate.
9.6.2
Pharmacokinetic Modeling and Simulation for Dose Selection
Population PK analysis will be performed on all participants who undergo PK sampling,
while noncompartmental analysis (NCA) will be performed on the subset of participants who 
undergo intensive PK in Age Groups 1 and 2 Panel A and Age Group 3.
NCA will be primarily used to verify that the LET exposures in Panel A or Age Group 3 
patients are within predetermined bounds believed to be both safe and efficacious based on 
experience with the Phase 3 adult HSCT population. In the event that any LET exposures in 
Panel A or Age Group 3 patients are outside the predetermined bounds, an interim population 
PK analysis will be initiated, based on the Phase 3 population PK model, using all 
cumulative pediatric PK data, and select PK data from prior Phase 1 and Phase 3 studies. In 
parallel, the PBPK model will be calibrated to the cumulative pediatric PK data. Both the 
interim population PK and updated PBPK models will then be used to determine doses for
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the Panel B and continuing Age Group 3 participants that are most likely to result in 
exposures that are within the predetermined bounds.
A final population PK analysis using all cumulative pediatric PK data will be used to 
establish the PK properties of LET in pediatric patients, enable exposure-efficacy and 
exposure-safety analyses, and to make final dosing recommendations in the pediatric 
population for all regimens, age groups, and relevant intrinsic/extrinsic covariates.
An exploratory exposure-response analysis will be conducted relating the HPCD NCA PK 
parameters to changes in creatinine-based renal function metrics during IV LET 
administration.
The methodology and employment for both the population PK and NCA methods will be 
detailed in a separate Modeling & Analysis Plan, and PK-related results reported in a
Modeling and Simulation report.
9.6.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis strategy of safety results is summarized in Table 16. The proportions of 
participants with AEs in the broad categories of any AE, a drug-related AE, a serious AE, an 
AE, which is both drug-related and serious, and who discontinued study medication due to an 
AE will be provided along with the corresponding 95% CIs. In addition, deaths will be 
summarized in the same manner. The 95% CIs for the safety parameters will be estimated 
using the Clopper-Pearson method [Clopper, C. J. 1934].
The primary safety analysis will summarize the safety data for participants through 28 days
following the last dose of study medication. Safety results will be summarized for the APaT 
population and will also be presented by Age Groups (12 years to <18 years, 2 years to
<12 years, birth to <2 years). If doses in Panel A and Panel B are different, results of 
participants in the Panel B will also be reported separately from those in Panel A. Limited 
summaries of safety may be provided in participants in Panel A if the starting doses in 
Panel A and Panel B are different. Adverse events will also be summarized through 
Week 48 post-transplant.
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Table 16
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 95% CI 
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Deaths
X
X
Specific AEs, SOCs or PDLCs
X
Change from Baseline results (Labs, ECGs, Vital Signs)
X
AE=adverse event; ECG=electrocardiogram; labs= laboratory values; SOC=System Organ Class; 
PDLC=Predefined Limit of Change; SOC=System Organ Class; X=results will be provided. 
95% CIs will be calculated using the Clopper-Pearson method.
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided in table format.
Missing safety laboratory, ECGs, or vital signs will be handled using the Data-As-Observed
approach, that is, any missing value will be excluded from the analysis. The only exception is 
when a Baseline/Day 1 result is missing; this will be replaced with the latest pretreatment
result, if available.
9.6.4
Statistical Methods for Efficacy Analyses
For the efficacy analysis to estimate the proportion of participants with CS-CMVi through 
Week 14 (~100 days) post-transplant and through Week 24 (~6 months) post-transplant, a 
95% CI will be calculated based on the exact binomial method proposed by Clopper and 
Pearson (1934) [Clopper, C. J. 1934]. The same method will be used to analyze all binary 
endpoints. 
The primary efficacy analysis will be performed on the FAS population. A sensitivity 
analysis including those participants who had detectable CMV viral DNA on Day 1 will be 
provided. The primary missing data approach will be the Non-Completer= Failure (NC=F) 
approach (see below for details). Supportive analyses using different missing data approaches 
will also be conducted (Table 17).
For the analyses of efficacy, results of participants in the Panel B will also be reported 
separately from those in Panel A, if doses in Panel A and Panel B are different. Limited 
summaries of efficacy may be provided in participants in Panel A if the starting doses in 
Panel A and Panel B are different. In addition, key summaries of efficacy will be provided 
separately by age groups as described in Section 9.10.
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Table 17
Analysis Strategy for key Efficacy Variables
Endpoint/Variable
(Description, 
Time Point)
Primary vs. 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Proportion of 
participants with 
clinically significant 
CMV infection through 
Week 14 (~100 days) 
post-transplant
P
95% CI (Clopper-Pearson)
FAS
NC=F
S
95% CI (Clopper-Pearson)
FAS
OF
S
95% CI(Clopper-Pearson)
FAS
DAO
Proportion of 
participants with 
clinically significant 
CMV infection through 
Week 24 (~6 months) 
post-transplant
P
95% CI (Clopper-Pearson)
FAS
NC=F
S
95% CI (Clopper-Pearson)
FAS
OF
S
95% CI (Clopper-Pearson)
FAS
DAO
CI=confidence interval; CMV=cytomegalovirus; DAO=Data-as-observed; FAS=full analysis set; NC=F: Non-completer 
equal failure.(non-completers refer to participants who prematurely discontinued from the study); OF= observed failure; 
P=primary approach; S=supportive approach. 
Missing Data Handling
The primary missing data approach will be the Non-Completer = Failure (NC=F) approach to 
be consistent with the adult study (P001). Non-completers refer to participants who 
prematurely discontinued from the study. A participant who had missing efficacy measures at 
the study time point (eg, Week 24 post-transplant) will be considered as a failure. A 
participant who discontinued study medication, but remained in the study follow-up will not 
be considered as a Non-Completer. 
Two secondary missing data approaches will be used for supportive analyses. The first is the 
Observed Failure (OF) approach. Using this approach, participants who were failing (ie, had 
viremia) when they discontinued prematurely from the study for any reason will be
considered as failures, and participants who were not failing (ie, had no viremia) when they 
discontinued prematurely from the study for any reason will not be considered as failures.
The second is the Data-As-Observed (DAO) approach. With this approach, any participant
with missing value for a particular endpoint will be excluded from the analysis.
9.6.5
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.5.1
Demographic and Baseline Characteristics
Baseline characteristics for all allocated and treated participants will be summarized by the
use of descriptive statistics. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants screened and allocated, and the 
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primary reasons for screen failure and discontinuation will be displayed. Demographic 
variables (eg, age, gender, race), indication for HSCT, prior and concomitant therapies will 
be summarized for continuous or categorical variables, as appropriate.
9.6.5.2
Palatability and Acceptance Assessment
Each participant will rate the palatability and respond to questions on the acceptability of
treatment with oral granules on the first day of oral granule administration and one week 
later. This will be based on the FHS facial expression scale depicting various degrees of 
pleasure as an assessment of palatability (Section 4.2.1.4 and Section 8.10).
Descriptive statistics will be used to summarize the palatability and acceptability responses. 
Missing data will not be imputed, and the analyses will be based on observed data only. 
These analyses will be based on the APaT population.
9.7
Interim Analyses
Initial PK evaluations will be conducted as described in Section 4.3.1.
To supplement the routine safety monitoring outlined in this protocol, an external DMC will 
be appointed to monitor ongoing safety data and provide recommendations to discontinuation 
of the study or protocol modifications to the EOC (see Appendix 1 Committees Structure–
Executive Oversight Committee). The DMC will periodically review the safety data at the 
following proposed time points:
1) when 6 PK-evaluable participants in Age Group 1, Panel A have completed intensive 
PK sampling at the Day 7 visit
2) when 6 PK-evaluable participants in Age Group 2, Panel A have completed intensive 
PK sampling at the Day 7 visit
3) when ~10 (which is ~50%) of participants in Age Group 1, Panel B have completed 
the Week 4 visit 
4) when ~10 (which is ~50%) of participants in Age Group 2, Panel B have completed 
the Week 4 visit 
5) when at least 3 participants in Age Group 3 have completed intensive PK sampling
Some DMC reviews may be combined at the request of the DMC. The DMC may review 
safety data at other time points (including after the last scheduled safety check) as needed. 
DMC reviews are primarily based on safety, but any available efficacy data will be provided 
upon request to facilitate a benefit-risk evaluation.
Study enrollment for an age group will be paused until after the interim PK analyses, and
reevaluation of the initial dose for the age group at the indicated time points, as shown in
Figure 2 are completed independent of DMC review of safety data. An internal statistician 
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not otherwise connected with the study will conduct analyses and present results to the DMC. 
Additional logistical details will be provided in the DMC Charter.
9.8
Multiplicity
There will be no multiplicity adjustments in the analysis of this study.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for PK Analysis
A sample size of 6 in Age Group 1 and 2 has approximately 95% power to show that the 
95% confidence interval of the geometric mean of AUC0-24 in this age group will be within 
60% and 140% of the geometric mean estimates of the AUC0-24 of LET. A between-subject 
standard deviation of 0.325 in log scale for AUC0-24 that was obtained from previous studies 
(P003 and P004) was used for these calculations. This calculation is based on the pediatric 
guidance proposed by Wang et al [Wang, Y., et al 2012].
A sample size of 8 in Age Group 3 has approximately 99% power to show that the 
95% confidence interval of the geometric mean of AUC0-24 in this age group will be within 
60% and 140% of the geometric mean estimates of the AUC0-24 of LET. A between-subject 
standard deviation of 0.325 in log scale for AUC0-24 that was obtained from previous studies 
(P003 and P004) was used for these calculations. This calculation is based on the pediatric 
guidance proposed by Wang et al [Wang, Y., et al 2012].
9.9.2
Sample Size and Power for Safety Analysis
This study will allocate 60 participants to receive LET. A total of at least 26 participants will 
be enrolled for each of the 2 oldest age groups. As this will be a descriptive study, the sample 
size used in this study is not based on statistical considerations. 
The probability of observing at least one of a particular AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population. If the underlying incidence of a particular AE is 1% (1 of every 100 
participants receiving the drug), there is a 45% chance of observing at least one of that 
particular AE among 60 participants. For analyses by Age Group, there is a 23% chance of 
observing at least one of that particular AE among 26 participants or an 8% chance of 
observing at least one of that particular AE among 8 participants. If no AE of that particular 
type are observed among the 26 participants, this study will provide 95% confidence that the 
underlying percentage of participants with that particular AE is <13.2% (one in every 8
participants). If no AE of that particular type are observed among the 8 participants, this 
study will provide 95% confidence that the underlying percentage of participants with that 
particular AE is <36.9% (one in every 3 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 
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of participants with the AE are provided in Table 18. These calculations are based on the 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 1934].
Table 18
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 Bounda
N=8
0 (0)
36.9
1 (12.5)
52.7
2 (25.0)
65.1
N=26
0 (0)
13.2
1 (3.8)
19.6
2 (7.7)
25.1
N=60
0 (0)
6.0
1 (1.7)
8.9
2 (3.3)
11.5
5 (8.3)
18.4
AE(s)=adverse event(s); N=number of participants.
a
Based on the two-sided exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
9.9.3
Sample Size and Power for Efficacy Analysis
This is a descriptive study with no hypotheses. A total of at least 26 participants will be 
enrolled for each of the 2 oldest age groups. The key efficacy objective will be assessed 
based on the proportion of participants with CS-CMVi through Week 24 (~6 months) 
post-transplant. The expected rate of participants with CS-CMVi through Week 24 
post-transplant is ~18% based on P001 data and assuming LET is expected to be similarly 
active in adults and pediatric participants. Since the primary missing data approach will be 
NC=F approach, 25% was added to the expected incidence of CS-CMVi through Week 24 
post-transplant with the assumption that higher discontinuation rate will be observed in the 
more vulnerable pediatric participants than adults. In terms of estimation with the proposed 
sample size, with 26 participants, the maximum half-width of the 95% exact confidence 
interval will be no greater than 21%. The calculation is based on the exact binomial method 
proposed by Clopper and Pearson (1934) [Clopper, C. J. 1934] and is carried out using SAS 
v9.4. Table 19 shows the 95% CIs for CS-CMVi given varying assumptions of number of
failures for 8, 26, and 60 participants. Note that the intervals are not symmetric around the 
point estimate.
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Table 19
Two-sided 95% Confidence Intervals for the Proportion of Participants With 
Clinically Significant CMV Infection Through Week 24 (~6 Months) Post-transplant
(FAS Population)
Number of Failuresa (%)
Two-Sided 95% Confidence Intervalb
N=8
2 (25.0)
(3.2, 65.1)
3 (37.5)
(8.5, 75.5)
4 (50.0)
(15.7, 84.3)
N=26
9 (34.6)
(17.2, 55.7)
10 (38.5)
(20.2, 59.4)
11 (42.3)
(23.4, 63.1)
12 (46.2)
(26.6, 66.6)
N=60
19 (31.7)
(20.3, 45.0)
21 (35.0)
(23.1, 48.4)
23 (38.3)
(26.1, 51.8)
25 (41.7)
(29.1, 55.1)
27 (45.0)
(32.1, 58.4)
CMV=-cytomegalovirus; FAS=full analysis set; N=number of participants.
a Based on Non-Completer = Failure approach.
b Based on the two-sided exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
9.10
Subgroup Analyses
To assess the consistency of the response across various subgroups, the proportion of 
participants with CS-CMVi through Week 14 (~100 days) post-transplant and associated 
95% CIs will be estimated within each category of the following classification variables:

Age category (birth to <2 years, 2 years to <12 years, 12 years to <18 years)

Sex (female, male)

Race (white, black, Asian, other)

Donor and/or Recipient Serostatus
The consistency of the response will be assessed descriptively via summary statistics by 
category for the classification variables listed above. Other clinically relevant variables may 
be identified for which additional subgroup analyses may be performed. 
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9.11
Compliance (Medication Adherence)
Drug accountability data for LET will be collected during the study. A day within the study 
will be considered an “On-Therapy” day if the participant takes at least one dose. For a 
participant who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from treatment allocation to the last scheduled day for 
treatment administration for that participant. For a participant who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from treatment allocation to the date of the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance for the APaT population.
In addition, percent of participants on CsA and duration of CsA use will be reported.
9.12
Extent of Exposure
The extent of exposure to study intervention will be evaluated by summary statistics (N, 
mean, and range) for the “Number of Days on Therapy”.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (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
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.
10.1.4.2
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.
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The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) 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.
10.1.4.3
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 Appendix 8, 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 8.
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.
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 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, 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.
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.
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants, documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests specified in Table 20 will be performed by the site’s local laboratory. The tests 
specified in Table 21 will be performed by the central laboratory. Local laboratory 
results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 20
Protocol-required Laboratory Assessments (Local Laboratory)
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
White Blood Cell (WBC) count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN)
If BUN testing is not 
available at the local 
laboratory, blood urea must 
be measured and reported.
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin
and direct
bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose [nonfasting]
Calcium
Alkaline phosphatase
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Other Tests

Urine or 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 (screening only). 

HCV RNA PCR: to be done only in participants who test positive for HCV antibody
(screening only)

Coagulation: PT/INR

Creatinine Clearance; calculated using the Cockcroft-Gault equation for participants ≥12 
years of age or the modified Schwartz equation for participants <12 years of age
(Appendix 12)

CMV DNA PCR using plasma or whole blood

pp65 antigen test (to be only reported by sites in Japan using the test in addition to CMV 
DNA PCR test results)
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Table 21
Protocol-required Laboratory Assessments (Central Laboratory)
Laboratory Assessments/Parameters
Plasma sample for cytomegalovirus (CMV) DNA Sequence Analysis: CMV DNA Sequence 
Analysis to be performed only in participants with clinically significant cytomegalovirus infection 
(CS-CMVi)and who have detectable CMV DNA.
PK samples testing 
Planned genetic analysis specimen (buccal swab)
Future Biomedical Research will be conducted on residual DNA collected from buccal swab as 
well as leftover main study plasma from CMV viral resistance
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Table 22, Table 23, and Table 24 summarize the approximate blood volumes collected by 
study visit and sample types for the research testing (central labs), in separate tables by Age 
Group.
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Table 22
Approximate Blood Volumes Drawn/Collected by Study Visit and by Sample Types – Research Testing (Age Group 1)
Treatment Period
Follow-up Period
Expected 
Maximum 
Total Blood 
Volume per 
participant
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
25
26
Visit Name
SCR
D1
D7
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
W14
W16
W18
W20
W22
W24
CMV 
Infec-
tion 
Visit
Early 
Study 
Discon 
Visit
Research Testing (Central Labs) 
CMV DNA 
Sequence Analysis
3 a
3
Sparse PK
3
3
3
3
3
3
3
3b
3c
21
Intensive PK c
15
15
Expected Total 
(mL)
0
0
15
3
0
3
0
3
0
3
0
3
0
3
0
3
0
0
0
0
0
6
3
39
CMV=cytomegalovirus; CS-CMVi=clinically significant cytomegalovirus infection; Discon=discontinuation; PK=pharmacokinetics.
Note: This table is based on the estimated maximum volume (in mL) to be required for each test. 
a Performed only in participants with CS-CMVi. Plasma samples required.
b Done only if the visit occurs during the Treatment Period. No subsequent Sparse PK samples would be taken.
c Refer to Section 8.6 for details.
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Table 23
Approximate Blood Volumes Drawn/Collected by Study Visit and by Sample Types – Research Testing (Age Group 2)
Treatment Period
Follow-up Period
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
25
26
Expected 
Maximum 
Total Blood 
Volume per 
participant
Visit Name
SCR
D1
D7
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
W14
W16
W18
W20
W22
W24
CMV 
Infec-
tion
Visit
Early 
Study 
Discon
Visit
Research Testing (Central Labs) 
CMV DNA 
Sequence Analysis
2 a
2
Sparse PK
1
1
1
1
1
1
1
1b
1b
7
Intensive PK c
5
5
Expected Total 
(mL)
0
0
5
1
0
1
0
1
0
1
0
1
0
1
0
1
0
0
0
0
0
3
1
14
CMV=cytomegalovirus; CS-CMVi=clinically significant cytomegalovirus infection; PK=pharmacokinetics.
Note: This table is based on the estimated maximum volume (in mL) to be required for each test. 
a Performed only in participants with CS-CMVi. Plasma samples required.
b Done only if the visit occurs during the Treatment Period. No subsequent Sparse PK samples would be taken.
c Refer to Section 8.6 for details.
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Table 24
Approximate Blood Volumes Drawn/Collected by Study Visit and by Sample Types – Research Testing (Age Group 3)
Treatment Period
Follow-up Period
Visit
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
25
26
Expected 
Maximum 
Total Blood 
Volume per 
participant
Visit Name
SCR
D1
D7
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
W14
W16
W18
W20
W22
W24
CMV 
Infec-
tion 
Visit
Early 
Study 
Discon 
Visit
Research Testing (Central Labs) 
CMV DNA 
Sequence 
Analysis
1 a
1
Sparse PK
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25b
0.25b
2.25
Intensive
PK c
1.25
1.25
HPCD PK
samplingd
0.5
0.5
Expected 
Total (mL)
0
0
1.75
0.25
0.25
0.25
0.25
0.25
0.25
0.25
1.25
0.25
5.0
CMV=cytomegalovirus; CS-CMVi=clinically significant cytomegalovirus infection; Discon=discontinuation; HPCD=hydroxypropyl-beta-cyclodextrin;
LET=letermovir; PK=pharmacokinetics.
Note: This table is based on the estimated maximum volume (in mL) to be required for each test. 
a Performed only in participants with CS-CMVi.
b Done only if the visit occurs during the Treatment Period. No subsequent Sparse PK samples would be taken.
c Refer to Section 8.6 for details. Collection will start on the 5th consecutive day of IV dosing.
d Start on the 4th consecutive day of IV dosing. See Sections 8.6.2 and 8.6.2.1 for additional sampling for serum creatinine with HPCD PK sampling.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, 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.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of 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.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
-
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the study intervention cause the AE?
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•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the study intervention in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
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(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) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF 
REQUIRED, THE IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
-
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
-
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
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.
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•
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
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
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 one of the contraception 
methods described in Table 25 consistently and correctly during the protocol-defined time 
frame in Section 5.1.
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Table 25
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
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen only hormonal contraception b
○
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
●Intrauterine hormone-releasing system (IUS)
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.
●Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
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 (CTFG) guidelines, 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 intervention, additional pregnancy testing will be performed at 
monthly intervals during the treatment period and until approximately 28 days following the 
last dose of study medication per the SoA.
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: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research 3,4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@msd.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@msd.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not Applicable.
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10.8
Appendix 8 Definition of CMV Disease in Hematopoietic Stem Cell Transplant 
(HSCT) Recipients
CMV Disease 
Type
Probable
Proven
Notes
Pneumonia
Signs and/or symptoms of 
pneumonia
AND
Detection of CMV by viral 
isolation, rapid culture of BAL 
fluid, or the quantitation of 
CMV DNA in BAL fluid
Signs and/or symptoms of 
pulmonary disease
AND
Detection of CMV in lung 
tissue by virus isolation, rapid 
culture, histopathology, 
immunohistochemistry, or 
DNA hybridization techniques

PCR may be too 
sensitive, so detection 
of CMV by PCR alone 
is insufficient for the 
diagnosis of CMV 
pneumonia.

Superinfection or 
coinfection with other 
pathogens may occur 
and should be noted 
when present.
GI Disease
Symptoms of upper and/or 
lower GI disease
AND
Evidence of CMV in tissue but 
without the requirement for 
macroscopic mucosal lesions
Symptoms of upper and/or 
lower GI disease
AND
Macroscopic mucosal lesions 
AND
Detection of CMV in GI tissue 
by histopathology, virus 
isolation, rapid culture, 
immunohistochemistry, or 
DNA hybridization

Detection of CMV by 
PCR alone is 
insufficient for the 
diagnosis of CMV GI 
disease.
Hepatitis
N/A
Abnormal liver function tests
AND
CMV documented in tissue by 
histopathology, 
immunohistochemistry, virus 
isolation, rapid culture, or DNA 
hybridization techniques
AND
Absence of other documented 
cause of hepatitis

Detection of CMV by 
PCR alone is 
insufficient as it may 
represent transient 
DNAemia. Hence, 
PCR is insufficient to 
diagnose CMV 
hepatitis.

Documentation of 
CMV in liver biopsy 
specimen (ie, by 
culture, 
histopathology, 
immunohistochemical 
analysis or in situ
hybridization) is 
needed. 

Coinfection with other 
pathogens like HCV 
may be present 
without excluding the 
diagnosis of CMV 
hepatitis.
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CMV Disease 
Type
Probable
Proven
Notes
Encephalitis / 
ventriculitis
CNS symptoms 
AND
Abnormal imaging results or 
evidence of encephalitis on 
electroencephalography
AND
Detection of CMV in CSF 
without visible contamination 
of blood
CNS symptoms
AND
Detection of CMV in CNS 
tissue by virus isolation, rapid 
culture, immunohistochemistry, 
in situ hybridization, or 
(preferably) quantitative PCR
N/A
Retinitis
N/A
Lesions typical of CMV 
retinitis confirmed by an 
ophthalmologist.
N/A
Nephritis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in 
situ hybridization in a kidney 
biopsy specimen obtained from 
a patient with renal dysfunction
AND
Identification of histologic 
features of CMV infection

Detection of CMV in 
urine by PCR or 
culture is insufficient 
for the diagnosis of 
CMV nephritis.
Cystitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in 
situ hybridization in a bladder 
biopsy specimen obtained from 
a patient with cystitis
AND
Identification of conventional 
histologic features of CMV 
infection

Detection of CMV in 
urine by PCR or 
culture is insufficient 
for the diagnosis of 
CMV cystitis.
Myocarditis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in 
situ hybridization in a heart 
biopsy specimen obtained from 
a patient with myocarditis
AND
Identification of conventional 
histologic features of CMV 
infection
N/A
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CMV Disease 
Type
Probable
Proven
Notes
Pancreatitis
N/A
Detection of CMV by virus 
isolation, rapid culture, 
immunohistochemistry, or in 
situ hybridization in a 
pancreatic biopsy specimen 
obtained from a patient with 
pancreatitis
AND
Identification of conventional 
histologic features of CMV 
infection
N/A
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BAL=bronchoalveolar lavage; 
CMV=cytomegalovirus; CNS=central nervous system; CSF=cerebrospinal fluid; DNA=deoxyribonucleic 
acid; GI=gastrointestinal; HCV=hepatitis C virus; PCR=polymerase chain reaction; ULN=upper limit of 
normal.
[Ljungman, P., et al 2016] [National Cancer Institute 2009]
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10.9
Appendix 9 Child-Pugh Classification for Severity of Liver Disease
Scoring by Anomaly
Signs or symptom 
1 point 
2 points 
3 points 
Hepatic encephalopathya
absent 
Grade 1 or Grade 2 
Grade 3 or Grade 4 
Ascites 
absent 
mild
moderate /severe
Bilirubin (mg/dL) 
<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
INR
<1.7 
1.7 – 2.3 
>2.3 
INR=international normalized ratio
aHepatic 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.
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10.10 Appendix 10: Medications Allowed for HSV/VZV Prophylaxis
10.10.1
Acyclovir
10.10.1.1
HSV Prophylaxis
Prevention of early reactivation
Note: Begin at conditioning and continue until engraftment or resolution of mucositis; 
whichever is longer (~30 days post-HSCT).
Infants, Children, and Adolescents <40 kg:
IV: 250 mg/m2/dose every 8 hours or 125 mg/m2/dose every 6 
hours; maximum daily dose: 80 mg/kg/day
Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum 
dose: 800 mg/dose twice daily
Children and Adolescents ≥40 kg:
IV: 250 mg/m2/dose every 12 hours
Oral: 400 to 800 mg twice daily
Prevention of late reactivation
Note: Treatment during first year after HSCT.
Infants, Children, and Adolescents <40 kg:
Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; maximum 
daily dose: 800 mg twice daily
Children and Adolescents ≥40 kg:
Oral: 800 mg twice daily
10.10.1.2
Varicella (Chickenpox) or Herpes Zoster (Shingles), Prophylaxis
Hematopoietic stem cell transplant (HSCT): Prophylaxis of disease reactivation
Note: Continue therapy for 1 year after HSCT [Tomblyn, M, et al 2009].
Infants, Children, and Adolescents <40 kg:
Oral: 60 to 80 mg/kg/day in 2 to 3 divided doses
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Children and Adolescents ≥40 kg:
Oral: 800 mg twice daily
10.10.2
Valacyclovir
10.10.2.1
Herpes Simplex Virus (HSV), Prophylaxis
Immunocompromised patients (eg, HSCT or leukopenic oncology patients)
Limited data available ([Tomblyn, M, et al 2009])
Children and adolescents, oral:
Early reactivation prevention
Begin at initiation of conditioning and continue until engraftment or resolution of 
mucositis (IDSA [Tomblyn, M, et al 2009])
Patient weight <40 kg:
250 mg twice daily
Patient weight ≥40 kg:
500 mg once or twice daily; twice daily dosing should be 
considered in patients who are highly suppressed
Late reactivation prevention
Continue throughout the first year following HSCT ([Tomblyn, M, et al 2009])
Patient weight <40 kg:
250 mg twice daily
Patient weight ≥40 kg:
500 mg once or twice daily; twice daily dosing should be 
considered in patients who are highly suppressed
10.10.2.2
Varicella (Chickenpox), Prophylaxis
Immunocompromised patients (eg, HSCT or leukopenic oncology)
Limited data available
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Children and adolescents:
Weight-directed: 
Oral: 15 to 30 mg/kg/dose 3 times daily ([Bomgaars, L., et 
al 2008])
Fixed dosing:
Patient weight <40 kg: 
Oral: 250 or 500 mg twice daily ([Tomblyn, M, et al 2009])
Patient weight ≥40 kg:
Oral: 500 mg twice daily ([Tomblyn, M, et al 2009])
Post exposure prophylaxis (IDSA [Tomblyn, M, et al 2009]):
Note: Continue for 22 days post exposure.
Patient weight <40 kg:
Oral: 500 mg 3 times daily
Patient weight ≥40 kg:
Oral: 1,000 mg 3 times daily
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10.11 Appendix 11: Palatability and Acceptance Assessment Form
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10.12 Appendix 12: Calculation of Creatinine Clearance by Age of Study Participant
Food and Drug Administration guidance recommends using Cockcroft-Gault equation in 
adolescents ≥12 years of age and the modified Schwartz equation for infants and children 
<12 years of age [Food and Drug Administration (CDER) 2014].
Cockcroft-Gault Equation (for Participants ≥12 Years of age):
Creatinine clearance (males) = (weight in kg) × (140 minus age)    
       
(72) × (creatinine in mg/dL)
Creatinine clearance (females) = 0.85 × the value obtained using the equation above
Modified Schwartz Equation (for Participants <12 Years of age):
Creatinine clearance =     K × (height in cm)___  
(creatinine in mg/dL)
K (proportionality constant):
Infant (term <1 year): K=0.45
Female child (≥1 year and <12 years): K=0.55
Male child (≥1 year and <12 years): K=0.70
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
alanine aminotransferase
APaT
All Participants as Treated
AST
aspartate aminotransferase
AUC0-24
area under the concentration-time curve for the dosing period (0 to 24 hours)
AUC0-inf
area under the concentration-time curve for the dosing period (0 to infinity)
CAC
Clinical Adjudication Committee
Ceoi
concentration at the end of infusion
CI
confidence interval
CL
clearance
CL/F
apparent clearance
Cmax
maximum concentration observed
CMV
Cytomegalovirus
CMVi
Cytomegalovirus infection
CNS
central nervous system 
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CrCl
creatinine clearance
CRF
Case Report Form 
CsA
Cyclosporin A
CS-CMVi
Clinically significant CMV infection
CSR
clinical study report
Ctrough
minimum concentration observed before next dose
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
DEHP
diethylhexyl phthalate
DILI
drug-induced liver injury
Discon
Discontinuation
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DAO
data-as-observed
EBMT
European Group for Blood and Marrow Transplantation
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FHS
facial hedonic scale
FSH
Follicle stimulating hormone 
G tube
Gastric tube
GCP
Good Clinical Practice 
GM
geometric mean
GMR
geometric mean ratios
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Abbreviation
Expanded Term
GVHD
graft-versus-host disease
HBsAG
hepatitis B surface antigen
HCV
hepatitis C virus
HCV-Ab
hepatitis C virus antibody
HHV
human herpes virus
HIV
human immunodeficiency virus
HIV-Ab
human immunodeficiency virus antibody
HPCD
hydroxypropyl-beta-cyclodextrin 
HSCT
hematopoietic stem cell transplantation
HSV
herpes simplex virus
IA(s)
Interim Analysis (ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council on Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LET
Letermovir
NC=F
Non-Completer=Failure
NCA
Noncompartmental analysis
NG tube
Nasogastric tube
NTR
narrow therapeutic range
OF
observed failure
PAA
Palatability Acceptance Assessment
PCL
Protocol Clarification Letter
PCR
polymerase chain reaction
PES
polyethersulfone 
PET
preemptive therapy
PBPK
physiologically based pharmacokinetics
PK
pharmacokinetics
PP
Per Protocol
PT
prothrombin time
QD
once daily
QP2
department of quantitative pharmacology and pharmacometrics
R+
CMV-seropositive recipients
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
siDMC
Standing Internal Data Monitoring Committee
SMD
study medication diary
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
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Abbreviation
Expanded Term
Tmax
time to maximum concentration observed
ULN
upper limit of normal
Vd
volume of distribution
VZV
varicella zoster virus
WOCBP
woman/women of childbearing potential 
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