Clinical trial NCT02927067
Conditions: Cytomegalovirus (CMV)
Sponsor: Shire
Start date: 2017-04-14; Completion date: 2022-07-01
Enrollment: 553 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is about treatment options for cytomegalovirus infections in people who have received stem cell transplants. The main aim of the study is to check if the cytomegalovirus infection can no longer be detected after treatment with marivabir or valganciclovir.

Participants will take 2 tablets of marivabir or valganciclovir and 2 tablets of placebo twice a day for 8 weeks. A placebo will look like marivabir or valganciclovir but will not have any medicine in it.

After treatment, each participant will be followed up for up to 12 weeks.

Participants will visit their study clinic up to 18 times during the study.

Detailed description:

Arms: arm 1: Participants received 900 milligrams (mg) of valganciclovir along with a placebo matched to maribavir, twice daily (BID) orally for 8 weeks. Valganciclovir dose was allowed to be adjusted to 450 mg BID or 450 mg QD based on renal function impairment assessed at baseline or development of neutropenia during the study. arm 2: Participants received 400 mg of maribavir along with a placebo matched to valganciclovir, BID orally for 8 weeks.
Interventions: intervention 1: Maribavir intervention 2: Valganciclovir intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will receive 400 mg of maribavir BID orally. intervention 2: Participants will receive valganciclovir tablets orally. intervention 3: Participants will receive placebo tablets matched to either maribavir or valganciclovir.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT02927067
SHP620-303
Protocol Amendment and Date: 
Amendment 9 (Version 10.0): 15 September 2021
A Phase 3, Multicenter, Randomized, Double-blind, 
Double-dummy, Active-controlled Study to Assess the 
Efficacy and Safety of Maribavir Compared to Valganciclovir 
for the Treatment of Cytomegalovirus (CMV) Infection in 
Hematopoietic Stem Cell Transplant Recipients
For non-commercial use only


TAKEDA DEVELOPMENT CENTER AMERICAS, INC
TITLE:
A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, 
Active-controlled Study to Assess the Efficacy and Safety of Maribavir 
Compared to Valganciclovir for the Treatment of Cytomegalovirus 
(CMV) Infection in Hematopoietic Stem Cell Transplant Recipients
DRUG:
SHP620
IND:
IND 051001
EUDRACT NO.:
2015-004726-34
SPONSOR:
Takeda Development Center Americas, Inc (TDC Americas)
95 Hayden Avenue, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Multicenter
PROTOCOL 
HISTORY:
Amendment 9 (Version 10.0): 15 September 2021
Amendment 8 (Version 9.0): 02 July 2021
Amendment 7 (Version 8.0): 25 March 2021
Amendment 6 (Version 7.0): 07 December 2020
Amendment 5 (Version 6.0): 12 February 2020
Amendment 4 (Version 5.0): 05 February 2019
Amendment 3 (Version 4.0): 01 September 2017
Amendment 2 (Version 3.0): 01 June 2017
Amendment 1 (Version 2.0): 02 March 2017
Original Protocol (Version 1.0): 04 August 2016
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda.
PROTOCOL: SHP620-302
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Takeda 
CONFIDENTIAL 
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9 
15 Sep 2021 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Takeda) Approval 
, MD 
Investigator's Acknowledgement 
I have read this protocol for Takeda Study SHP620-302. 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled 
Study to Assess the Efficacy and Safety ofMaribavir Compared to Valganciclovir for the 
Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant 
Recipients 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
The investigator completes the bottom section of the 
(please hand print or type) 
protocol signature page 
Signature: 
Date: 
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
SUMMARY OF CHANGES FROM PREVIOUS VERSION
(AMENDMENT 8)
Noteworthy changes to the protocol are captured in the table below. The protocol has been 
amended to update the information on drug interactions and contraindications, consistent with 
the current Investigator’s Brochure.
Other minor editorial revisions (including changes for consistency and clarity) are not described 
in this table.
Protocol Amendment
Summary of Changes Since Protocol Version 8.0 (Protocol Amendment 7)
Amendment Number
9
Amendment Date
15 September 2021
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated description of drug interactions consistent with the 
latest Investigator’s Brochure
Section 1.2.1 Pharmacokinetics, Metabolism, and 
Drug-Drug Interactions
Section 4.5.1 Reasons for Discontinuation and/or 
Withdrawal
Section 5.2.1 Permitted Treatment 
Section 5.2.2 Prohibited Treatment
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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EMERGENCY CONTACT INFORMATION
Please refer to Section 8.2.2 for information on serious adverse event reporting procedures.
For protocol- or safety-related issues (but with no information that would unblind the 
study treatment assignment) during normal business hours 8:00am - 5:00pm (local time 
per region), the investigator must contact the PPD blinded medical monitor:
Hotline numbers (24 hours a day/7 days a week):
North America: 
Europe, Middle East, Africa (EMEA)/Asia-Pacific (APAC): 
Fax numbers:
North America: 
 and 
EMEA/APAC: 
Email:
North America: RTP Safety Mailbox (SM) –
EMEA/ASIA: Safety Central Mailbox (SM) –
For protocol- or safety-related issues outside of normal business hours, the Investigator must 
contact:
Hotline numbers (24 hours a day/7 days a week):
North America: 
EMEA/APAC: 
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Takeda within 
24 hours. This includes any instances wherein the quality or performance of a Takeda product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use PQC@shire.com to report the Product Quality Complaint.
Telephone number and address (provided for reference if needed):
95 Hayden Avenue, Lexington, MA 02421 USA
1-800-828-2088
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE..............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION (AMENDMENT 8).................3
EMERGENCY CONTACT INFORMATION ...........................................................................4
PRODUCT QUALITY COMPLAINTS......................................................................................5
TABLE OF CONTENTS ..............................................................................................................6
LIST OF TABLES.......................................................................................................................10
LIST OF FIGURES.....................................................................................................................10
LIST OF APPENDICES .............................................................................................................10
ABBREVIATIONS......................................................................................................................11
DEFINITIONS.............................................................................................................................14
STUDY SYNOPSIS .....................................................................................................................15
STUDY SCHEDULES.................................................................................................................30
1. BACKGROUND INFORMATION .......................................................................................37
1.1 Indication and Current Treatment Options...................................................................37
1.2 Maribavir Background and Clinical Information .........................................................38
1.2.1 Pharmacokinetics, Metabolism, and Drug-Drug Interactions...............................39
1.2.2 Efficacy........................................................................................................................40
1.2.3 Safety ...........................................................................................................................43
2. STUDY OBJECTIVES AND PURPOSE ..............................................................................45
2.1 Rationale for the Study.....................................................................................................45
2.2 Rationale for the Study Design ........................................................................................46
2.3 Rationale for Dose Selection.............................................................................................47
2.4 Study Objectives................................................................................................................48
2.4.1 Primary Objective ......................................................................................................48
2.4.2 Key Secondary Objective...........................................................................................48
2.4.3 Secondary Objectives .................................................................................................48
2.4.4 Exploratory Objectives ..............................................................................................49
3. STUDY DESIGN......................................................................................................................50
3.1 Study Design and Flow Chart..........................................................................................50
3.2 Duration and Study Completion Definition ......................................................................54
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3.3 Sites and Regions...............................................................................................................55
3.4 Changes to Study Procedures Due to COVID-19 Pandemic.........................................55
4. STUDY POPULATION ..........................................................................................................57
4.1 Inclusion Criteria ..............................................................................................................57
4.2 Exclusion Criteria .............................................................................................................59
4.3 Restrictions ........................................................................................................................60
4.4 Reproductive Potential .....................................................................................................60
4.4.1 Female Contraception................................................................................................60
4.4.2 Male Contraception....................................................................................................62
4.5 Discontinuation and/or Withdrawal of Subjects............................................................62
4.5.1 Reasons for Discontinuation and/or Withdrawal....................................................63
4.5.2 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit..................................64
5. PRIOR AND CONCOMITANT MEDICATIONS, THERAPIES, AND 
PROCEDURES .......................................................................................................................65
5.1 Prior Medications, Therapies, and Procedures..............................................................65
5.2 Concomitant Medications, Therapies, and Procedures.................................................66
5.2.1 Permitted Treatment..................................................................................................67
5.2.2 Prohibited Treatment.................................................................................................68
5.2.3 Treatments Taken During the Follow-up Phase......................................................69
6. IDENTITY OF INVESTIGATIONAL PRODUCTS...........................................................70
6.1 Identity of Investigational Product..................................................................................70
6.2 Administration of Investigational Product(s).................................................................70
6.2.1 Interactive Response Technology for Investigational Product Management.......70
6.2.2 Allocation of Subjects to Treatment .........................................................................70
6.2.3 Dosing ..........................................................................................................................71
6.2.4 Blinding Procedures ...................................................................................................76
6.3 Labeling, Packaging, Storage, and Handling .................................................................77
6.3.1 Packaging and Labeling.............................................................................................77
6.3.2 Storage.........................................................................................................................78
6.4 Drug Accountability..........................................................................................................79
6.5 Subject Compliance ..........................................................................................................80
7. STUDY PROCEDURES .........................................................................................................81
7.1 Study Schedule ..................................................................................................................81
7.1.1 Screening Period.........................................................................................................81
7.1.2 Study Drug Administration Period...........................................................................83
7.1.3 Follow-up Period ........................................................................................................85
7.1.4 Additional Care of Subjects after the Study............................................................87
7.2 Study Evaluations and Procedures..................................................................................87
7.2.1 Demographic and Other Baseline Characteristics ..................................................87
7.2.2 Efficacy........................................................................................................................87
7.2.2.1 CMV DNA Quantitation .....................................................................................87
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7.2.2.2 CMV Genotyping and Phenotyping...................................................................87
7.2.2.3 
88
7.2.2.4 
89
7.2.2.5 Underlying Disease Assessment..........................................................................89
7.2.2.6 Graft-versus-host-disease Assessments..............................................................89
7.2.2.7 Comorbidity Status..............................................................................................90
7.2.2.8 Medical History....................................................................................................90
7.2.2.9 Subject Survival ...................................................................................................91
7.2.3 Safety ...........................................................................................................................91
7.2.3.1 Physical Examination (Including Weight).........................................................91
7.2.3.2 Vital Signs.............................................................................................................92
7.2.3.3 Electrocardiogram...............................................................................................92
7.2.3.4 Clinical Laboratory Evaluations ........................................................................92
7.2.3.5 Adverse Event Collection ....................................................................................95
7.2.4 Others ..........................................................................................................................95
7.2.4.1 Clinical Pharmacology Assessments ..................................................................95
7.2.4.2
97
7.2.4.3
98
7.2.5 Volume of Blood to Be Drawn from Each Subject..................................................99
8. ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..................................100
8.1 Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...............................................................................................................................100
8.1.1 Severity Categorization............................................................................................100
8.1.2 Relationship Categorization ....................................................................................101
8.1.3 Outcome Categorization ..........................................................................................102
8.1.4 Adverse Events of Special Interest..........................................................................102
8.1.5 Disease Under Study.................................................................................................103
8.1.6 Clinical Laboratory and Other Safety Evaluations ..............................................105
8.1.7 Pregnancy..................................................................................................................105
8.1.8 Abuse, Misuse, Overdose, and Medication Error .................................................106
8.2 Serious Adverse Event Procedures................................................................................107
8.2.1 Reference Safety Information .................................................................................107
8.2.2 Reporting Procedures ..............................................................................................107
8.2.3 Serious Adverse Event Definition ...........................................................................108
8.2.4 Serious Adverse Event Collection Time Frame.....................................................109
8.2.5 Serious Adverse Event Onset and Resolution Dates .............................................109
8.2.6 Fatal Outcome...........................................................................................................109
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ..................................................................................................................109
9. DATA MANAGEMENT AND STATISTICAL METHODS............................................111
9.1 Data Collection ................................................................................................................111
9.2 Clinical Data Management.............................................................................................111
9.3 Data Handling Considerations.......................................................................................111
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9.4 Statistical Analysis Process.............................................................................................111
9.5 Data Monitoring Committee..........................................................................................112
9.6 Sample Size Calculation and Power Considerations ...................................................112
9.7 Study Population.............................................................................................................114
9.8 Efficacy Analyses.............................................................................................................114
9.8.1 Primary Efficacy Endpoint......................................................................................114
9.8.2 Key Secondary Efficacy Endpoint ..........................................................................117
9.8.3 Multiplicity Adjustment...........................................................................................118
9.8.4 Subgroup Analyses ...................................................................................................119
9.8.5 Secondary Efficacy Endpoints.................................................................................119
9.8.6 Exploratory Efficacy Endpoints..............................................................................121
9.9 Safety Analyses.................................................................................................................121
9.10 Other Analyses ..............................................................................................................124
9.10.1
124
9.10.2
124
9.10.3 Pharmacokinetic and Pharmacokinetic/pharmacodynamic Analyses ..............124
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES .....................................126
10.1 Sponsor’s Responsibilities ............................................................................................126
10.1.1 Good Clinical Practice Compliance......................................................................126
10.1.2 Indemnity/Liability and Insurance.......................................................................126
10.1.3 Public Posting of Study Information ....................................................................127
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees .........................................127
10.1.5 Reporting of COVID-19 Cases During the Study ...............................................127
10.1.6 Study Suspension, Termination, and Completion...............................................127
10.2 Investigator’s Responsibilities......................................................................................127
10.2.1 Good Clinical Practice Compliance......................................................................127
10.2.2 Protocol Adherence and Investigator Agreement ...............................................128
10.2.3 Documentation and Retention of Records ...........................................................129
10.2.3.1 Case Report Forms ..........................................................................................129
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents .129
10.2.3.3 Audit/Inspection...............................................................................................130
10.2.3.4 Financial Disclosure.........................................................................................130
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation ..........................130
10.3 Ethical Considerations..................................................................................................130
10.3.1 Informed Consent...................................................................................................130
10.3.2 Institutional Review Board or Ethics Committee................................................131
10.4 Privacy and Confidentiality .........................................................................................132
10.5 Study Results/Publication Policy .................................................................................132
11. REFERENCES.....................................................................................................................135
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LIST OF TABLES
Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase...............30
Table 2. Schedule of Assessment 2: Follow-up Phase...............................................................35
Table 3. Prior Medications, Therapies, and Procedures..........................................................65
Table 4. Common Excluded Treatments and Associated Washout Period............................68
Table 5. Study Treatment Dosing – Standard Regimen...........................................................72
Table 6. Valganciclovir Dosing – Adjustment for Renal Function .........................................73
Table 7. Valganciclovir Dose Adjustment Based on ANC Level and CMV DNA 
Clearance .................................................................................................................................74
Table 8. Subjects ≥18 Years Sparse PK Schedule.....................................................................96
Table 9. Subjects ≥16 to <18 Years Including Intensive PK (Week 1) Schedule...................96
Table 10. Volume of Blood Drawn Per Study Visit ..................................................................99
Table 11.
104
Table 12. Assessments of Virological Responders at Study Week 8 .....................................115
Table 13. Assessments of Responders for Key Secondary Endpoint ....................................117
LIST OF FIGURES
Figure 1. Study Design Flow Chart............................................................................................51
LIST OF APPENDICES
Appendix 1 Protocol History.....................................................................................................141
Appendix 2 Child-Pugh Classification of Chronic Liver Disease..........................................162
Appendix 3 CMV Genetic Mutations Associated with Resistance to Anti CMV Drugs.....163
Appendix 4
169
Appendix 5 Karnofsky Performance Status Scale..................................................................172
Appendix 6
173
Appendix 7 Acute Graft-Versus-Host Disease: Clinical Staging and Grading....................174
Appendix 8 Recommendations for Chronic GVHD Diagnosis and Grading.......................176
Appendix 9 Diagnostic Criteria for Chronic GVHD..............................................................181
Appendix 10 Bacterial and Fungal Infections Assessment ....................................................187
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ABBREVIATIONS
AAG
alpha-1-1acid-glycoprotein
AE
adverse event
AESI
adverse events of special interest
AIDS
acquired immune deficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration versus time curve
-hCG
beta-human chorionic gonadotropin
BAL
bronchoalveolar lavage
BID
twice daily
CI
confidence interval
Cmax
maximum observed plasma concentration
Cmin
minimum observed plasma concentration
CMH
Cochran-Mantel-Haenszel
CMV
cytomegalovirus
CNS
central nervous system
CoD
Certificates of Destruction
COVID-19
Coronavirus Disease 2019
CRA
clinical research associate
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
DDI
drug-drug interaction
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DTP
direct-to-patient
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EC
ethics committee
ECG/EKG
electrocardiogram
eIC
electronic informed consent
EIND
emergency investigational new drug
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
FU
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyltransferase
GI
gastrointestinal
GVHD
graft-versus-host disease
HBV
hepatitis B virus
HCMV
human cytomegalovirus
HCV
hepatitis C virus
HHC
home healthcare
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HSA
human serum albumin
HSCT
hematopoietic stem cell transplant
HSV
herpes simplex virus
ICH
International Conference on Harmonisation
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
IV
intravenous
IVIg
intravenous immunoglobulin
KPS
Karnofsky Performance Status
LAR
legally authorized representative
LLOQ
lower limit of quantification
MMF
mycophenolate mofetil
NCI
National Cancer Institute
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NI
noninferiority
NIH
National Institutes of Health
NPP
named patient program
OTC
over-the-counter
PBPK
physiologically-based pharmacokinetics
PCR
polymerase chain reaction
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PI
Principal Investigator
PO
per os (oral)
PT
preferred term
QD
once daily
qPCR
quantitative polymerase chain reaction
QTc
corrected QT interval
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SMQ
standardized MedDRA queries
SOC
system organ class
SOT
solid organ transplant
TEAE
treatment-emergent adverse event
TID
3 times daily
ULN
upper limit of normal
US
United States
VZV
varicella zoster virus
WBC
white blood cell
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DEFINITIONS
Term
Definition
Confirmed viremia 
clearance
Defined as plasma cytomegalovirus (CMV) DNA concentration 
below the lower limit of quantification (<LLOQ; ie, <137 IU/mL]), 
when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV 
Test at a central specialty laboratory, in 2 consecutive postbaseline 
samples, separated by at least 5 days.
Recurrence of CMV 
viremia
Defined as plasma CMV DNA concentration ≥LLOQ when 
assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 
2 consecutive plasma samples at least 5 days apart, after being 
unquantifiable (<LLOQ) for at least 5 days in 2 consecutive 
samples.
Rebound of CMV 
viremia
Defined as increase in viral DNA load for >1 log10 above nadir 
without prior clearance of viremia.
Recurrence of the CMV 
disease
Defined as the presence of signs or symptoms of the tissue invasive 
CMV disease (same or new symptomatology) confirmed as per 
Ljungman et al. (2017), after the period of resolution of the disease 
in subjects symptomatic at baseline.
Refractory
Documented failure to achieve >1 log10 (common logarithm to 
base 10) decrease in CMV DNA level in whole blood or plasma 
after 2 or more weeks of treatment with IV ganciclovir, oral 
valganciclovir, IV foscarnet, or IV cidofovir (or any combination 
thereof).
Resistant
Documentation of 1 or more CMV genetic mutations associated 
with resistance to ganciclovir, valganciclovir, foscarnet, and/or 
cidofovir.
Symptomatic subjects
HSCT recipients who have tissue-invasive CMV disease as 
determined by the investigator according to the criteria specified by 
Ljungman et al. (2017).
Asymptomatic subjects
HSCT recipients who do not have tissue-invasive CMV disease as 
determined by the investigator according to the criteria specified by 
Ljungman et al. (2017).
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STUDY SYNOPSIS
Protocol number: SHP620-302
Drug: Maribavir
Title of the study: A Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study to 
assess the efficacy and safety of maribavir compared to valganciclovir for the treatment of cytomegalovirus 
(CMV) infection in hematopoietic stem cell transplant recipients
Number of subjects (total and for each treatment arm): Approximately 612 subjects will be screened to 
randomize approximately 550 subjects in the study, allowing for a 10% screen failure rate. Approximately 
550 subjects will be randomized in a 1:1 ratio to a double-blind treatment with maribavir or valganciclovir. 
Assuming a 10% dropout rate during the double-blind phase, approximately 494 subjects (247 each in the 
maribavir and valganciclovir arms) are required to provide 90% power to assess the noninferiority of maribavir 
to valganciclovir.
Investigator(s): A multicenter study to be conducted at approximately 105 sites worldwide.
Site(s) and Region(s): Approximately 105 sites in North America, Europe, and Asia Pacific.
Study periods (planned): 2017 - 2022
Clinical phase:
3
Primary Objective:
To compare the efficacy of maribavir to valganciclovir in CMV viremia clearance at the end of Study Week 8 in 
asymptomatic CMV infection in hematopoietic stem cell transplant (HSCT) recipients.
Key Secondary Objective:
To compare the efficacy of maribavir and valganciclovir on maintenance of CMV viremia clearance, achieved 
at the end of Study Week 8 through Study Week 16 (8 weeks of post-treatment/follow-up Phase).
Secondary Objectives:

To compare the efficacy of maribavir to valganciclovir in CMV viremia clearance after completion of 
8 weeks of treatment for asymptomatic CMV infection in HSCT recipients.

To compare the efficacy of maribavir and valganciclovir on maintenance of CMV viremia clearance, 
achieved after completion of 8 weeks of treatment, through Study Weeks 12 (4 weeks of post-treatment 
period), 16 (8 weeks of post-treatment/follow-up phase), and 20 (12 weeks post-treatment).

To assess the maintenance of CMV viremia clearance achieved at the end of Study Week 8, through 
Weeks 12 (4 weeks post-treatment), and 20 (12 weeks post-treatment).

To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study treatment arms 
during the first 8 weeks of the study, during the 12-weeks of the follow-up study phase, and at any time 
during the study.

To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study treatment arms when 
subjects are on treatment and off treatment.

To evaluate the incidence of grade 3 or 4 neutropenia (defined as absolute neutrophil count [ANC] 
<1000/mm3 or ANC<500/mm3) while on treatment.

To assess the safety and tolerability of maribavir compared to valganciclovir.

To characterize the pharmacokinetics (PK) of maribavir.
Exploratory Objectives:
 
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Rationale:
There are no anti-viral drugs specifically approved for treatment of CMV infection in transplant recipients. Both 
(IV) ganciclovir, approved for the treatment of CMV retinitis in immunocompromised patients including 
patients with HIV/AIDS and prevention of CMV disease in transplant recipients at risk for CMV disease, and 
oral valganciclovir approved for treatment of CMV retinitis in patients with HIV/AIDS and prevention of CMV 
disease in solid organ transplant recipient are widely used in clinical practice to treat CMV infection. The most 
common adverse effect of this treatment is bone marrow suppression, which is of particular concern for HSCT 
recipients whose marrow has been ablated and who are significantly immunosuppressed to prevent 
graft-versus-host disease (GVHD). The rates of valganciclovir-related neutropenia in HSCT range from 19% 
(Barkam et al., 2012) and 33% (Takahata et al., 2015) to 55% (Boeckh et al., 2015).
Maribavir is an anti-CMV agent that may be of particular benefit to HSCT patients as it does not appear to cause 
bone marrow suppression. In addition to the favorable safety profile of maribavir observed in earlier Phase 1-3 
studies (studies evaluating prophylactic administration of maribavir), results from a recent large Phase 2 
randomized trial (Study 1263-203) support the safety, tolerability, as well as anti-viral activity of maribavir as a 
potential option for the treatment of CMV infections in transplant recipients. Study 1263-203 was a multicenter, 
randomized, dose-ranging, parallel-group study of maribavir versus valganciclovir for the treatment of CMV 
infections in HSCT or solid organ transplant (SOT) recipients. Eligible subjects were randomized in a 1:1:1:1 
allocation ratio (40 subjects per group) to receive oral maribavir at 400 mg, 800 mg, or 1200 mg twice daily 
(BID); or valganciclovir (900 mg BID for 3 weeks, 900 mg once daily (QD) after 3 weeks) for up to 12 weeks. 
Maribavir, at doses 400 mg BID, had comparable efficacy to valganciclovir at clearing CMV viremia and was 
generally well tolerated across the dose range studied. In the subgroup of subjects whose transplant type was 
HSCT, a numerically higher percentage of subjects in the overall maribavir group (75%) than the valganciclovir 
group (48%) achieved confirmed undetectable plasma CMV DNA within 6 weeks of treatment. There was a 
higher incidence of neutropenia through Week 12 for valganciclovir-treated subjects compared with maribavir-
treated subjects. This was evident for both measured degrees of neutropenia: 18% versus 5% (ANC<1000/mm3), 
and 5% versus 2% (ANC<500/mm3) through Week 12 for the valganciclovir and overall maribavir groups, 
respectively.
This Phase 3 study is designed to further assess and demonstrate the efficacy and safety of maribavir, 
administered at 400 mg BID, compared to valganciclovir administered at 900 mg BID for the treatment of 
asymptomatic CMV infection in HSCT recipients.
Study treatment, dose, and mode of administration
Investigational product:
The sponsor will provide maribavir 200 mg strength tablets, which will be administered orally (PO) at 400 mg 
BID with food. Administration with food is not required for maribavir however it is required for valganciclovir 
(as per valganciclovir label), therefore same administration conditions (ie, with food) will be used to protect the 
blind.
Active control:
Valganciclovir will be provided in 450 mg strength tablets, which will be administered PO at 900 mg BID 
(or adjusted dosage, as required) with food.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Placebo:
To protect the study blind, maribavir and valganciclovir tablets will each have matching placebo tablets with 
same mode of administration.
Methodology:
This is a multicenter, randomized, double-blind, double-dummy, active-controlled study of maribavir compared 
to valganciclovir for the treatment of asymptomatic CMV infection in HSCT recipients. “Asymptomatic 
subjects” at baseline will be defined as HSCT recipients who do not have tissue-invasive CMV disease as 
diagnosed by the investigator. The study will assess the efficacy of maribavir by measuring the plasma CMV 
DNA clearance. To be eligible for the study, subjects must have a documented asymptomatic CMV infection 
with a screening value of CMV DNA ≥1365 IU/mL to ≤273000 IU/mL in whole blood or ≥455 IU/mL to 
≤91000 IU/ml in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or 
central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV 
DNA results. Results should be available before the subject is randomized to verify subject eligibility for the 
study. Both samples should be taken within 14 days prior to randomization with the second sample obtained 
within 5 days before randomization. The same laboratory and sample type should be used for these assessments. 
Subjects must not have CMV tissue invasive disease (symptomatic CMV infection) and must not have a CMV 
infection that is known to be genotypically resistant to anti-CMV drugs and must meet the remaining specified 
eligibility criteria.
All eligible subjects will be stratified based on the last prebaseline whole blood or plasma CMV DNA 
concentration as determined by the local or central specialty laboratory qPCR and acute GVHD (presence or 
absence at baseline):

High viral load with CMV DNA ≥27300 IU/mL in whole blood or ≥9100 IU/mL in plasma;

Low viral load with CMV DNA ≥2730 IU/mL to <27300 IU/mL in whole blood or ≥910 IU/mL to 
<9100 IU/mL in plasma, and

Very low viral load and high-risk infection with CMV DNA >1365 IU/mL to <2730 IU/mL in whole 
blood or >455 IU/mL to <910 IU/mL in plasma
Subjects in each stratum will then be randomized in a 1:1 allocation ratio to receive double-blind maribavir 
400 mg BID or valganciclovir 900 mg BID (with dose adjustment for renal function or neutropenia) for 
8 weeks.
As shown in the study schematic in Study Design Flow Chart below, the study will have 3 phases: (1) Up to a 
2-week screening phase; (2) 8-week double-blind study treatment phase; and (3) 12-week follow-up phase. 
Subjects will be required to visit the site up to 18 times for up to a 22-week period.
Screening Phase
Approximately 612 subjects will be screened during an approximate 2-week screening phase to establish 
eligibility for study participation. If applicable, those subjects who meet eligibility requirements will undergo 
washout of any prohibited medications, the length of which will be specified in the eligibility criteria. Subjects 
treated with ganciclovir, valganciclovir, foscarnet, or letermovir for the current CMV infection must not be 
treated with these anti-CMV agents for longer than 72 hours prior to enrolling in the study. Subjects who 
discontinue from screening due to COVID-19-related factors but are otherwise qualified to participate in the 
trial may be rescreened at any time if the Takeda medical monitor agrees.
Study Treatment Phase
Approximately 550 subjects with an asymptomatic CMV infection who meet eligibility requirements during the 
screening phase, including the presence of quantifiable (local or central specialty laboratory) whole blood or 
plasma CMV DNA levels as specified, will be stratified based on their CMV viral load and GVHD status, and 
then randomized at Visit 2/Day 0 to receive either double-blind maribavir/placebo or valganciclovir/placebo 
(collectively, the study treatment) for 8 weeks.
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Historical laboratory results for tests specified in the Schedule of Assessment 1 may be used for eligibility 
assessment (HIV test results, relevant hematology, and chemistry results) as long as those are obtained within 
the specified time period. The Screening and Visit 2/Day 0 visits can occur on the same day, if laboratory results 
are available for the determination of eligibility.
All Visit 2/Day 0 procedures and screening laboratory results needed to confirm eligibility must be completed 
and documented prior to randomization and study treatment administration and all clinical laboratory results 
required for eligibility verification must be available prior to randomization, including two separate CMV DNA 
assessments. Initiation of study treatment (ie, first dose) will only occur after completion of all required 
Visit 2/Day 0 procedures, confirmation of eligibility, and completion of randomization. This will be done under 
the supervision of investigator site personnel.
Subjects randomized to receive maribavir will take the 400 mg BID dose for the 8 weeks of the study treatment 
phase. Maribavir 200 mg strength tablets will be utilized for the daily dosing.
Although typically valganciclovir treatment in HSCT patients is started as an induction dose of 900 mg BID for 
up to 14 days and then reduced to a maintenance dose of 900 mg QD for a further 2 weeks or until CMV viral 
load clearance (Tomblyn et al., 2009), a different dosing strategy was selected for this study based on input from 
regulatory authorities. Treatment with valganciclovir 900 mg BID for the duration of 8 weeks was chosen in 
order to eliminate a potential bias for efficacy in favor of the investigational treatment (maribavir) by 
administering the comparator (valganciclovir) at a lower dose. Dosage for valganciclovir (450 mg QD up to 
900 mg BID, as adjusted for renal function) will utilize 450 mg strength tablets.
Depending on the time of the first dose of study treatment on Visit 2/Day 0, a second dose should be 
administered on Visit 2/Day 0 provided that doses can be separated by a minimum of 8 hours; otherwise, 
only 1 dose should be administered on Visit 2/Day 0. Study treatment will then be administered (preferably) 
every 12 hours (q12h). When q12h dosing is not feasible, the doses should be separated by a minimum of 
8 hours.
To protect the study blind, subjects will be required to take 2 tablets of their assigned study treatment and 
2 tablets of the placebo q12h in a double-dummy format as shown in the table below.
Study Treatment Dosing – Standard Regimen
Regimen
AM
PM
maribavir
400 mg BID
maribavir active
400 mg (2 tablets)
400 mg (2 tablets)
valganciclovir placebo
placebo (2 tablets)
placebo (2 tablets)
valganciclovir
900 mg BIDa
valganciclovir active
900 mg (2 tablets)
900 mg (2 tablets)
maribavir placebo
placebo (2 tablets)
placebo (2 tablets)
BID: twice daily
a Starting dose for valganciclovir could be lower based on renal function results at screening (refer to dose 
adjustment tables for renal function).
Subjects randomized to receive valganciclovir will follow the 900 mg BID dosing regimen for the 8 weeks of 
the study treatment phase, with the exception of a permitted dose adjustment based on renal function and/or 
neutropenia. Subjects with estimated CrCl of ≥30 mL/min will be enrolled; adjustment of the valganciclovir 
dose for renal function will be allowed at study entry and during the study treatment phase consistent with 
valganciclovir label, as indicated in the table below. Placebo tablets will be assigned to make up for adjusted 
dose and decrease in valganciclovir tablets.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Valganciclovir Dosing – Adjustment for Renal Function
Valganciclovir 450 mg Tablets
CrCla (mL/min)
Dose
≥60
900 mg (2 tablets) BID
40 – 59
450 mg (1 tablet) BID
25 – 39
450 mg (1 tablet) QD
10 – 24
450 mg every 2 days
BID: twice daily; CrCl: creatinine clearance; QD: once daily
a An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas: 
For Males = (140 – age [years]) × (body weight [kg]) / [(72) × (serum creatinine [mg/dL])]
For Females = 0.85 × male value.
Valganciclovir administration is not recommended below CrCl of 10 mL/min.
In addition, as shown in the table below, predefined criteria for valganciclovir dose adjustment based on ANC 
level and CMV DNA clearance may be used to manage subjects that experience neutropenia.
Valganciclovir Dose Adjustment Based on ANC level and CMV DNA Clearance
ANC >1000/mm3
[1.0×109/L]
ANC based on local 
or central 
laboratory results
ANC 500/mm3 [0.5×109/L] 
to 1000/mm3 [1.0×109/L]
ANC based on local or 
central laboratory results
ANC<500/mm3 [0.5×109/L]
ANC based on local or central 
laboratory results
CMV DNA ≤ LLOQ 
(based on local or 
central specialty 
laboratory, most 
recent result prior to 
dose assessment 
should be considered)
Continue 
valganciclovir 
900 mg BID
Hematopoietic 
growth factors may 
be used at 
investigator’s 
discretion
May adjust valganciclovir 
dose to 450 mg BID or 
interrupt the dose and resume 
at 450 mg BID or 900 mg 
BID (dose choice at 
investigator’s discretion) once 
ANC >1000/mm3 [1.0×109/L]
Hematopoietic growth factors 
may be used at investigator’s 
discretion
May interrupt valganciclovir dose 
and resume at 450 mg BID or 
900 mg BID (dose choice at 
investigator’s discretion) once ANC 
>1000/mm3 [1.0×109/L]
Permanent valganciclovir 
discontinuation and alternative 
anti-CMV treatment may be 
considered at investigator’s 
discretion
Hematopoietic growth factors should 
be strongly considered
CMV DNA ≥LLOQ 
(based on local or 
central specialty 
laboratory, most 
recent result prior to 
dose assessment 
should be considered)
Continue 
valganciclovir 
900 mg BID
Hematopoietic 
growth factors may 
be used at 
investigator’s 
discretion
May adjust valganciclovir 
dose to 450 mg BID
Hematopoietic growth factors
may be used at investigator’s 
discretion
May interrupt valganciclovir dose 
and resume at resume at 450 mg BID 
or 900 mg BID (dose choice at 
investigator’s discretion) once ANC 
>1000/mm3 [1.0×109/L]
Permanent valganciclovir 
discontinuation and alternative 
anti-CMV treatment may be 
considered at investigator’s 
discretion
Hematopoietic growth factors should 
be strongly considered
ANC=absolute neutrophil count; BID=twice daily; CMV=cytomegalovirus; DNA=deoxyribonucleic acid; LLOQ=lower 
limit of quantitation; QD=once daily
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Various clinical scenarios of neutropenia will be programmed in the interactive response technology (IRT) and 
appropriate options will be selected by the investigator. Interruptions and discontinuation of study treatment will 
be conducted in a blinded manner; therefore, it is possible that treatment with either valganciclovir or maribavir 
will be interrupted or discontinued for neutropenia presence. The investigator may also select to interrupt study 
treatment, for other adverse events, regardless of the treatment assignment (maribavir or valganciclovir). The 
interruption for a maximum of 7 consecutive days will not result in permanent study treatment discontinuation. 
Up to 2 study treatment interruptions for a total of up to 7 days will be allowed. If study drug is interrupted for 
any reason and subsequently resumed, the end of the study drug administration period would remain fixed at a 
maximum of 8 weeks after the date of the start of treatment. A third study treatment interruption will lead to 
permanent study treatment discontinuation; the subject will complete the end of treatment procedures described 
for Visit 10/Study Week 8 in the Schedule of Assessment 1, and will follow a modified schedule of assessments 
through the remaining weekly visits scheduled for the study treatment phase and the regular schedule of 
assessments through the 12-week follow-up phase.
All subjects will undergo study-specific evaluations weekly during the study treatment phase. All subjects who 
complete the study treatment phase through Visit 10/Week 8 will enter the 12-week follow-up phase.
Subjects who permanently discontinue study treatment will complete the end of treatment procedures described 
for Visit 10/Study Week 8 in the Schedule of Assessment 1; these subjects will follow a modified schedule of 
assessments through the remaining weekly visits of the study treatment phase and the regular schedule of 
assessments through the 12-week follow-up phase. The end of treatment sample for immunosuppressant drug 
concentration will be collected at the next visit scheduled 1 week after the treatment discontinuation. Subjects 
who discontinue study treatment early will not be asked to complete the following procedures for subsequent 
visits in the treatment phase: the use of the diary for study treatment compliance, dispense or use of any study 
treatment, and PK sample collection. After completing the 8-weeks specified for the study treatment phase, 
subjects will enter the 12-week follow-up phase. After the permanent discontinuation of study treatment and 
until the end of the study, subjects might be administered other anti-CMV treatment as deemed necessary by the 
investigator. Subjects who withdraw from the study during the follow-up phase will perform the end of study 
evaluations and procedures for Visit 18/Week 20 (Follow-up Week 12) as soon as possible.
Subjects who withdraw consent during the study treatment phase will be asked to undergo all end of treatment 
evaluations and procedures listed for Visit 10/Week 8, if they agree; subjects who withdraw from the study 
during the follow-up phase will undergo all end of study evaluations and procedures listed for Visit 18/Week 20 
(Follow-up Week 12) as soon as possible and, whenever possible, if they agree, prior to initiation of any 
nonstudy anti-CMV treatment (as deemed necessary by the investigator); no further follow-up will be 
performed.
Follow-up Phase
Study-specific evaluations including central specialty laboratory CMV testing and safety assessments will occur 
weekly for the first 4 weeks, then every 2 weeks for the final 8 weeks of the 12-Week Follow-up Phase. Refer to 
Study Schedule 2 for a complete list of the evaluations.
Study Design Flow Chart
Visit 1
Wks -2 to -1
Screening
Phase
Double-blind
Phase
Follow-up
Phase
Visits 11-18
Wks 9-20
Every 2 Weeks
(last 8 wks)
Weekly
(first 4 weeks)
Visit 2
Wk 0
SHP620 400mg BID OR
ValGCV 900 mg BIDa
BL/
Rand
Visits 3-10
Wks 1-8
Double-blind
Study Drug Administration
Visit
2Ab
BID=twice daily; BL=baseline; Rand=randomized; wks=weeks
a Unless dose adjustment is required for moderate renal impairment.
b Visit 2A is required only for subjects receiving tacrolimus, cyclosporine, everolimus, or sirolimus at baseline.
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Notable Study Evaluations during Study Treatment Phase and Follow-up Phase
CMV DNA Quantitation
Blood samples will be assessed at a central specialty laboratory for the quantification of CMV DNA in plasma 
using the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test. Central specialty laboratory plasma CMV 
DNA results will be reported to the investigator site as available. Additional CMV DNA testing at local 
specialty laboratories may be performed at more frequent intervals or using additional assay methods at the 
discretion of the investigator.
Confirmed CMV viremia clearance will be defined as plasma CMV DNA concentration below the lower limit 
of quantification (<LLOQ; ie, <137 IU/mL]), when assessed by COBAS® AmpliPrep/COBAS® TaqMan® 
CMV Test at a central specialty laboratory, in two consecutive postbaseline samples, separated by at least 
5 days.
Confirmed Recurrence or the confirmed CMV viremia recurrence will be defined as plasma CMV DNA 
concentration ≥LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive 
plasma samples at least 5 days apart, after being unquantifiable (<LLOQ) for at least 5 days in 2 consecutive 
samples.
CMV Genotyping and Phenotyping
Subjects with known resistance to anti-CMV agents as determined by site local specialty laboratory (testing will 
be done as directed by the investigator) will be excluded from the study. At Visit 2/Day 0 plasma samples will 
be obtained and tested by the central specialty laboratory to identify mutations in the viral UL97 and UL54 
genes known to confer resistance to anti-CMV agents. In addition, UL 27 will be tested. Given the urgency to 
treat the subjects, it is not possible to wait for this central specialty laboratory assessment prior to a subject’s 
randomization to confirm lack of resistance to any previously used agents. In instances when a mutation will be 
reported in the baseline sample analyzed by the central specialty laboratory these subjects will be excluded from 
the Per Protocol Set for analysis. Subjects will be managed based on investigator clinical judgments, and if 
resistance is suspected genotyping may be conducted by a local specialty laboratory at investigator discretion. It 
is not expected that the genotyping results from central specialty laboratory will be available in time to direct 
patient management.
 
 
Rebound is defined as increase in viral DNA load without prior clearance of viremia. The entire UL97, UL54, 
and UL27 CMV genes will be sequenced in every sample that meets the criteria for genotyping, including the 
baseline samples.
 
 
PK Assessment
Pharmacokinetic samples will be obtained for all subjects as in the Schedule of Assessments 1, but analyzed for 
only those subjects who are taking maribavir. Bioanalysis of PK samples will be conducted while the study is 
ongoing. The analysis will be conducted by unblinded staff from the bioanalysis lab/contract research 
organization (CRO) to allow for the identification of the PK samples from the subjects randomized to the 
maribavir treatment arm.
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Inclusion and exclusion criteria:
Approximately 550 subjects, ≥16 years of age, who are HSCT recipients with asymptomatic CMV infections 
will be enrolled.
Inclusion Criteria:
Subjects must:
1.
Be able to provide written, personally signed, and dated informed consent to participate in the study 
before completing any study-related procedures. As applicable, a parent/both parents or legally 
authorized representative (LAR) must provide signature of informed consent and there must be 
documentation of assent by the subject before completing any study-related procedures. During the 
COVID-19 public health emergency, informed consent from a potential or current trial participant 
may, if permitted by local laws and regulations, be obtained via electronic informed consent (eIC) 
capabilities or an electronic face-to-face consent interview when these individuals are unable to travel 
to the site (Food and Drug Administration [FDA] COVID-19 Guidance, 27 Jan 2021, Q11).
2.
Be ≥16 years of age at the time of consent.
3.
Be a recipient of hematopoietic stem cell transplant.
4.
Have a documented asymptomatic CMV infection, with a screening value of CMV DNA 
≥1365 IU/mL to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤ 91000 IU/mL in plasma in 
2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty 
laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA 
results. Both samples should be taken within 14 days prior to randomization with second sample 
obtained within 5 days prior to randomization. Same laboratory and same sample type (whole blood or 
plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection 
that does not present with tissue invasive CMV disease, as assessed by the investigator. Subjects with 
CMV DNA <910 and ≥455 IU/mL in plasma or <2730 and ≥1365 IU/mL in whole blood will also 
need to meet at least 1 of the following criteria for high-risk CMV infection to be eligible:

Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 1 of the 
following 3 HLA-gene loci: HLA-A, -B or -DR,

Haploidentical donor,

Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: HLA-A, -B, -C 
and -DRB1,

Use of umbilical cord blood as stem cell source,

Use of ex vivo T-cell-depleted grafts,

Grade 2 or greater GVHD, requiring the use of systemic corticosteroids (defined as the use of 
≥1 mg/kg/day of prednisone or equivalent dose of another corticosteroid).
5.
Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or 
reactivation, which, in the investigator’s opinion, requires treatment.
6.
Per investigator’s judgment, be eligible for treatment with valganciclovir.
7.
Have all of the following results as part of screening laboratory assessments (results from either the 
central laboratory or a local laboratory can be used for qualification):
a.
Absolute neutrophil count ≥1000/mm3 [1.0 x 109/L]
b.
Platelet count ≥25,000/mm3 [25 x 109/L]
c.
Hemoglobin ≥8 g/dL
d.
Estimated creatinine clearance ≥30 mL/min
8.
Have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test at screening, if a 
female of childbearing potential. Urine pregnancy tests may be done per institutional requirements; 
however, they are not sufficient for eligibility determination. Sexually active females of childbearing 
potential must agree to comply with any applicable contraceptive requirements of the protocol. If 
male, must agree to use an acceptable method of birth control, as defined in the protocol, during the 
study treatment administration period and for 90 days afterward the last dose of study treatment.
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9.
Be able to swallow tablets.
10. Have life expectancy of ≥8 weeks.
11. Weigh ≥40 kg.
12. Be willing and have an understanding and ability to fully comply with study procedures and 
restrictions defined in the protocol.
Exclusion Criteria:
Subjects must not:
1.
Have CMV tissue invasive disease as assessed by the investigator at the time of screening and 
randomization at Visit 2/Day 0.
2.
Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, 
foscarnet, or cidofovir based on documented evidence.
3.
Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a 
subject who had at least one previously documented episode of CMV infection post-transplant, and 
who has had at least 2 weeks of undetectable CMV DNA between the episodes during active 
surveillance, based on same local laboratory and same sample type). The subject must also have been 
off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection 
may be considered continuation of the prior infection.
4.
Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than 
CMV when study treatment is initiated (example: herpes simplex virus [HSV] co-infection requiring 
use of any of these agents after the randomization) or would need a co-administration with maribavir 
for CMV infection.
5.
Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated. NOTE: Subjects 
who may be receiving leflunomide must discontinue the use at least 14 days prior to randomization at 
Visit 2/Day 0 and the first dose of study treatment. Subjects receiving letermovir must discontinue 
3 days prior to first dose of study treatment. Subjects receiving artesunate must discontinue the use 
prior to the first dose of study treatment.
6.
Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet, or letermovir) for the 
current CMV infection for longer than 72 hours.
7.
Have known hypersensitivity to the active substance or to an excipient of the study treatments.
8.
Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the 
first dose of study treatment that would preclude administration of oral medication.
9.
Require mechanical ventilation or vasopressors for hemodynamic support at the time of 
randomization.
10. Be female and pregnant or nursing.
11. Have previously completed, discontinued, or have been withdrawn from this study.
12. Have received any investigational agent with known anti-CMV activity within 30 days before 
initiation of study treatment or CMV vaccine at any time.
13. Have received any unapproved agent or device within 30 days before initiation of study treatment.
14. Have any clinically significant medical or surgical condition that, in the investigator’s opinion, could 
interfere with interpretation of study results, contraindicate the administration of the assigned study 
treatment, or compromise the safety or well-being of the subject.
15. Have previously received maribavir.
16. Have serum aspartate aminotransferase (AST) >5 times upper limit of normal (ULN) at screening, or 
serum alanine aminotransferase (ALT) >5 times ULN at screening, or total bilirubin ≥3.0 x ULN at 
screening (except for documented Gilbert’s syndrome), as analyzed by local or central lab.
17. Have known (previously documented) positive results for human immunodeficiency virus (HIV). 
Subjects must have a confirmed negative HIV test result within 3 months of study entry or, if 
unavailable, be tested by a local laboratory during the screening period.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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18. Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the 
investigator. Subjects who experience relapse or progression of their underlying malignancy (for 
which HSCT was performed), as determined by the investigator, are not to be enrolled.
19. Be undergoing treatment for acute or chronic hepatitis C.
Maximum duration of subject involvement in the study:

Planned duration of Screening Phase: Up to 2 weeks

Planned duration of Study Treatment Phase: 8 weeks

Planned duration of Follow-up Phase: 12 weeks
Endpoints and statistical analysis:
Subject Populations:

The Enrolled Set will consist of all subjects who have signed an informed consent and have begun 
some study procedures.

The Randomized Set will consist of all subjects in the Enrolled Set for whom a randomization number 
has been assigned.

The Modified Randomized Set will consist of all subjects in the Randomized Set who have taken at 
least 1 dose of assigned study treatment.

The Safety Set will consist of all subjects who have taken at least 1 dose of study treatment.

The Per Protocol (PP) Set will consist of all subjects in the Randomized Set who do not have major 
predefined protocol deviations that may affect the primary efficacy assessment.

The Pharmacokinetic Set will consist of all subjects in the Safety Set who had plasma samples drawn 
and tested for maribavir concentrations.
o
The adolescent pharmacokinetic set will consist of a subset of the PK set of subjects 
of ≥16-<18 years of age who had plasma samples drawn and tested for maribavir 
concentrations.
The Modified Randomized Set and PP Set will be used for efficacy analyses. Pharmacokinetic data will be 
analyzed using the Pharmacokinetic Set.
Primary Efficacy Endpoint:
The primary efficacy endpoint of this study is confirmed clearance of plasma CMV DNA (CMV viremia 
clearance) at the end of Study Week 8.
For clearance of CMV viremia at the end of Study Week 8, the subject must have received exclusively a 
study-assigned treatment.
Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint is defined as the maintenance of confirmed CMV viremia clearance 
achieved at the end of Study Week 8 through Week 16.
For clearance of CMV viremia achieved at the end of Study Week 8, and maintenance of such effect through 
Week 16, the subject must have received exclusively a study-assigned treatment and must also have symptom 
control.
Secondary Efficacy Endpoints:

The achievement of the confirmed CMV viremia clearance after 8 weeks of receiving study-assigned 
treatment.

The maintenance of the confirmed CMV viremia clearance achieved after completion of 8 weeks of 
study-assigned treatment, through Study Weeks 12 (4 weeks of post-treatment period), 16 (8 weeks of 
post-treatment/follow-up phase), and 20 (12 weeks post-treatment).
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
The maintenance of confirmed CMV viremia clearance achieved at the end of Study Week 8 through 
Weeks 12 and 20, regardless of whether either study-assigned treatment was discontinued before the 
end of the stipulated 8 weeks of therapy. For maintenance effect to be achieved at a time point, the 
subject must have received exclusively study-assigned treatments up to that time point and also must 
have symptom control.

The recurrence of confirmed CMV viremia in the 2 study treatment arms during the first 8 weeks of the 
study, during the 12 weeks of the follow-up study phase, and at any time during the study, regardless of 
whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of 
therapy.

The recurrence of confirmed CMV viremia in the 2 study treatment arms when subjects are on 
treatment and off treatment.

The incidence of grade 3 or 4 neutropenia (defined as ANC <1,000/mm3 [1.0×109/L] or ANC 
<500/mm3 [0.5×109/L], respectively) while receiving study treatment, time to first neutropenia 
development while receiving study treatment.
Exploratory Efficacy Endpoints:
 
 
Safety Endpoints (Secondary):

Treatment-emergent AEs and treatment-emergent SAEs, overall study AEs and overall study SAEs

Clinical laboratory evaluations (including incidence of neutropenia defined as ANC <500/mm3
[0.5×109/L] or ANC <1,000/mm3 [1.0×109/L] at any time during the study (on treatment and overall 
study period), time to neutropenia development).
Pharmacokinetic endpoints for maribavir treatment
Pharmacokinetic samples will be obtained for all subjects as in the Schedule of Assessment 1, but analyzed for 
only those subjects who are taking maribavir.

Maribavir Cmin (predose maribavir concentration)
For adolescent subjects who provided intensive PK samples at Visit 3/Week 1:

AUC(0-tau): area under the concentration time curve over the 12-hour dosing interval at steady state

Cmax: maximum concentration

Tmax: time when maximum concentration is observed

CL/F: apparent oral clearance

Vz/F: apparent volume of distribution
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Exploratory endpoints:
 
Statistical Methodology for Primary Efficacy Endpoint:
Confirmed CMV viremia clearance at the end of Study Week 8, irrespective of treatment duration is defined as 
plasma CMV DNA concentrations <LLOQ (ie, <137 IU/mL), when assessed by COBAS® AmpliPrep/COBAS®
TaqMan® CMV Test at a central specialty laboratory, in 2 consecutive postbaseline samples separated by at 
least 5 days at the end of Study Week 8.
Assessments of Virological Responders at Study Week 8
Scenario
CMV DNA Weeks on Study
Response
Rationale
Week 6
Week 7
Week 8
Week 9a
1
+ / -
-
-
+/-/NA
Yes
2 consecutive “-” at Week 7 and 
Week 8
2
+ / -
-
+
+/-/NA
No
Not 2 consecutive “-” at Week 7 and 
Week 8
3
+ / -
+
-
+/-/NA
No
Not 2 consecutive “-” at Week 7 and 
Week 8
4
+ / -
-
NA
-
Yes
2 consecutive “-” as shown by 
available data and both “-”at Week 7 
and Week 9 for missing Week 8, 
otherwise nonresponder
5
-
NA
-
+/-/NA
Yes
2 consecutive “-” as shown by 
available data and both “-” at Week 6 
and Week 8 for missing Week 7, 
otherwise nonresponder
6
-
NA
NA
-
Yes
2 consecutive “-” as shown by 
available data at Week 6 and Week 9 
and both “-”, otherwise nonresponder
NA = not available for evaluation of study drug effect; reason could be starting alternative anti-CMV treatment, withdrawal 
from study etc.
a Week 9 data, if available to evaluate effect of study drug, to be used only if Week 8 data is unavailable or missing.
Notes: Scenarios in the table above are provided as examples and may not be inclusive of all possibilities. Only CMV DNA 
data evaluable for assessment of effect of study drug will be included (ie, prior to the start of alternative anti-CMV treatment 
if any).
"-" = CMV DNA concentration <LLOQ (<137 IU/mL)
"+" = CMV DNA concentration ≥LLOQ (ie, quantifiable)
Confirmed clearance of plasma CMV DNA (CMV viremia clearance) = 2 consecutive postbaseline assessments of CMV 
DNA target <LLOQ, separated by at least 5 days.
Statistical Methodology for Primary Efficacy Endpoint:
The difference in proportion of subjects with confirmed CMV viremia clearance, at the end of Study Week 8, 
irrespective of treatment duration, between treatment groups (maribavir and valganciclovir) will be obtained 
using Cochran-Mantel-Haenszel (CMH) weighted average across strata with baseline plasma CMV DNA 
concentration levels and presence or absence of acute GVHD as the stratification factors. The baseline plasma 
CMV DNA concentration will be the last central laboratory assessment before the first dose of study treatment. 
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The 2-sided 95% confidence interval (CI) of the weighted average of difference across strata will be calculated 
using the normal approximation method. If the lower limit of the 95% CI is greater than -7%, it will be 
concluded that maribavir is as efficacious as valganciclovir. The noninferiority analysis will be performed on 
the PP Set as the primary analysis and on the Modified Randomized Set as a secondary analysis.
Sensitivity and supportive analyses of the primary endpoint of confirmed CMV viremia clearance at Week 8 
will be conducted to evaluate the robustness of the results from the primary method.
Subject to the multiplicity adjustment method, the superiority will be tested by comparing the lower limit of the 
95% CI of the difference in proportion of subjects with confirmed CMV viremia clearance between maribavir 
and valganciclovir with 0. The superiority testing will be performed on the Modified Randomized Set.
Analyses will be conducted for the following subgroups (inclusive, but not limited to):

Cytomegalovirus DNA viral load (high, low, very low/high-risk)

Acute GVHD presence/absence at baseline

Adolescents ≥16 to <18 years of age (exploratory analysis: may be conducted if sample size is 
adequate)
Statistical Methodology for Key Secondary Efficacy Endpoint:
The difference in proportion of subjects who achieve response as defined for the key secondary efficacy 
endpoint between treatment groups (maribavir and valganciclovir) will be obtained using CMH weighted 
average across strata with baseline plasma CMV DNA concentration (based on the last central laboratory 
assessment before the first dose of study treatment) and presence or absence of acute GVHD as the stratification 
factors. The 2-sided 95% CI of the weighted average of difference across strata will be calculated using the 
normal approximation method. Sensitivity analyses for the key secondary endpoint will also be conducted.
Subject to the multiplicity adjustment method, the noninferiority testing will be done using the same NI margin 
as the primary efficacy endpoint. If the lower limit of the 95% CI is greater than -7%, it will be concluded that 
maribavir is as efficacious as valganciclovir in maintaining treatment effect. The noninferiority analysis will be 
performed on the PP Set as the primary analysis and on the Modified Randomized Set as a secondary analysis.
Subject to the multiplicity adjustment method, the superiority in key secondary efficacy endpoint will be tested 
by comparing the lower limit of the 95% CI of the difference in proportion of subjects who achieve response as 
defined for the key secondary efficacy endpoint between maribavir and valganciclovir with 0. The superiority 
testing will be performed on the Modified Randomized Set.
Multiplicity Adjustment:
The hypothesis testing of the primary and key secondary efficacy endpoints will be adjusted for multiple 
comparisons following the gatekeeping strategy as described below to control the family-wise Type 1 error rate 
at α=5% level. The testing will be done in the order of primary efficacy endpoint NI hypothesis testing (H11) 
first, the superiority hypothesis testing for primary efficacy endpoint (H12) and the key secondary efficacy 
endpoint NI hypothesis testing (H21) second, and lastly the superiority testing for key secondary efficacy 
endpoint (H22).

First, the NI hypothesis of the primary efficacy endpoint will be tested based on the 2-sided 95% CI of 
the adjusted difference in proportion of subjects who have CMV viremia clearance at the end of Study 
Week 8 stratified by baseline CMV DNA concentration level and presence/absence of acute GVHD at 
baseline. This analysis will be conducted using PP Set as the primary and Modified Randomized Set as 
secondary. If the lower limit of the 95% CI is above -7%, NI of the primary efficacy endpoint is 
considered established.

If and only after the NI of the primary efficacy endpoint is established, the superiority hypothesis of the 
primary efficacy endpoint and the NI hypothesis of the key secondary endpoint will be tested in 
parallel. Hochberg procedure will be used to control family-wise Type 1 error rate at α=5% level.

If and only if the superiority of the primary efficacy endpoint and NI of key secondary efficacy 
endpoint are established, the superiority hypothesis of the key secondary efficacy endpoint will be 
tested.
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Statistical Methodology for Safety Endpoints:
The safety analyses will include evaluation and procedures to meet the secondary objective of assessing the 
safety and tolerability of study treatments.
Safety evaluation will be made during the periods as illustrated in the Study Design Flow Chart, (ie, Screening 
Phase, Treatment Phase, and Follow-up Phase).
Two observation periods are defined for the purpose of analyses:
1)
The on-treatment observation period starts at the time of study treatment initiation through 7 days after
the last dose of study treatment. For subjects who transfer from the study treatment to a nonstudy
anti-CMV treatment, the on-treatment observation period starts at the time of the study treatment
initiation through 7 days after the last dose of study treatment, or until the nonstudy anti-CMV
treatment initiation, whichever is earlier.
2)
The overall-study observation period starts at the time of the start of the study treatment through the
end of the study.
Treatment-emergent AEs (TEAEs) are defined as those with a start date on or after the first dose of study 
treatment, or with a start date before the date of first dose of study treatment, but increasing in severity 
after the first dose of study treatment.
The overall study AEs are those occurring during the overall-study observation period.
Safety endpoints will be summarized descriptively for the on-treatment period, and overall-study period, 
as appropriate. Baseline assessments will be the last assessment before the first dose of study treatment.
The number of events, incidence, and percentage of TEAEs and overall-study AEs will be displayed for each 
treatment group by preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA®). 
Summaries in terms of severity and relationship to study medication will also be provided. Treatment-emergent 
SAEs will be summarized separately in a similar fashion. Summaries of AEs causing discontinuation of study 
medication, withdrawals, AEs leading to death, SAEs, and adverse events of special interest (AESI) will be 
provided.
Adverse events of special interest (AESIs) will be analyzed according to primary system organ classes 
(SOCs) and preferred terms (PTs). Standardized MedDRA queries (SMQs) may be used, as applicable. 
Summary tables with SOCs and PTs will be generated presenting the number and percentage of subjects 
by AE, severity, seriousness, and relationship to study medication. Invasive bacterial and fungal 
infections, if any, will be noted.
Usage of concomitant medications will be summarized descriptively for each of the treatment groups for 
the on-treatment period and overall-study period. Additionally, administration of hematopoietic growth 
factors, blood, and blood products will be summarized.
Change from Baseline in vital signs and clinical laboratory tests will be summarized for each treatment 
group with descriptive statistics at each assessment visit. Additional shift tables may be produced for 
selected laboratory parameters using severity grades based on National Cancer Institute (NCI) common 
terminology criteria for adverse events (CTCAE v4.0) or using normal/above normal/below normal 
range. Analyses of shifts in NCI CTC toxicity grades from baseline to maximum grade postbaseline for 
the on-treatment period and the overall-study period will be analyzed. Potentially clinically important 
findings will also be summarized.
Treatment-emergent grade 3 or 4 neutropenia (defined respectively as ANC <1,000/mm3 [1.0 x 109/L]) or ANC 
<500/mm3 [0.5 x 109/L]) will be summarized as shifts in laboratory results from lower grade to maximum grade 
of either 3 or 4 postbaseline for the on-treatment period and the overall-study period. Time to neutropenia 
development will be evaluated.
Study treatment dose adjustment, specifically valganciclovir dose adjustment, and interruptions for 
neutropenia or renal function impairment or other AE, and maribavir dose interruptions for any AE, will 
be summarized.
Abnormal physical examination findings will be listed.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Summary of ECG findings will be provided by treatment groups.
An independent Data Monitoring Committee (DMC) will be established to assess the data for safety and 
to ensure the validity and scientific merit of the trial. Detailed plans for the DMC’s purpose and 
responsibilities will be described in the DMC charter and the statistical analysis plan.
PK Analysis:
In order to maintain the study blind, if needed, an interim population PK analysis of maribavir PK data obtained 
from the study subjects will be performed by an independent unblinded team.
Sample Size Justification:
The primary testing is to establish that maribavir is not inferior to valganciclovir in treatment of CMV infection 
in HSCT recipients. For ethical reasons it would not be possible to conduct a study of maribavir versus placebo 
since different treatment strategies are already used and well established in clinical practice to treat CMV 
infection. Valganciclovir has been selected as the active control because of its documented effectiveness for the 
treatment of CMV infection, including in patients after hematopoietic stem cell transplantation. While clinical 
trials of ganciclovir and valganciclovir versus placebo have been conducted for CMV prophylaxis, no 
placebo-controlled studies have been done to date for the treatment of CMV infection or disease. Therefore, the 
effect size of valganciclovir against placebo is not available, and treatment effect estimate had to be derived 
indirectly. Literature reports viremia clearance rate for valganciclovir at 70% to 100%. In the VICTOR study, a 
randomized controlled study to compare valganciclovir with ganciclovir for the treatment of CMV disease in 
SOT subjects (Asberg et al., 2007), the Week 7 viremia clearance rate was reported at 67% and the derived 
lower limit of the 95% CI was 60% for valganciclovir treatment group (n=164). In Phase 2 treatment 
SHP620-203 study, 75% of HSCT subjects (n=61 across 3 dose groups) in the maribavir group and 48% in 
valganciclovir group (n=21) had confirmed CMV viremia clearance within 6 weeks. Based on these available 
data, the proportion of subjects who achieve viremia clearance after 8 weeks of treatment in the current study is 
assumed at 60% for the valganciclovir treatment group.
A 7% NI margin is chosen for the current study based on the following considerations. First, a 7% of margin 
preserves at least 85% of the effect size assumed for the valganciclovir treatment group. Secondly, a 7% margin 
is less than half of 15%, a common NI margin used in antiviral trials and is considered very conservative. 
Two NI studies on comparing valganciclovir with ganciclovir in CMV treatment were identified after a 
thorough literature research. One study was reported by Chawla et al. 2011, and the other is VICTOR study 
(Asberg et al., 2007); both used a NI margin of 15%. Discussions with clinical experts confirmed that a 7% NI 
margin is considered a conservative choice and in clinical practice, a lower response rate might even be 
considered given the favorable safety profile of the test drug and where toxicities of available treatments such as 
valganciclovir limit their use.
Based on SHP620-203 study reporting 75% of HSCT subjects in the maribavir group and 48% in valganciclovir 
group having confirmed CMV viremia clearance within 6 weeks, it could be expected that maribavir may be 
superior to valganciclovir in the treatment setting in the HSCT population. However, given the uncertainties 
from the differences in this study design from that of SHP620-203, literature reported treatment effect for 
valganciclovir, and practical consideration for enrollment of sufficient number of patients in this orphan patient 
population, the primary objective of this study is testing for noninferiority, with testing for superiority to be 
conducted only after non inferiority is established.
For sample size calculation, to be conservative, it is assumed that 68% and 60% subjects will achieve confirmed 
CMV viremia clearance for the primary efficacy endpoint, in the maribavir and valganciclovir groups, 
respectively. Using the normal approximation method, a 2-sided 95% confidence interval (CI) of the difference 
in the proportions of subjects with the confirmed CMV viremia clearance will be calculated. If the lower limit of 
the CI is greater than the predefined NI of 7%, the noninferiority will be assumed. The sample size is estimated 
based on a 2-group test of equivalence in proportions by using nQuery Advisor 7.0. Based on the above 
assumptions, 494 eligible subjects (247 per treatment group) will result in a >90% power to declare 
noninferiority of maribavir to valganciclovir for the primary efficacy endpoint. Considering 10% subjects who 
are not in the PP Set due to dropout, 550 subjects (275 subjects per treatment arm) will be enrolled and 
randomized.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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STUDY SCHEDULES
Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phasea
Double-blind Study Treatment Phasea,b
Study Visit
1c
2
2Ad
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Weeke
-2 to 0
0
1
1
2
3
4
5
6
7
8
Study Day (permitted window)
-14 to 0
0f
4 (±1)
7 (+2) 14 (±2) 21 (±2) 28 (±2) 35 (±3) 42 (±3) 49 (±3)
56
Informed consentg
X
Inclusion/exclusion criteria
X
X
Randomization
X
Physical examination (including weight)h
X
X
X
Height
X
Weight
X
X
X
Vital signs
X
X
X
X
X
X
Medical history
X
Xi
Prior medications, therapies, and procedures
X
X
12-lead ECGj
X
X
Hematology/Chemistryk
X
X
X
X
X
X
X
X
X
X
X
Urinalysisk
X
X
X
X
X
Pregnancy testl
X
X
X
X
HIV statusm
X
HBV, HCV test
Xn
CMV DNA testo
Xp
X
X
X
X
X
X
X
X
X
Immunosuppressant drug concentration levelsd
Xs
Xs
Xs
X
PK samplest
X
Xs
X
Interactive Response Technologyu
X
X
X
X
X
X
X
X
X
Study treatment dispensedv
X
X
X
X
X
X
X
X
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phasea
Double-blind Study Treatment Phasea,b
Study Visit
1c
2
2Ad
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Weeke
-2 to 0
0
1
1
2
3
4
5
6
7
8
Study Day (permitted window)
-14 to 0
0f
4 (±1)
7 (+2) 14 (±2) 21 (±2) 28 (±2) 35 (±3) 42 (±3) 49 (±3)
56
Study diaryw
X
X
X
X
X
X
X
X
X
X
Underlying disease assessmentx
X
X
X
X
X
X
X
X
X
X
Invasive bacterial and fungal 
infection/transplant relevant infections 
assessment
X
X
X
X
X
X
X
X
X
X
GVHD assessmenty
X
X
X
X
X
X
X
X
X
X
Liver function assessment by Child-Pugh 
classification
X
Comorbidity status evaluation
X
X
X
Concomitant medications, therapies, and 
proceduresz
X
X
X
X
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
X
X
X
X
X
AE=adverse event; CMV=cytomegalovirus; ECG=electrocardiogram; 
; GVHD=graft-versus-host-disease; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; hx=history; IRT=interactive response technology PK=pharmacokinetic; 
SAE=serious adverse event; 
a Study Visit 1 (Screening) and Study Visit 2 (Randomization) must be done with the subject present at the investigative site. Study Visits 2A through 10 may be conducted at 
the clinic or by optional home healthcare visits to extend flexibility to subjects during the COVID-19 public health emergency, although it is preferable to conduct Study 
Visit 10 (End of Treatment) with the subject present at the investigative site. Home healthcare visits will be documented in the study records and eCRF. 
b Subjects who permanently discontinue study treatment will complete the end-of-treatment procedures described for Visit 10/Study Week 8; these subjects will continue a 
modified schedule of assessments through the remaining weekly visits scheduled for the study treatment phase and the regular schedule of assessments through the 12-week 
follow-up phase. The end of treatment sample for immunosuppressant drug concentration level will be collected at the next visit scheduled one week after the treatment 
discontinuation. Subjects who discontinue study treatment early will not be asked to complete the following procedures after the end of treatment visit for subsequent visits in 
the study treatment phase: the use of the diary for study treatment compliance, dispense or use of any study treatment, and PK sample collection. After completing the 8-week 
duration specified for the study treatment phase, subjects will enter the 12-week follow-up phase.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phasea
Double-blind Study Treatment Phasea,b
Study Visit
1c
2
2Ad
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Weeke
-2 to 0
0
1
1
2
3
4
5
6
7
8
Study Day (permitted window)
-14 to 0
0f
4 (±1)
7 (+2) 14 (±2) 21 (±2) 28 (±2) 35 (±3) 42 (±3) 49 (±3)
56
c Obtaining Informed Consent is not restricted to Study Visit 1 but can be obtained during the course of the screening phase (Study Weeks -2 to 0) as long as it is obtained 
before any study-specific procedures are performed. During the COVID-19 public health emergency, informed consent from a potential or current trial participant may be
obtained via electronic informed consent (eIC) capabilities or an electronic face-to-face consent interview when these individuals are unable to travel to the site (FDA 
COVID-19 Guidance, 27 Jan 2021, Q11), if permitted by local laws and regulations. All other assessments must be done at the investigative site. 
d Immunosuppressant drug concentration testing and Visit 2A are solely for subjects receiving immunosuppressive therapy with tacrolimus, cyclosporine, everolimus, or 
sirolimus. Visit 2A will occur at Day 4±1 day for subjects receiving immunosuppressive agent at baseline; or 4±1 days after initiating one of these immunosuppressive 
treatments for subjects who start during the study.
e Permissible assessment windows: Study Visit 2A, ±1 day, Study Visit 3 (Week 1) +2 days, Study Weeks 2-4, ±2 days; Study Weeks 5-8, ±3 days.
f Screening and Visit 2/Day 0 visits can occur on the same day in the case when historical laboratory values are available for determination of the eligibility. All Visit 2/Day 0 
procedures and screening laboratory results needed to confirm eligibility must be completed and documented prior to randomization and initiation of study treatment. The test 
results for the samples taken at Visit 2, from central laboratory or central specialty laboratory, will not be available to be used for the screening. Initiation of study treatment 
(ie, first dose) will only occur after completion of all required Visit 2/Day 0 procedures, confirmation of eligibility, and completion of randomization. This will be done under 
the supervision of investigator site personnel.
g Informed consent must be obtained before any study-specific procedures are performed. All screening procedures will be completed within 14 days prior to initiation of study 
treatment, with the exception of: 1) screening clinical laboratory tests (hematology, chemistry, pregnancy), which must be performed and verified within 3 days prior to 
initiation of study treatment; either central or local laboratory results for hematology/chemistry/pregnancy testing can be used for qualification, and 2) documentation of CMV 
infection in whole blood or plasma, with a screening value of ≥1365 IU/mL to <273000 IU/mL in whole blood or ≥455 IU/mL to <91000 IU/mL in plasma in 2 assessments, 
separated by at least one day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA 
results. Results should be available before the subject is randomized to verify subject eligibility for the study. Both samples should be taken within 14 days of randomization 
with second sample obtained within 5 days before randomization. Same laboratory and sample type (whole blood or plasma) should be used for these assessments.
h Symptom-oriented physical examinations other than protocol-specified examinations will be performed when clinically indicated.
i Updated medical history on Visit 2/Day 0 (Section 5.1).
j ECGs other than protocol-specified ECGs will be performed when clinically indicated. For home healthcare visits, ECGs may be performed by a qualified healthcare 
professional who is certified/authorized by the Principal Investigator to perform such tests routinely.
k Clinical laboratory tests will be performed at a central laboratory for all specified time points during the study with the exception of Visit 2A (for subjects receiving 
tacrolimus, cyclosporine, everolimus, or sirolimus); a local lab will assess potassium and magnesium at Visit 2A for these subjects. Central or local laboratory results for 
hematology/chemistry/ pregnancy testing can be used for eligibility and their results must be available prior to randomization. Local laboratory beta human chronic 
gonadotropin test results can be used for the assessment of pregnancy on Visit 2/Day 0/Week 0, prior to study drug administration. Sample for 
hematology/chemistry/pregnancy will be taken for analyses by the central laboratory before study drug administration at baseline. For subsequent visits, in addition to 
samples taken for central laboratory analysis at the visit, samples for complete blood count with differential and serum creatinine should be drawn and analyzed by a local
laboratory within 2 days prior to study treatment dispensation. These local laboratory results should be available and reviewed, to ascertain any dose adjustment of study drug 
(valganciclovir dose adjustment for renal function and/or neutropenia) can be conducted, if needed, prior to each study treatment dispensation during the treatment phase. For 
home healthcare visits, collection of clinical laboratory samples (blood specimen collection or other diagnostic tests) may be performed by the investigator or qualified site 
staff who can visit the trial participant’s residence.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phasea
Double-blind Study Treatment Phasea,b
Study Visit
1c
2
2Ad
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Weeke
-2 to 0
0
1
1
2
3
4
5
6
7
8
Study Day (permitted window)
-14 to 0
0f
4 (±1)
7 (+2) 14 (±2) 21 (±2) 28 (±2) 35 (±3) 42 (±3) 49 (±3)
56
l Female subjects of childbearing potential will have serum pregnancy testing performed at a central or local laboratory. Urine test results may be performed to accommodate 
institutional requirements, however, are not sufficient for eligibility determination.
m HIV status confirmed within 3 months prior to randomization will be used for the evaluation of this criterion. If a subject is known (previously documented) to be HIV 
positive, this information will be used in the eligibility assessment. Local testing during screening will be required for the eligibility assessment for subjects for whose HIV 
status within the 3 months prior to study entry is unknown; negative results must be confirmed prior to randomization.
n HBV and HCV historical results available within 3 months prior to study treatment initiation will be accepted. If historical values are not available then the test will be 
performed at Visit 2/Day 0. The results of test do not have to be available prior to start of dosing.
o Blood samples taken at all study visits (processed to obtain plasma), for all CMV DNA tests (quantitation, genotyping) will be tested in the central specialty laboratory. 
During screening period, local specialty laboratory results for CMV DNA quantitation (from whole blood or plasma as per site’s standard practice) could be used for 
eligibility assessment; in this case CMV DNA results from central laboratory are not required. At baseline (Visit 2/Day 0/Week 0) a sample for the CMV DNA quantification 
will be taken and tested at the central specialty lab. At all other visits CMV DNA tests will be conducted at a central specialty laboratory, local specialty laboratory testing 
will be done at the investigator’s discretion. The screening results, regardless whether from the local or central specialty laboratory, will be utilized for stratification for 
randomization.
p To be eligible for randomization, both CMV DNA results must be ≥455 IU/mL in plasma or ≥1365 IU/mL in whole blood.
q Subjects with CMV disease at screening/baseline will be excluded. Subjects will be assessed at subsequent visits during the study for the development of new tissue invasive 
CMV disease, and disease outcome (no change, improvement, resolution).
 
s If the subject is receiving immunosuppressant drugs (cyclosporine, tacrolimus, sirolimus, or everolimus), as mentioned in Section 7.2.3.4, on Study Day 0, then a blood 
sample to measure immunosuppressant drug concentration will be obtained on Visit Day 0 prior to study treatment administration, at Visit 2A (Day 4 ±1 day), and on Visit 
Day 7 (+2 day). If the subject is not receiving immunosuppressant drugs at Day 0, but starts any time after Day 0 while still receiving study treatment, then a blood sample to 
measure immunosuppressant drug concentration will be obtained 4 days±1 day after initiating the immunosuppressant), and at the next scheduled study visit. Tests will be 
performed at a local laboratory. For more details see Section 7.2.3.4.
t Pharmacokinetic (PK) samples should be obtained for all subjects and analyzed for only those subjects who are taking maribavir. A PK sample will be taken before the 
morning dose of study drug at all 3 PK visits. A PK sample will also be taken 2-4 hour after the morning dose of study at Visit 3/Week 1 and Visit 10/Week 8. There will be 
no postdose PK sample collected for Visit 6/Week 4. At Visit 3/Week 1 an intensive PK sampling for children ≥16 and <18 years of age will be performed as follows: 
premorning dose, 1, 2, 3, 4, 6, 8 (all ±5 min), and 12 hours (±15 min) postmorning dose. PK sample collection for children ≥16 and <18 years of age will also be performed at 
Visit 6/Week 4 (one premorning dose PK sample) and at Visit 10/Week 8 (one premorning dose and one between 2-4 hours postmorning dose PK samples). Additional PK 
samples will be collected from the subjects with biopsy proven GI graft-versus host-disease (GVHD) with diarrhea (>300 ml/day) or biopsy proven GI GVHD with nausea 
and vomiting or documented acute GVHD of liver (Stage II), total bilirubin >3 mg/dL or biopsy-proven) with diarrhea (>500 ml/day) or biopsy proven acute GVHD of the 
skin with diarrhea (>500 mL/day) per Boeckh et al. (1998). See Section 7.2.4.1 for more details.
u The IRT system will be used for stratification and randomization of eligible subjects at baseline. IRT will be used for dispensing study treatment.
v All dispensed study treatments will be documented on the CRFs and/or other investigational product records, and may include additional information as required per 
applicable regulations. The disposition of unused supply of dispensed study treatment that has been prescribed to the subject will be documented in the accountability log.
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Table 1. Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phasea
Double-blind Study Treatment Phasea,b
Study Visit
1c
2
2Ad
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Weeke
-2 to 0
0
1
1
2
3
4
5
6
7
8
Study Day (permitted window)
-14 to 0
0f
4 (±1)
7 (+2) 14 (±2) 21 (±2) 28 (±2) 35 (±3) 42 (±3) 49 (±3)
56
w The study diary will be dispensed at baseline and will be collected at the last follow-up visit. 
 
x Underlying disease that led to HSCT, including relapse/progression, will be assessed at all visits throughout the study treatment phase.
y Subjects will be stratified at baseline according to presence/absence of acute GVHD.
z Includes recording of medications and transfusions of blood products. Changes in immunosuppression regimens will also be recorded.
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Table 2. Schedule of Assessment 2: Follow-up Phase
Phase
Follow-up Phasea,b
Visit
11
12
13
14
15
16
17
18 (End of 
Study)
Study Week (Follow-up Week)c
9 (1)
10 (2)
11 (3)
12 (4)
14(6)
16 (8)
18 (10)
20 (12)
Study Day (Follow-up Day)
63 (7)
70 (14)
77 (21)
84 (28)
98(42)
112 (56)
126 (70)
140 (84)
Physical examination (including weight)
X
Vital signs
X
12-lead ECGd
X
Hematology/Chemistrye
X
X
X
X
Urinalysise
X
Immunosuppressant drug concentration levelf
X
Underlying disease assessmentg
X
X
X
X
X
X
X
X
Invasive bacterial and fungal infection(s) assessment
X
X
X
X
X
X
X
X
CMV DNA testh
X
X
X
X
X
X
X
X
GVHD assessment
X
X
X
X
X
X
X
X
Comorbidity status evaluation
X
X
X
AE monitoringk
X
X
X
X
X
X
X
X
SAE monitoringk
X
X
X
X
X
X
X
X
Concomitant medications, therapies, and proceduresl
X
X
X
X
X
X
X
X
AE=adverse event; CMV=cytomegalovirus; ECG=electrocardiogram; GVHD=graft-versus-host-disease; HBV=hepatitis B virus; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; IRT=interactive response system; SAE=serious adverse event; 
a Subjects who withdraw from the study during the follow-up phase will perform the Visit 18/Week 20 (Follow-up Week 12) end-of-study procedures.
b If the subject is unable to or unwilling to travel to the site for the follow-up visits, these visits may be performed remotely (ie, at the subject’s home) by a qualified and 
authorized Principal Investigator’s designee, and only if permitted by local laws and regulations. However, it is preferable to conduct Study Visit 18 (End of Study) with the 
subject present at the investigative site. Blood sample for CMV DNA quantitation and clinical laboratory assessments will be collected. AE and SAE collection may be 
completed by telephone follow-up call on the day of the scheduled visit.
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Table 2. Schedule of Assessment 2: Follow-up Phase
Phase
Follow-up Phasea,b
Visit
11
12
13
14
15
16
17
18 (End of 
Study)
Study Week (Follow-up Week)c
9 (1)
10 (2)
11 (3)
12 (4)
14(6)
16 (8)
18 (10)
20 (12)
Study Day (Follow-up Day)
63 (7)
70 (14)
77 (21)
84 (28)
98(42)
112 (56)
126 (70)
140 (84)
c Permissible assessment windows: Study Weeks 9-12 (Follow-up Weeks 1-4) ±2 days; Study Weeks 14-20 (Follow-up Weeks 6-12) ±3 days.
d ECGs other than protocol-specified ECGs will be performed when clinically indicated. For home healthcare visits, ECGs may be performed by a qualified healthcare 
professional who is certified/authorized by the Principal Investigator to perform such tests routinely.
e Clinical laboratory testing performed at a central laboratory for all specified time points during the follow-up phase.
f See Section 7.2.3.4 for more details.
g Underlying disease that led to HSCT, including relapse/progression, will be assessed at all visits throughout the follow-up phase.
 
k SAEs and nonserious AEs deemed related to study drug will be monitored and recorded through Visit 18/Week 20/Follow-up Week 12 (end of study). Nonserious AEs will 
be recorded through 30 days after the last dose of study medication.
l All medications, therapies, and procedures used to treat AEs will be recorded through Visit 18/Week 20 (Follow-up Week 12/end of study).
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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1. BACKGROUND INFORMATION
1.1 Indication and Current Treatment Options
Cytomegalovirus (CMV) is a beta herpesvirus that commonly infects humans; serologic 
evidence of prior infection can be found in 40-100% of various adult populations 
(de la Hoz et al., 2002). It is one of the most important complications associated with 
significant morbidity and mortality in the individuals with compromised immune systems after 
allogenic hematopoietic stem cell transplantation (HSCT) (de la Hoz et al., 2002; 
Razonable and Emery, 2004; Maffini et al., 2016). Cytomegalovirus can cause multiorgan 
disease in recipients of stem cell transplants, including pneumonia, hepatitis, gastroenteritis, 
retinitis, and encephalitis, and the disease can develop both early and late after the 
transplantation procedure (Boeckh et al., 2003; Boeckh and Ljungman, 2009; Krause et al., 1997; 
Zaia et al., 1997). In addition to the direct effects that manifest as CMV organ disease or 
symptomatic infection, CMV also is known to have several potential indirect effects. These 
indirect effects include an increased incidence of opportunistic infections, an association between 
CMV and graft-versus-host disease (GVHD), and reduced survival in HSCT patients 
(Boeckh and Ljungman, 2009). These effects are believed to be mediated by the virus’s ability to 
modulate the immune system, either directly or secondary to the host antiviral response through 
regulation of cytokine, chemokine, and/or growth factor production.
Prevention strategies based on prophylactic antiviral therapy have not been common in HSCT in 
contrast with solid organ transplant (SOT). Before the introduction of ganciclovir (one of the 
available anti-CMV agents), the vast majority of CMV infections occurred in the time period 
between engraftment and day 100 after hematopoietic SCT, with sporadic occurrences before 
engraftment (Bueno et al., 2002). However, whereas the prevalence of early CMV disease 
declined with intense antiviral drug use, the incidence of bacterial and fungal infections as well 
as late CMV disease increased, without an impact on the mortality rate 
(Ariza-Heredia et al., 2014; Boeckh et al., 2003; Zaia et al., 1997).
Although currently available systemic anti-CMV agents, intravenous (IV) or oral ganciclovir, 
oral valganciclovir (a prodrug of ganciclovir with improved bioavailability), IV foscarnet, and 
IV cidofovir are generally effective, however, their use is limited by their respective toxicities; 
bone marrow suppression caused by ganciclovir/valganciclovir and renal impairment caused by 
foscarnet or cidofovir (Boeckh et al., 2003; Ljungman et al., 2001; Maffini et al., 2016;
Reusser et al., 2002; Salzberger et al., 1997). These toxicities are of particular concern in HSCT 
recipients, in whom the bone marrow has been ablated or significantly suppressed, who receive 
ongoing immunosuppressants to prevent GVHD, or who may require the use of other therapies 
that are potentially toxic to the kidneys or other organs.
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Regardless of currently available antiviral strategies that exist for various high-risk transplant 
subjects, the adverse effects of these strategies have led to low use of prophylaxis in the HSCT 
recipients who continue to remain at risk for CMV infection within the early (initial ~3 months) 
or later post-transplantation time periods (Boeckh et al., 2003; Legendre and Pascual, 2008).
In contrast, pre-emptive strategies are widely preferred as a prevention method by transplant 
centers and include close surveillance of target viral DNA concentration (CMV viremia), which 
varies depending on host’s risk for CMV disease, current immunosuppression, and treatment 
center practice. Cytomegalovirus viremia is considered one of the most important predictors of 
development of CMV disease (Emery et al., 2000; Humar et al., 1999).
The currently available anti-CMV agents (ganciclovir, valganciclovir, foscarnet, or cidofovir) 
albeit extensively used in preemptive and treatment setting for CMV infection are not approved 
for this indication, and their use is limited by their toxicities. Also, development of anti-viral 
resistance to these anti-CMV agents is an ongoing clinical problem leading to graft loss and even 
mortality for some transplant patients, including HSCT patients.
Maribavir is currently under development for the treatment of CMV infection or disease, 
including those resistant or refractory to ganciclovir, valganciclovir, foscarnet, or cidofovir, in 
transplant recipients (HSCT and SOT). Based on clinical studies completed to date, maribavir 
does not appear to cause bone marrow suppression or renal toxicities and therefore may offer a 
safer option for CMV treatment in HSCT patients.
1.2 Maribavir Background and Clinical Information
Maribavir is a potent and selective, orally bioavailable antiviral drug with a novel mechanism of 
action against CMV (Chulay et al., 1999) and a favorable nonclinical and clinical safety profile. 
It is a potent member of a new class of drugs, the benzimidazole ribosides 
(Williams et al., 2003). In side-by-side in vitro assays it is 3- to 20-fold more potent than 
ganciclovir and cidofovir, and at least 100-fold more potent than foscarnet 
(Biron et al., 2002; Drew et al., 2006). Unlike currently available anti-CMV agents that inhibit 
CMV deoxyribonucleic acid (DNA) polymerase, maribavir inhibits the CMV UL97 
serine/threonine kinase by competitively inhibiting the binding of adenosine triphosphate (ATP) 
to the kinase ATP-binding site (Biron et al., 2002; Williams et al., 2003; Krosky et al., 2003; 
Wolf et al., 2001; Kern et al., 2004); the dominant phenotypic inhibitory effect of maribavir is on 
viral DNA assembly and egress of viral capsids from the nucleus of infected cells 
(Biron et al., 2002). Except for ganciclovir, maribavir does not antagonize the effects of other 
anti-viral (anti-CMV) agents. Since ganciclovir is dependent on its initial phosphorylation by the 
viral UL97 kinase, maribavir may antagonize its clinical efficacy. Maribavir is active in vitro 
against strains of CMV that are resistant to ganciclovir, foscarnet, or cidofovir.
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1.2.1 Pharmacokinetics, Metabolism, and Drug-Drug Interactions
Following oral administration, maribavir was rapidly and well absorbed with mean peak plasma 
concentrations generally achieved between 1 and 3 hours postdose. Total exposure to maribavir, 
as measured by area under the curve (AUC), was approximately dose-proportional following a 
single dose from 50 to 1600 mg, or multiple doses from 300 to 2400 mg per day. Maribavir 
demonstrates time independent pharmacokinetics (PK). When coadministered with a moderate 
fat meal, maribavir AUC was not changed, while the maximum observed plasma concentration 
(Cmax) was reduced by 28%. Maribavir can be taken with or without food, as the slight to 
moderate decrease in exposure is not considered clinically significant based on the accumulated 
efficacy and safety data. Bioavailability of a 100 mg tablet was unaffected by crushing the tablet 
or changes in gastric pH. Maribavir is highly bound to plasma proteins (98.0% in vitro and 
98.5% to 99.0% ex vivo), and binding appears to be independent of maribavir plasma 
concentrations at the therapeutic doses and populations (healthy subjects, subjects with renal or 
hepatic impairment, and transplant patients). Maribavir can penetrate the blood-retinal barrier, 
with the ratio of vitreous humor to plasma maribavir concentrations ranging from 0.026 to 0.281, 
which is greater than the free fraction in plasma. Maribavir is not expected to cross the blood 
brain barrier in human based on the nonclinical data. Following 400 mg BID doses, the 
elimination half-life (t1/2) of maribavir was estimated to be 4.32 hours in adult transplant 
patients. Due to the relatively short t1/2, steady state was reached within 2 days of dosing, with 
the accumulation ratio ranging from 1.24 to 1.49 for AUC after BID dosing. Maribavir is 
metabolized primarily in the liver through cytochrome P450 (CYP) 3A4 (primary) and CYP1A2 
(secondary) pathways with the formation of the primary metabolite, VP44469. Renal clearance is 
a minor route of elimination of maribavir.
Based on in vivo data and population PK analysis, no maribavir dose adjustment is needed based 
on transplant type, age, gender, race, in patients with mild or moderate hepatic impairment, or in 
patients with mild, moderate, or severe renal impairment.
Maribavir is contraindicated with valganciclovir/ganciclovir as it may antagonize ganciclovir’s 
antiviral effects due to maribavir’s inhibitory effect on UL97 serine/threonine kinase, which is 
required for activation/phosphorylation of ganciclovir. Maribavir can be administered with other 
anti-CMV drugs, including letermovir, foscarnet, and cidofovir as clinically significant PK- or 
pharmacodynamic-based drug-drug interactions (DDIs) are not expected. Based on extensive in 
vitro and in vivo data, maribavir has a low propensity to cause, or be the victim of DDIs. Dose 
adjustment of maribavir is only needed when maribavir is coadministered with a strong or 
moderate CYP3A4 inducer. With the exceptions of selected immunosuppressants and 
rosuvastatin, coadministration with maribavir does not impact the use or outcomes of a wide 
range of other drugs commonly used in the target patient population.
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Strong or moderate CYP3A inducers may significantly decrease the plasma exposure to 
maribavir. Coadministration with rifampin (a strong inducer of CYP3A and moderate inducer of 
CYP1A2) decreased Cmax, AUC and predose trough concentration (Ctrough) by 39%, 60% and 
82%, respectively, and therefore, is not recommended due to the potential for a decrease in 
efficacy of maribavir based on the magnitude of the reduction in maribavir Ctrough. Alternative 
antimicrobial or antituberculosis therapy with a lower CYP3A induction potential (eg, 
pyrazinamide, ethionamide) should be considered.
Strong CYP3A4 inhibitors may increase the plasma exposure to maribavir. Coadministration 
with ketoconazole (a strong CYP3A and P-glycoprotein [P-gp] inhibitor) increased Cmax and 
AUC by 10% and 53%, respectively. Based on the less than 3-fold increase in maribavir 
exposure expected, lack of dose-limiting toxicity and a wide therapeutic window, maribavir can 
be coadministered with a strong CYP3A4 inhibitor (eg, clarithromycin, ketoconazole, 
itraconazole, posaconazole, and voriconazole) without dose adjustment.
Coadministration of 400 mg BID maribavir with tacrolimus (an immunosuppressant and a 
CYP3A4 and P-gp substrate) increased the tacrolimus whole blood Cmax, AUC, and Ctrough by 
38%, 51%, and 57%, respectively. When immunosuppressants tacrolimus, cyclosporine, 
everolimus, or sirolimus are coadministered with maribavir, their whole blood concentrations 
should be frequently monitored during treatment and after discontinuation of maribavir.
Maribavir is an in vitro inhibitor of breast cancer resistance protein (BCRP). To be cautious, it is 
recommended that when initiating maribavir dosing in patients who are taking rosuvastatin (a 
sensitive BCRP substrate), patients should be closely monitored for rosuvastatin-related events, 
especially the occurrence of myopathy and rhabdomyolysis.
1.2.2 Efficacy
Once the safety and tolerability of maribavir was established across a wide range of doses (up to 
2400 mg/day for 28 days) in 17 Phase 1 studies, the clinical development plan focused on 
maribavir as an anti-CMV agent for the prevention of CMV disease in transplant patients. 
Results from the Phase 3 trials for CMV prevention, where maribavir was administered at 
100 mg BID for up to 12 weeks in HSCT recipients and up to 14 weeks in liver transplant 
recipients, failed to show reduction in the incidence of endpoint adjudication committee 
confirmed CMV disease within 6 months following HSCT when compared with placebo 
(Study 1263-300), and failed to show noninferiority to ganciclovir with respect to the incidence 
of endpoint adjudication committee confirmed CMV disease within 6 months following liver 
transplantation (Study 1263-301).
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Maribavir was used for treatment of CMV infections in 6 transplant recipients (5 SOT, 1 HSCT) 
under individual emergency investigational new drug (EIND) applications in the 
United States (US) (Avery et al., 2010).
All patients had previously been treated with multiple other anti-CMV drugs, and 4 out of 6 had 
known genotypic CMV resistance to 1 or more of those CMV drugs. For all 6 patients, oral 
maribavir treatment was initiated at a dose of 400 mg BID. In 2 patients, the dose was increased 
to 800 mg BID. The duration of treatment was individualized for each patient based on response. 
Maribavir appeared to be safe and well-tolerated, as it was administered for prolonged periods of 
time (4 out of 6 patients were dosed >6 months). Three patients reported 7 serious adverse events 
(SAEs), all of which were considered to be unrelated to maribavir.
Within 6 weeks of starting maribavir treatment, all subjects had a >1 log decrease in blood CMV 
DNA, and 4 of the 6 patients had no detectable CMV. Cytomegalovirus viremia persisted in 
2 patients despite dosing >6 months; 1 of these patients had unusually low exposure to maribavir 
based on trough blood levels. The other patient in whom CMV viremia persisted had a very high 
baseline CMV DNA level. The genotypic analysis for this patient revealed the presence of 
UL97 maribavir-resistance mutations T409M and H411Y (Strasfeld et al., 2010).
Subsequently, in Europe, more than 200 patients received maribavir through a named patient 
program (NPP), and in France, through the authorized therapeutic-use procedure. Data from only 
a small subset of the French NPP were reported. These data were consistent with the US EIND 
experience. Additional details regarding these patients are available in the maribavir 
investigator’s brochure.
The data obtained from the small number of patients in EIND and NPP, suggested that maribavir 
was associated with a reduction in CMV DNA in the blood in the majority of subjects, and could 
be useful for the treatment of CMV infections including these that are resistant or refractory to 
currently available anti-CMV therapies. As a result, two Phase 2 studies were conducted to 
assess the safety, tolerability, and anti-CMV activity of maribavir for treatment of CMV 
infections: Study SHP620-202 in transplant recipients with CMV infections or disease that are 
resistant or refractory to treatment with anti-CMV agents conducted in the US and 
Study 1263-203 (SHP620-203) in transplant recipients with wild-type CMV infections who do 
not have CMV organ disease (asymptomatic) conducted in Europe. In these studies subjects 
received maribavir at 1 of 3 dose strengths: 400, 800, or 1200 mg BID. Both studies 
demonstrated favorable anti-CMV activity of maribavir and showed that maribavir was 
well-tolerated with no safety concerns at all doses evaluated.
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The primary efficacy endpoint for Study SHP620-202 was confirmed undetectable plasma CMV 
DNA within the 6 weeks after starting study drug treatment, defined as 2 consecutive 
postbaseline, on treatment undetectable results (<200 copies/mL) separated by at least 5 days. 
Overall, 67% of subjects achieved confirmed undetectable plasma CMV DNA within 6 weeks. 
Among maribavir groups, there was no strong evidence of dose strength differentiation in the 
proportion of subjects achieving the endpoint. Among subjects with ≥1 investigator-reported 
CMV genetic mutation associated with resistance to ganciclovir/valganciclovir or foscarnet at 
baseline, 43/71 (61%) achieved confirmed undetectable plasma CMV DNA within 6 weeks after 
starting treatment with maribavir.
Secondary efficacy endpoints for Study SHP620-202 included CMV recurrence, defined as 
achievement of undetectable plasma CMV DNA in at least 2 consecutive samples separated by at 
least 5 days at any time after Day 1, followed by detectable plasma CMV DNA in at least 
2 consecutive samples separated by at least 5 days. Overall, 30/86 (35%) maribavir subjects had 
a CMV recurrence at any time during the study (Note: Percentage is based on the number of 
subjects achieving undetectable CMV DNA). Twenty-four of the 30 subjects had a CMV 
recurrence while on study drug. Thirteen of these 24 subjects developed UL97 mutations 
previously described to confer resistance to maribavir that were not present prior to study drug 
dosing. The remaining 6 maribavir subjects had a CMV recurrence after the end of treatment 
with study drug.
The primary efficacy endpoint for Study SHP620-203 was confirmed undetectable plasma 
CMV DNA within 3 and 6 weeks after starting study drug treatment, defined as 2 consecutive 
postbaseline, on treatment undetectable results (<200 copies/mL) separated by at least 5 days. 
The proportion of subjects with undetectable plasma CMV DNA within 3 and 6 weeks 
after starting study drug treatment was numerically higher in the maribavir group than the 
valganciclovir group. Among the 3 maribavir dose strength groups, there was no difference 
in the proportion of subjects achieving the endpoint. In the subgroup of subjects whose 
transplant type was HSCT, a numerically higher percentage of subjects in the overall 
maribavir group (75%) than the valganciclovir group (48%) achieved confirmed undetectable 
plasma CMV DNA within 6 weeks. Although the percentage of subjects with high baseline 
plasma CMV DNA (≥10000 copies/mL) was similar between the overall maribavir and 
valganciclovir groups (34% vs. 33%), a numerically higher percentage of maribavir subjects 
(77%) achieved confirmed undetectable plasma CMV DNA within 6 weeks compared with 
valganciclovir (65%).
Secondary efficacy endpoints for Study SHP620-203 included CMV recurrence; this was 
assessed within 6 weeks after starting study drug treatment and within the study participation 
period. 
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Overall, 22/98 (22%) maribavir subjects and 5/28 (18%) valganciclovir subjects experienced a
CMV recurrence within the study participation period (Note: Percentages are based on the 
number of subjects achieving undetectable CMV DNA). Four of the 22 maribavir subjects 
recurred while on study drug (2 subjects each in the 400 mg BID and 800 mg BID groups). All 
4 of these subjects developed UL97 mutations previously described to confer resistance to 
maribavir that were not present prior to study drug dosing. The remaining 18 maribavir subjects 
and all 5 valganciclovir subjects experienced a CMV recurrence after the end of study drug 
treatment.
Phase 3 registration trials have been planned based on the results from these Phase 2 studies for 
CMV treatment.
1.2.3 Safety
Maribavir has been administered across a broad range of oral doses from 50-2400 mg/day. 
Clinical safety experience has been obtained from 17 Phase 1 studies in adult healthy volunteers, 
special populations (subjects with renal and hepatic impairment, and stable renal transplant 
recipients), and HIV-infected subjects.
Maribavir had a favorable safety and tolerability profile in both the Phase 2 and Phase 3 trials for 
CMV prophylaxis. Adverse events (AEs) were most commonly associated with gastrointestinal 
(GI) disorders (eg, diarrhea, dysgeusia, nausea, and vomiting). These events were generally of
mild or moderate intensity. There were no signals of clinically significant effects of maribavir on 
vital signs, electrocardiogram (ECG) parameters, or laboratory findings in the studies conducted 
for CMV prophylaxis.
In both Phase 2 studies for treatment of CMV infection (Studies SHP620-202 and SHP620-303), 
subjects received maribavir at 1 of 3 dose strengths: 400, 800, or 1200 mg BID, and both 
studies demonstrated that maribavir was well-tolerated with no safety concerns at all doses 
evaluated. In Study SHP620-202, treatment-emergent AEs (TEAEs) that occurred were events 
already observed in previous studies (ie, dysgeusia, GI events, elevated immunosuppressant drug 
levels, and rash) and there were no additional safety concerns raised from this study. In 
Study SHP620-203, TEAEs that occurred at a higher frequency in maribavir subjects compared 
with valganciclovir were events already observed in previous studies with maribavir 
(ie, dysgeusia, GI events, and elevated immunosuppressant drug levels). Analyses of clinical 
laboratory, vital signs, and ECG data did not identify any clinically meaningful differences 
across the maribavir treatment groups.
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Based on the Phase 2 CMV treatment and Phase 3 CMV prophylaxis studies, the adverse drug 
reactions (ADRs) associated with maribavir use are: abdominal pain, abdominal pain upper, 
decreased appetite, diarrhea, dizziness, dysgeusia, fatigue, headache, immunosuppressant drug 
level increased, nausea, and vomiting.
To date, maribavir has shown an overall favorable safety profile in placebo-controlled studies, 
open-label studies, and in studies that compared maribavir with other CMV therapies 
(ganciclovir, valganciclovir) for prophylaxis and for CMV treatment in HSCT and SOT patients. 
Treatment effect on viral load reduction (confirmed undetectable plasma CMV DNA: 67% of 
subjects within 6 weeks in Study SHP620-202; 60.5% of subjects in 3 weeks and 77.3% of 
subjects in 6 weeks in Study SHP620-203) seen in Phase 2 treatment studies coupled with 
acceptable safety and tolerability establish the positive benefit-risk profile and warrant further 
investigation of maribavir in the treatment of CMV infections in transplant recipients.
Refer to the latest version of the maribavir investigator’s brochure for the most detailed and most 
current information regarding the drug metabolism, pharmacokinetics, efficacy, and safety of 
maribavir.
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2. STUDY OBJECTIVES AND PURPOSE
2.1 Rationale for the Study
There are no anti-viral drugs specifically approved for treatment of CMV infection in transplant 
recipients, including in pediatric populations. However, both (IV) ganciclovir, approved for the 
treatment of CMV retinitis in immunocompromised patients including patients with AIDS and 
prevention of CMV disease in transplant recipients at risk for CMV disease, and oral 
valganciclovir approved for treatment of CMV retinitis in patients with AIDS and prevention of 
CMV disease in solid organ transplant recipient are widely used in clinical practice to treat CMV 
infection. The most common adverse effect of both treatments is bone marrow suppression, 
which is of particular concern for HSCT recipients whose marrow has been ablated or who are 
significantly immunosuppressed to prevent GVHD. Contributing factors for development of 
cytopenias include viral infection, septicemia, GVHD, and myelotoxic drugs in addition to 
valganciclovir. Of the commonly used drugs with myelotoxic potential, ganciclovir is 
particularly prone to cause neutropenia. The underlying mechanism of ganciclovir-related 
neutropenia is a dose-dependent inhibition of DNA-polymerase in hematopoietic progenitor cells 
(Sommadossi and Carlisle, 1987). The rates of valganciclovir-related neutropenia in HSCT range 
from 19% (Barkam et al., 2012) and 33% (Takahata et al., 2015) to 55% (Boeckh et al., 2015). In 
the study by Salzberger et al. (1997), a clear trend was observed between the degree of 
neutropenia and the rate of bacterial infections while an increased incidence of fungal infections 
was present only in patients with an absolute neutrophil count (ANC) of less than 200/μL, 
whereas there was no significant trend over the different degrees of neutropenia. In the same 
study neutropenia was found to be an independent risk factor for poor long-term outcome. This 
was shown as a negative effect on overall survival and nonrelapse mortality.
Maribavir is an anti-CMV agent that may be of particular benefit to transplant patients as it does 
not appear to cause bone marrow suppression. In addition to the favorable safety profile of 
maribavir observed in earlier Phase 1-3 studies (studies evaluating prophylactic administration of 
maribavir), results from a recent large Phase 2 randomized trial (Study 1263-203) support the 
safety, tolerability, as well as anti-viral activity of maribavir as a potential option for the 
treatment of CMV infections in transplant recipients. Study 1263-203 was a multicenter, 
randomized, dose-ranging, parallel-group study of maribavir versus valganciclovir for the 
treatment of CMV infections in HSCT or SOT recipients. Eligible subjects were randomized in a 
1:1:1:1 allocation ratio (40 subjects per group) to receive oral maribavir at 400 mg, 800 mg, or 
1200 mg BID; or valganciclovir (900 mg BID for 3 weeks, 900 mg once daily (QD) after 
3 weeks) for up to 12 weeks. Maribavir, at doses ≥400 mg BID, had comparable efficacy to 
valganciclovir at clearing CMV viremia and was generally well tolerated across the dose range 
studied. 
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In the subgroup of subjects whose transplant type was HSCT, a numerically higher percentage 
of subjects in the overall maribavir group (75%) than the valganciclovir group (48%) achieved 
confirmed undetectable plasma CMV DNA within 6 weeks of treatment. There was a 
higher incidence of neutropenia through Week 12 for valganciclovir-treated subjects 
compared with maribavir-treated subjects. This was evident for both measured degrees of 
neutropenia: 18% versus 5% (absolute neutrophil count [ANC] <1000/mm3), and 5% versus 
2% (ANC<500/mm3) through Week 12 for the valganciclovir and overall maribavir groups, 
respectively.
This Phase 3 study is designed to further assess and demonstrate the efficacy and safety of 
maribavir, administered at 400 mg BID, compared to valganciclovir administered at 900 mg BID 
for the treatment of asymptomatic CMV infection in HSCT recipients.
2.2 Rationale for the Study Design
This Phase 3 study will be conducted in HSCT recipients due to the relatively high risk for 
CMV infection resulting from ongoing immunosuppression to prevent GVHD. Ganciclovir and 
valganciclovir are commonly used to treat CMV infection in HSCT recipients and are generally 
considered effective, but present toxicity issues with respect to bone marrow suppression which 
may require management with hematopoietic growth factors, discontinuation of treatment, 
and may increase risk for opportunistic infections (Busca et al., 2007; Reusser et al., 2002). 
Additional constraints are present if treatment initiation is required in the pre-engraftment period. 
Alternative treatment by foscarnet or cidofovir is limited by nephrotoxicity of these medications 
(Reusser et al., 2002; Tomblyn et al., 2009). Maribavir may address safety limitations of 
currently available treatment.
Oral valganciclovir is the active control for this study to allow for the interpretation of 
virologic response to maribavir. While IV ganciclovir may be appropriate for certain 
patients, it presents the challenges inherently associated with administration of any IV 
medication, particularly when treatment may last longer. Oral valganciclovir (Valcyte®) 
900 mg provides ganciclovir exposure comparable to that of IV ganciclovir 5 mg/kg 
(refer to the Valcyte Prescribing Information as documented in the Study Pharmacy Manual; 
Winston et al., 2006) and the VICTOR study provided evidence that valganciclovir has 
comparable safety and is not inferior to standard IV ganciclovir treatment for eradication of 
viremia and clinical success in solid organ transplant recipients with CMV disease (Asberg et al., 
2007; Tomblyn et al., 2009).
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Study subjects will be randomized to receive either maribavir or valganciclovir for 8 weeks 
during the double-blind treatment phase. In the SHP620-203 study (HSCT and SOT recipients 
with asymptomatic CMV infection), the majority of maribavir and valganciclovir subjects 
achieved confirmed undetectable plasma CMV DNA levels by Week 6 of study drug treatment, 
while CMV recurrence occurred at rates expected for such a population with continued 
immunosuppression. Maribavir administered at 400 mg, 800 mg, and 1200 mg BID achieved 
CMV viremia clearance within 3 weeks to 6 weeks after starting the study drug treatment. 
Therefore, an 8-week treatment regimen will be administered in this Phase 3 study to account for 
maximum treatment period of 6 weeks where maribavir demonstrated a comparable efficacy to 
valganciclovir (900 mg BID from Weeks 1-3, and 900 mg QD after Week 3) in 
Study SHP620-203, adding 2 weeks for secondary prophylaxis.
As there are currently no approved therapies for the treatment of CMV infections in the pediatric 
transplant recipient population, this study will initiate the assessment of maribavir use in the 
pediatric population by enrolling adolescent subjects ≥16 to <18 years of age.
2.3 Rationale for Dose Selection
Results from the Phase 2 studies SHP620-202 (HSCT and SOT recipients with resistant or 
refractory CMV infections) and SHP620-203 (HSCT and SOT recipients with asymptomatic 
CMV infection) demonstrated comparable efficacy across the 400 mg BID, 800 mg BID, 
and 1200 mg BID maribavir dose groups in the clearance of CMV viremia within up to 
6 weeks after starting study drug treatment. In both Phase 2 studies, the most common 
treatment-emergent adverse events included dysgeusia, nausea, vomiting, and diarrhea, and 
elevated immunosuppressant drug concentration levels. There was a dose-dependence for 
dysgeusia and elevated immunosuppressant drug concentration levels. These findings 
(comparable efficacy and better safety profile with the 400 mg dose) support the further 
evaluation of 400 mg BID maribavir for the treatment of CMV.
Currently available maribavir pharmacokinetics, PK modeling and extrapolation of systemic 
exposure from adults, and safety and tolerability data in adults support the administration of the 
400 mg BID dose in adolescents who weigh ≥35 kg and are able to swallow tablets. Per Lu and 
Rosenbaum (2014), the expression of CYP3A4 and CYP 2C19, which are primary enzymes for 
maribavir metabolism in the liver, occurs during the first weeks of life. The expression of 
CYP1A2, which is also involved with maribavir metabolism, the last enzyme to develop, is 
present by 1 to 3 months of life. By 1 to 2 years of age, all the isoenzyme activities are similar to 
those of adults. Therefore, the bioavailability and systemic exposure of maribavir in adolescent 
subjects (≥16 and <18 years of age) is not expected to be different from adults at the same oral 
dose.
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Although typically valganciclovir treatment in HSCT patients is started as an induction dose of 
900 mg BID for up to 14 days and then reduced to a maintenance dose of 900 mg QD for a 
further 2 weeks or until CMV viral load clearance (Tomblyn et al., 2009), a different dosing 
strategy was selected for this study based on input from regulatory authorities. Treatment with 
valganciclovir 900 mg BID for the duration of 8 weeks was chosen in order to eliminate a 
potential bias for efficacy in favor of the investigational treatment (maribavir) by administering 
the comparator (valganciclovir) at the higher dosage throughout. Treatment with valganciclovir 
at a lower dosage based on CrCl would be allowed to ensure comparable exposures in renally 
impaired subjects.
2.4 Study Objectives
2.4.1 Primary Objective
The primary objective of the study is to compare the efficacy of maribavir to valganciclovir in 
CMV viremia clearance at the end of Study Week 8 in asymptomatic CMV infection in HSCT 
recipients.
2.4.2 Key Secondary Objective
The key secondary objective of this study is to compare the efficacy of maribavir and 
valganciclovir on maintenance of CMV viremia clearance, achieved at the end of Study Week 8 
through Study Week 16 (8 weeks of post-treatment/follow-up phase).
2.4.3 Secondary Objectives
The secondary objectives of this study are:

To compare the efficacy of maribavir to valganciclovir in CMV viremia clearance after 
completion of 8 weeks of treatment for asymptomatic CMV infection in HSCT recipients.

To compare the efficacy of maribavir and valganciclovir on maintenance of CMV viremia 
clearance, achieved after completion of 8 weeks of treatment, through Study Weeks 12 
(4 weeks of post-treatment period), 16 (8 weeks of post-treatment/follow-up phase), and 
20 (12 weeks post-treatment).

To assess the maintenance of CMV viremia clearance, achieved at the end of Study Week 8, 
through Weeks 12 (4 weeks of post-treatment period), and 20 (12 weeks post-treatment).

To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study treatment 
arms during the first 8 weeks of the study, during the 12 weeks of the follow-up study phase, 
and at any time during the study.
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
To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study treatment
arms when subjects are on treatment and off treatment.

To evaluate the incidence of treatment-emergent grade 3 or 4 neutropenia (defined as
ANC<1000/mm3 or ANC<500/mm3) while on treatment.

To assess the safety and tolerability of maribavir compared to valganciclovir.

To characterize the PK of maribavir.
2.4.4 Exploratory Objectives
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3. STUDY DESIGN
3.1 Study Design and Flow Chart
This is a multicenter, randomized, double-blind, double-dummy, active-controlled study of 
maribavir compared to valganciclovir for the treatment of asymptomatic CMV infection in 
HSCT recipients. “Asymptomatic subjects” at baseline will be defined as HSCT recipients who 
do not have tissue-invasive CMV disease as determined by the investigator according to the 
criteria specified by Ljungman et al. (2017). The study will assess the efficacy of maribavir by 
measuring the plasma CMV DNA clearance. To be eligible for the study, subjects must have a 
documented asymptomatic CMV infection with a screening value of CMV DNA ≥1365 IU/mL 
to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤91000 IU/mL in plasma in 2 consecutive 
assessments, separated by at least 1 day, as determined by local or central specialty laboratory 
quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results.
Results for CMV and, in subjects with very low viral load, evaluations for high-risk CMV 
infection (Section 7.1.1) should be available before the subject is randomized to verify subject 
eligibility for the study. Both samples should be taken within 14 days prior to randomization 
with the second sample obtained within 5 days before randomization. The same laboratory and
sample type should be used for these assessments. Subjects must not have CMV tissue invasive 
disease (symptomatic CMV infection), must not have a CMV infection that is known to be 
genotypically resistant to anti-CMV drugs, and must meet the remaining specified eligibility 
criteria. Subjects treated with ganciclovir, valganciclovir, foscarnet, or letermovir for the current 
CMV infection should not be treated with these anti-CMV agents for longer than 72 hours prior 
to enrolling in the study.
All eligible subjects will be stratified based on last prebaseline whole blood or plasma 
CMV DNA concentration (high viral load with CMV DNA ≥27300 IU/mL in whole blood or 
≥9100 IU/mL in plasma, low viral load with CMV DNA ≥2730 IU/mL to <27300 IU/mL in 
whole blood or ≥910 IU/mL to <9100 IU/mL in plasma, and in subjects with high-risk infection, 
very low viral load with CMV DNA <2730 IU/mL in whole blood or <910 IU/mL in plasma) as 
determined by the local or central specialty laboratory qPCR; and acute GVHD status (presence 
or absence at baseline). Subjects in each stratum will then be randomized in a 1:1 allocation ratio 
to receive double-blind maribavir (400 mg BID) or valganciclovir (900 mg BID, 450 mg BID, or 
450 mg QD, based on subject's CrCl at eligibility) for 8 weeks. Valganciclovir dose may be 
adjusted during the study for renal function impairment or neutropenia.
An independent Data Monitoring Committee (DMC) will be established to assess the data at 
specified periodic intervals for safety and to ensure the validity and scientific merit of the trial. 
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Detailed plans for the DMC’s purpose and responsibilities will be described in the DMC charter 
and the statistical analysis plan.
As shown in the study schematic in Figure 1 (Study Design Flow Chart) below, the study will 
have 3 phases: (1) Up to a 2-week screening phase; (2) 8-week double-blind study treatment 
phase; and (3) 12-week follow-up phase.
Figure 1. Study Design Flow Chart
Visit 1
Wks -2 to -1
Screening
Phase
Double-blind
Phase
Follow-up
Phase
Visits 11-18
Wks 9-20
Every 2 Weeks
(last 8 wks)
Weekly
(first 4 weeks)
Visit 2
Wk 0
SHP620 400 mg BID OR
ValGCV 900 mg BIDa
BL/
Rand
Visits 3-10
Wks 1-8
Double-blind
Study Drug Administration
Visit
2Ab
BID=twice daily; BL=baseline; Rand=randomized; Wks=weeks
a
Unless dose adjustment is required for moderate renal impairment.
b
Visit 2A is required only for subjects receiving tacrolimus, cyclosporine, everolimus, or sirolimus at baseline.
Subjects will be required to visit the site up to 18 times for up to a 22-week period. During the 
COVID-19 public health emergency, remote visits may be conducted by phone (eg, collection of 
AEs and monitoring), video conferencing (Telehealth or Telemedicine, physician), or site staff 
visiting the participant’s residence. Local visits and telemedicine must comply with national and 
local laws and regulations. The type of alternative visit must be recorded on the eCRF.
For home healthcare visits, collection of clinical laboratory samples (blood specimen collection 
or other diagnostic tests) may be performed by a qualified and authorized Principal Investigator’s 
(PI) designee who can visit the trial participant’s residence.
Screening Phase
As presented in Schedule of Assessment 1, Table 1, approximately 612 subjects will be screened 
to establish eligibility for study participation. All screening procedures will be completed within 
14 days prior to initiation of study treatment, with the exception of the following:
1. Screening clinical laboratory tests (hematology, chemistry, and pregnancy) must be 
performed within 3 days prior to initiation of study treatment.
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2. Subjects must have a documented CMV infection with a screening value of CMV DNA 
≥1365 IU/mL to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤91000 IU/mL in 
plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or 
central specialty laboratory qPCR or comparable quantitative CMV DNA results. The first 
sample must be obtained within 14 days prior to study enrollment (ie, start of study 
treatment) at Visit 2/Day 0. The second sample must be obtained within 5 days prior to the 
study enrollment.
3. Historical results for human immunodeficiency virus (HIV) tests performed within 
3 months prior to the study treatment initiation will be acceptable for screening. If no HIV 
test result within 3 months is available, the subject must have testing done locally during 
the screening period and have negative results available prior to randomization.
Study Treatment Phase
Approximately 550 subjects with an asymptomatic CMV infection who meet eligibility 
requirements during the screening phase, including the presence of quantifiable (local or central 
specialty laboratory) whole blood or plasma CMV DNA levels as specified (≥1365 IU/mL in 
whole blood or ≥455 IU/mL in plasma), will be stratified based on their CMV viral load and 
GVHD status, and then randomized 1:1 at Visit 2/Day 0 to receive either double-blind 
maribavir/placebo or valganciclovir/placebo (collectively, the study treatment) for 8 weeks.
Historical laboratory results for tests within the time period specified in the Schedule of 
Assessment 1 (Table 1) may be used for eligibility assessment (HIV test results within 3 months, 
relevant hematology, and chemistry results). The Screening and Visit 2/Day 0 visits can occur on 
the same day, if laboratory results are available for the determination of eligibility. Local 
laboratory results may be used for stratification and randomization if central laboratory results 
are not available at Visit 2/Day 0.
All Visit 2/Day 0 procedures, including blood collection for CMV DNA quantification, 
hematology and chemistry analysis in the central laboratory, must be completed and documented 
prior to randomization and study treatment administration and all clinical laboratory results 
required for eligibility verification must be available prior to randomization, including 2 separate 
CMV DNA assessments. Central laboratory results of CMV DNA quantification and genotyping, 
hematology and chemistry from samples taken at Visit 2/Day 0 will not be available for use for 
screening the subjects. Initiation of study treatment (ie, first dose) will only occur after 
completion of all required Visit 2/Day 0 procedures, confirmation of eligibility, and completion 
of randomization. This will be done under the supervision of investigator site personnel. Blood 
sample for central laboratory CMV DNA quantification and genotyping will be obtained at 
Visit 2/Day 0. 
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If baseline central laboratory CMV DNA quantification results do not meet the specified 
screening value of ≥455 IU/mL, the subject will remain in the study, but will be excluded from 
the Per Protocol population for efficacy analysis.
All subjects will perform study-specific evaluations weekly during the 8-week study treatment 
phase. Refer to Schedule of Assessment 1 (Table 1) for a complete list of the evaluations 
performed in the study treatment phase.
Subjects randomized to receive maribavir will take the 400 mg BID dose for the 8 weeks of the 
study treatment phase. Maribavir 200 mg strengths will be utilized for the daily dosing. Subjects 
randomized to valganciclovir will take the 900 mg BID for the duration of 8 weeks of the study 
treatment phase (unless dose adjustment is required for moderate renal impairment) and will 
utilize 450 mg strength tablets.
Depending on the time of the first dose of study treatment on Visit 2/Day 0, a second dose 
should be administered on Visit 2/Day 0 provided that doses can be separated by a minimum of 
8 hours; otherwise, only 1 dose should be administered on Visit 2/Day 0. Study treatment will 
then be administered (preferably) every 12 hours (q12h). When q12h dosing is not feasible, the 
doses should be separated by a minimum of 8 hours.
To protect the study blind, subjects will be required to take 2 tablets of their assigned study 
treatment and 2 tablets of the placebo q12h in a double-dummy format as shown in Table 5 in 
Section 6.2.3.
Subjects randomized to receive valganciclovir will follow the 900 mg BID dosing regimen for 
the 8 weeks of the study treatment phase, with the exceptions of permitted lower starting dose 
based on renal function, or dose adjustments based on renal function and/or neutropenia (Table 6
and Table 7, respectively; see Section 6.2.3). The clinical laboratory test results (see 
Section 7.2.3.4) for a minimum of complete blood count with differential and serum creatinine 
will be verified before providing the revised valganciclovir dose.
In exceptional situations, eg, neutropenia or other adverse events, study treatment may be 
interrupted at investigator's discretion for a maximum of 7 consecutive days, and this 
interruption will not result in permanent study treatment discontinuation. Up to 2 study treatment 
interruptions for a total of up 7 days will be allowed. A third study treatment interruption will 
lead to permanent study treatment discontinuation; the subjects will complete the end of 
treatment procedures described for Visit 10/Study Week 8 in the Schedule of Assessment 1 
(Table 1), and will follow a modified schedule of assessments through the remaining weekly 
visits scheduled for the study treatment phase and the regular schedule of assessments through 
the 12-week follow-up phase as described in Section 4.5. 
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Various clinical scenarios of neutropenia, as shown in Table 7, will be programmed in the 
interactive response technology (IRT) and appropriate options will be selected by the investigator. 
Interruptions and discontinuation of study treatment will be conducted in a blinded manner; 
therefore, it is possible that treatment with either valganciclovir or maribavir will be interrupted or 
discontinued for neutropenia presence. The investigator may also select to interrupt study treatment, 
for other adverse events, regardless of the treatment assignment (maribavir or valganciclovir). If 
study drug is interrupted for any reason and subsequently resumed, the end of the study drug 
administration period would remain fixed at a maximum of 8 weeks after the date of the start of 
treatment.
If the subject is unable to travel to the site for the treatment visits, these visits may be on exceptional 
basis performed remotely (ie, at subjects’ home) by a qualified and authorized PI’s designee, and 
only if permitted by local laws and regulations. Clinical laboratory samples will be collected, and all 
other follow-up assessments will be completed. Adverse events and SAE collection may be 
completed by telephone follow-up call on the day of the scheduled visit. It is recommended that the 
end of study visit be completed at the site if the subject is able to travel.
All subjects who complete the study treatment phase through Visit 10/Week 8 will enter the 12-week 
follow-up phase. See Section 4.5 for details regarding discontinuation and/or withdrawal from the 
study treatment/study.
Follow-up Phase
Study-specific evaluations including central specialty laboratory CMV testing and safety assessments 
will occur weekly for the first 4 weeks, then every 2 weeks for the final 8 weeks of the 12-Week 
Follow-up Phase. See Schedule of Assessment 2 (Table 2) for a complete list of evaluations. See 
Section 4.5 for details regarding discontinuation and withdrawal.
If the subject is unable to travel to the site for the follow-up visits, these visits may be on exceptional 
basis performed remotely (ie, at subjects’ home) by a qualified and authorized PI’s designee, and 
only if permitted by local laws and regulations. Clinical laboratory samples will be collected, and all 
other follow-up assessments will be completed. Adverse events and SAE collection may be 
completed by telephone follow-up call on the day of the scheduled visit. It is recommended that the 
end of study visit be completed at the site if the subject is able to travel.
3.2 Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 22 weeks 
(screening: up to 2 weeks; double-blind study treatment phase: 8 weeks; follow-up phase: 12 weeks). 
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Follow-up visits will occur weekly for the first 4 weeks (Weeks 9-12), followed by visits every 
2 weeks for the last 8 weeks (Weeks 12-20) of this 12-week follow-up phase.
The study will be completed in approximately 48 months. The Study Completion Date is defined 
as the date the final subject, across all sites, completes their final protocol-defined assessment. 
This includes the follow-up visit or contact, whichever is later. The Study Completion Date is 
used to ascertain timing for study results posting and reporting.
3.3 Sites and Regions
This is a multicenter study. Approximately 105 sites in North America, Europe, and Asia Pacific 
will participate.
3.4 Changes to Study Procedures Due to COVID-19 Pandemic
The following information provides guidance regarding changes to study procedures that may be 
implemented for study participants or study sites affected by a pandemic (eg, coronavirus disease 
[COVID-19]) that require physical distancing that may result in subjects missing their visits. 
This guidance takes references from the FDA Guidance on Conduct of Clinical Trials of Medical 
Products during COVID-19 Public Health Emergency – Guidance for Industry, Investigators, 
and Institutional Review Boards, March 2020, updated 27 January 2021; the EMA Guidance on 
the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic, Version 4 
(04 February 2021); and the EMA Points to consider on implications of Coronavirus disease 
(COVID-19) on methodological aspects of ongoing clinical trials, dated 26 June 2020.
Because a pandemic (eg, COVID-19) may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case-by-case basis by the principal investigator in 
consultation with the study team and the medical team as needed, while maintaining patient 
safety and confidentiality as the priority.
Procedural changes due to COVID-19 may include the following (refer to DTP guidance 
document for further details):

Allow study sites to follow COVID-19 screening requirements per local regulations.

Informed Consent Procedure: If necessary and permitted by local laws and regulations, 
informed consent from a potential or current trial participant may be obtained via 
electronic informed consent (eIC) capabilities, or an electronic face-to-face consent 
interview when these individuals are unable to travel to the site (see Section 4). The site
must contact the sponsor for approval of the alternative method for obtaining informed 
consent prior to implementation.
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
Study Visit 1 (Screening) and Study Visit 2 (Randomization) must be done with the subject 
present at the investigative site. Study Visits 2A through 10 may be conducted at the clinic or 
by optional home healthcare visits to extend flexibility to subjects during the COVID-19 
public health emergency, although it is preferable to conduct Study Visit 10 (End of 
Treatment) and Study Visit 18 (End of Study) with the subject present at the investigative 
site. The data collected from home healthcare visits may be handled differently in the final 
data analysis, with this documented in the statistical analysis plan. 

More flexibility by allowing some assessments and, where allowed per local laws and 
regulations, remote source document verification to be conducted remotely (see 
Study Schedule). 

‘Remote visits’ via virtual communications (eg, TeleHealth application) may be performed as 
a safety check on subject well-being, concomitant medication use, etc.

For home healthcare visits, collection of clinical laboratory samples (blood specimen 
collection or other diagnostic tests) may be performed by a qualified and authorized PI’s 
designee who can visit the trial participant’s residence.

ECG procedures: For home healthcare visits, ECGs may be performed by a qualified health 
care professional who is certified/authorized by the PI to perform such tests routinely.

Missed clinic visits or subject withdrawals due to COVID-19 must be recorded on the eCRF 
(see Section 4.5, Discontinuation and/or Withdrawal of Subjects).

Subjects who discontinued from screening due to COVID-19-related factors but were 
otherwise qualified to participate in the trial may be rescreened at any time if the Takeda 
medical monitor agrees (see Section 7.1.1, Screening Period).

Allow transfer of study participants to investigational sites away from risk zones or closer to 
their home to sites already participating in the trial or new ones.

Deviations from the protocol-specified procedures (eg, not collecting a protocol-specified 
specimen, such as post-dose bloodwork) will be recorded as related to COVID-19.

Alternative study drug deliveries may include dispensing additional study drug at clinic visits 
or direct-to-patient (DTP) delivery of the study drug from the investigational site to subjects 
in compliance with national laws or temporary national emergency measures (see 
Section 6.4, Drug Accountability). When utilizing DTP, the investigator remains responsible 
for ensuring the safety of subjects and the dispensation of the investigational product.

In accordance with local laws and regulations, relevant health authorities are to be notified of 
participants who contract COVID-19 during the study.
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4. STUDY POPULATION
Approximately 550 subjects, ≥16 years of age, who are HSCT recipients with asymptomatic 
CMV infections will be enrolled.
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. 
4.1 Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
Subjects must:
1. Be able to provide written, personally signed, and dated informed consent to participate in 
the study before completing any study-related procedures. As applicable, a parent/both 
parents or legally authorized representative (LAR) must provide signature of informed 
consent and there must be documentation of assent by the subject before completing any 
study-related procedures. During the COVID-19 public health emergency, informed 
consent from a potential or current trial participant may, if permitted by local laws and 
regulations, be obtained via electronic informed consent (eIC) capabilities or an electronic 
face-to-face consent interview when these individuals are unable to travel to the site (FDA 
COVID-19 Guidance, 27 Jan 2021, Q11).
2.
Be ≥16 years of age at the time of consent.
3.
Be a recipient of hematopoietic stem cell transplant.
4.
Have a documented asymptomatic CMV infection, with a screening value of CMV DNA 
≥1365 IU/mL to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤91000 IU/mL in 
plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or 
central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable 
quantitative CMV DNA results. Both samples should be taken within 14 days prior to 
randomization with second sample obtained within 5 days prior to randomization. Same 
laboratory and same sample type (whole blood or plasma) should be used for these 
assessments. Asymptomatic CMV infection is defined as an infection that does not present 
with tissue invasive CMV disease, as assessed by the investigator.
Subjects with CMV DNA <910 and ≥455 IU/mL in plasma or <2730 and ≥1365 IU/mL in 
whole blood will also need to meet at least 1 of the following criteria for high-risk CMV 
infection to be eligible:

Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 
1 of the following 3 HLA-gene loci: HLA-A, -B or -DR,
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
Haploidentical donor,

Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: 
HLA-A, -B, -C and -DRB1,

Use of umbilical cord blood as stem cell source,

Use of ex vivo T-cell-depleted grafts,

Grade 2 or greater GVHD, requiring the use of systemic corticosteroids (defined as 
the use of ≥1 mg/kg/day of prednisone or equivalent dose of another corticosteroid).
5.
Have the current CMV infection as the first episode of CMV viremia after HSCT, either 
primary or reactivation, which in the investigator’s opinion requires treatment.
6.
Per investigator’s judgment, be eligible for treatment with valganciclovir.
7.
Have all of the following results as part of screening laboratory assessments (results from 
either the central laboratory or a local laboratory can be used for qualification):
a. Absolute neutrophil count ≥1000/mm3 [1.0 x 109/L]
b. Platelet count ≥25,000/mm3 [25 x 109/L]
c. Hemoglobin ≥8 g/dL
d. Estimated creatinine clearance ≥30 mL/min.
8.
Have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test at 
screening, if a female of childbearing potential. Urine pregnancy tests may be done per 
institutional requirements; however, they are not sufficient for eligibility determination. 
Sexually active females of childbearing potential must agree to comply with any applicable 
contraceptive requirements of the protocol. If male, must agree to use an acceptable 
method of birth control, as defined in the protocol, during the study treatment 
administration period and for 90 days afterward the last dose of study treatment.
9.
Be able to swallow tablets.
10. Have life expectancy of ≥8 weeks.
11. Weigh ≥40 kg.
12. Be willing and have an understanding and ability to fully comply with study procedures 
and restrictions defined in the protocol.
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4.2 Exclusion Criteria
Subjects must not:
1.
Have CMV tissue invasive disease as assessed by the investigator at the time of screening 
and randomization at Visit 2/Day 0.
2.
Have a CMV infection that is known to be genotypically resistant to ganciclovir, 
valganciclovir, foscarnet, or cidofovir based on documented evidence.
3.
Be presenting with recurrent CMV infection (defined as a new detection of CMV infection 
in a subject who had at least one previously documented episode of CMV infection 
post-transplant, and who has had at least 2 weeks of undetectable CMV DNA between the 
episodes during active surveillance, based on same local laboratory and same sample type). 
The subject must also have been off any anti-CMV treatment between the current and prior 
infection. Otherwise, the current infection may be considered continuation of the prior 
infection.
4.
Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions 
other than CMV when study treatment is initiated (example: herpes simplex virus [HSV] 
co-infection requiring use of any of these agents after the randomization) or would need a 
co-administration with maribavir for CMV infection.
5.
Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated. 
Note: Subjects who may be receiving leflunomide must discontinue the use at least 14 days 
prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Subjects 
receiving letermovir must discontinue use 3 days prior to first dose of study treatment. 
Subjects receiving artesunate must discontinue the use prior to the first dose of study 
treatment.
6.
Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet, or 
letermovir) for the current CMV infection for longer than 72 hours.
7.
Have known hypersensitivity to the active substance or to an excipient of the study 
treatments.
8.
Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours 
prior to the first dose of study treatment that would preclude administration of oral 
medication.
9.
Require mechanical ventilation or vasopressors for hemodynamic support at the time of 
randomization.
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10. Be female and pregnant or nursing.
11. Have previously completed, discontinued, or have been withdrawn from this study.
12. Have received any investigational agent with known anti-CMV activity within 30 days 
before initiation of study treatment or CMV vaccine at any time.
13. Have received any unapproved agent or device within 30 days before initiation of study 
treatment.
14. Have any clinically significant medical or surgical condition that, in the investigator’s 
opinion, could interfere with interpretation of study results, contraindicate the 
administration of the assigned study treatment, or compromise the safety or well-being of 
the subject.
15. Have previously received maribavir.
16. Have serum aspartate aminotransferase (AST) >5 times upper limit of normal (ULN) at 
screening, or serum alanine aminotransferase (ALT) >5 times ULN at screening, or total 
bilirubin ≥3.0 x ULN at screening (except for documented Gilbert’s syndrome), as 
analyzed by local or central laboratory.
17. Have known (previously documented) positive results for human immunodeficiency virus 
(HIV). Subjects must have a confirmed negative HIV test result within 3 months of study 
entry or, if unavailable, be tested by a local laboratory during the screening period.
18. Have active malignancy with the exception of nonmelanoma skin cancer, as determined by 
the investigator. Subjects who experience relapse or progression of their underlying 
malignancy (for which HSCT was performed), as determined by the investigator, are not to 
be enrolled.
19. Be undergoing treatment for acute or chronic hepatitis C.
4.3 Restrictions 
There will be no special restrictions for subjects participating in this study. Subjects are to 
maintain their normal diets, medications (except those listed in Section 5.2.2), and activities of 
daily life as determined by the investigator.
4.4 Reproductive Potential
4.4.1 Female Contraception
There is no clinical experience with maribavir in pregnant subjects.
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There are no data from the use of valganciclovir in pregnant subjects. Its active metabolite, 
ganciclovir, readily diffuses across the human placenta. Based on its pharmacological 
mechanism of action and reproductive toxicity observed in animal studies with ganciclovir, 
valganciclovir should be considered a potential teratogen and carcinogen in humans (refer to the 
Valcyte Prescribing Information and Valcyte Summary of Product Characteristics as documented 
in the Study Pharmacy Manual).
All female subjects of child-bearing potential will be tested and should have negative 
serum -human chorionic gonadotropin pregnancy test results prior to randomization. They must 
agree to abstain from sexual activity that could result in pregnancy or agree to use an acceptable 
method of contraception. Females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 90 days after the last dose of study treatment. 
If hormonal contraceptives are used they should be administered according to the package insert 
and in conjunction with another acceptable method of contraception. Females of child-bearing 
potential who are not currently sexually active must agree to use acceptable contraception, as 
defined below, if they become sexually active during the period of the study and 90 days 
following the last dose of study treatment. Sexually active females of child-bearing potential 
should be using an acceptable form of contraception, as defined below.
Methods of contraception that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered highly effective birth control methods for females of 
child-bearing potential are presented below:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, implantable [low user 
dependency]) stabilized for at least 30 days prior to the screening visit (Visit 1), plus 
condoms.
Note: Since hormonal contraception may be susceptible to interaction with the study 
treatment(s) in the study, which may reduce the efficacy of the contraception method, this 
method must be supplemented with a barrier method (preferably male condom).

Intrauterine devices (IUD, all types) or intrauterine hormone releasing systems (IUS) plus 
condoms. Note: contraception methods that in the context of the clinical trial facilitation 
group (CTFG) guidance are considered to have lower user dependency.

Bilateral tubal occlusion.
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
Vasectomized male partner is a highly effective birth control method provided that partner is 
the sole sexual partner of the female trial participant who is of childbearing potential and that 
the vasectomized partner has received medical assessment of the surgical success.

Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. Note: the reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical trial and the preferred and 
usual lifestyle of the subject.
Female subjects 16 years of age and older, who are amenorrheic for reasons other than 
menopause (12 consecutive months of spontaneous amenorrhea in patients with previous normal 
menstruation), including subjects who did not yet have the menarche, would be allowed to 
participate provided they agree to abstinence or an acceptable form of contraception, as defined 
below.
Female subjects who are postmenopausal (12 consecutive months of spontaneous amenorrhea) or 
surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, bilateral 
tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and are at least 6 weeks 
poststerilization do not need a pregnancy test performed prior to randomization and do not have 
to agree to the use of acceptable methods of contraception.
4.4.2 Male Contraception
Per Clinical Trial Facilitation Group requirements (CTFG), male subjects will be required to use 
a condom in conjunction with a highly effective method of birth control for their female partners 
of childbearing age. Both male participants and their female partners must use this form of birth 
control from the time prior to first dosing until 90 days after the last dose of study treatment 
(ie, maribavir or valganciclovir). For male subjects, sexual intercourse with pregnant partners 
should also be avoided during the course of the study unless condoms are used from the time 
prior to the first dose until 90 days after the last dose of study treatment. Male subjects must not 
donate sperm until 90 days after the last dose of study treatment.
4.5 Discontinuation and/or Withdrawal of Subjects
Subjects Who Withdraw from the Study
A subject may withdraw (eg, withdraw consent) from the study at any time for any reason 
without prejudice to their future medical care by the physician or at the institution. The 
investigator or the sponsor may withdraw the subject at any time (eg, in the interest of the 
subject’s safety).
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The investigator is encouraged to discuss withdrawal of a subject from study treatment with the 
sponsor’s medical monitor when possible. Subjects who withdraw consent during the study 
treatment phase will be asked to undergo all end of treatment evaluations and procedures listed 
for Visit 10/Week 8, if they agree; no further follow-up will be performed.
Subjects who withdraw from the study during the follow-up phase will undergo all end of study 
evaluations and procedures listed for Visit 18/Week 20 (Follow-up Week 12) as soon as possible 
and whenever possible, if they agree, prior to initiation of any nonstudy anti-CMV treatment (as 
deemed by the investigator); no further follow-up will be performed.
Subjects Who Discontinue from Screening
Subjects who discontinue from screening due to COVID-19-related factors but are otherwise 
qualified to participate in the trial may be rescreened at any time if the Takeda medical monitor 
agrees.
Subjects Who Discontinue Study Treatment
Subjects who permanently discontinue study treatment, but do not withdraw consent, will 
complete the end of treatment procedures described for Visit 10/Study Week 8 in the Schedule of 
Assessment 1 (Table 1); these subjects will follow a modified schedule of assessments through 
the remaining weekly visits scheduled for the study treatment phase and the regular schedule of 
assessments through the 12-week follow-up phase. The end of treatment sample for 
immunosuppressant drug concentration level will be collected at the next visit scheduled 1 week 
after the treatment discontinuation. Subjects who discontinue study treatment early will not be 
asked to complete the following procedures after the end of treatment visit for subsequent visits 
in the treatment phase: the use of the diary for study treatment compliance, dispense or use of 
any study treatment, and PK sample collection. After completing the 8-week duration specified 
for the study treatment phase, subjects will enter the 12-week follow-up phase. After the 
permanent study treatment discontinuation and until the end of the study, subjects might be 
administered other anti-CMV treatment as deemed necessary by the investigator.
Subjects who discontinue will not be replaced.
4.5.1 Reasons for Discontinuation and/or Withdrawal
The reason for study treatment discontinuation and/or withdrawal must be determined by the 
investigator and recorded in the subject’s medical record and on the case report form (CRF). If a 
subject discontinues treatment or is withdrawn from the study for more than 1 reason, each 
reason should be documented in the source document and the most clinically relevant reason 
should be entered in the CRF.
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Reasons for discontinuation include but are not limited to:

Withdrawal of consent (by subject or by a parent or both parents/legal guardian for 
pediatric subjects). If a subject chooses to withdraw from study participation due to 
personal concerns related to the COVID-19 pandemic (other than a COVID-19-related 
AE), this should be specified as the reason for subject withdrawal in the eCRF.

Adverse event (must specify on the CRF)

CMV central nervous system (CNS) infection (Note: Maribavir is unlikely to penetrate the 
blood-brain barrier in humans based on animal data. If a subject in the study develops 
CMV CNS infection [eg, meningo-encephalitis], then the subject will discontinue study 
treatment in order to be treated for this condition.)

Protocol deviation (eg, lack of compliance, use of experimental drug)

Pregnancy

Sponsor decision (must specify on the CRF)

Death

Lost to follow-up

Lack of efficacy

Other (must specify on the CRF, including unavoidable circumstances such as the 
COVID-19 pandemic)
The end of study treatment and the end of study date for each subject (ie, the date of completion 
of the study or premature withdrawal from the study) will be recorded in the CRF.
4.5.2 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5. PRIOR AND CONCOMITANT MEDICATIONS, THERAPIES, AND PROCEDURES
5.1 Prior Medications, Therapies, and Procedures
Prior treatment information must be recorded on the appropriate CRF page, and will include the 
following presented in Table 3.
Table 3. Prior Medications, Therapies, and Procedures 
Time Period
(prior to Visit 2/Day 0)
Category
Prior Medications, Therapies, and Procedures
Medications/procedures 
administered/performed 
for transplant related 
reason from their start 
or date of transplant 
(whichever is first) to 
the first dose of study 
treatment on 
Visit 2/Day 0
Preparative/conditioning 
regimena
Including but not limited to:

Pretransplant irradiation

Various agents including:
o
Chemotherapy agents
o
Lymphocyte depleting and nondepleting 
therapies, including monoclonal, polyclonal, 
and anti-thymocyte globulin preparations
Anti-CMV prophylaxis 
and treatmentb
Including, but not limited to:

Ganciclovir

Valganciclovir

Foscarnet

Cidofovir

Cytomegalovirus immune globulin

Intravenous immunoglobulin (IVIG)

Leflunomide

Artesunate

Letermovir

Cytomegalovirus specific T-cell transfer 
(considered investigational)
GVHD prophylaxis, 
treatment, adjuvant 
therapies, and other 
related therapies
Including, but not limited to:

Cyclosporin

Methotrexate

Tacrolimus

Sirolimus

T-cell depleting therapies, including 
antithymocyte globulin, alemtuzumab

Mycophenylate mofetil

Steroids

Photopheresis
Transplant maintenance 
therapy
Including, but not limited to

Systemic steroids

Cyclosporine, tacrolimus, sirolimus, everolimus, 
mycophenylate mofetil
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Table 3. Prior Medications, Therapies, and Procedures 
Time Period
(prior to Visit 2/Day 0)
Category
Prior Medications, Therapies, and Procedures
All medications within 
3 months prior to the 
first dose of study 
treatment on 
Visit 2/Week 0/Day 0
Hematopoietic growth 
factors
Treatment for the 
underlying disease
Blood or blood product 
transfusions
Anti-Infective agents

Prophylaxis and/or treatment of viral, bacterial 
and fungal infections
Within 30 days or 
5 half-lives
(whichever is longer)
All Other

All other prescription medications

All herbal supplements

All other over-the-counter (OTC) medications
Any therapeutic or 
diagnostic intervention/
procedure performed 
within 30 days prior to 
the first dose of study 
treatment on 
Visit 2/Week 0/Day 0
Including, but not limited to:

Biopsies (along with the results)

X-rays, CT scans (along with results)

Dialysis

Total parenteral nutrition
CMV=cytomegalovirus; CT=computerized tomography; GVHD=graft-versus-host-disease; IVIg=intravenous 
immunoglobulin; OTC=over-the-counter medications
a Subjects for whom transplant was performed >3 months from the time of screening, limited (no dose data) information for 
preparative/conditioning regimen will be collected.
b NOTE: as only subjects with first CMV infection after HSCT will be enrolled, prior anti-CMV medications may include 
anti-CMV prophylaxis; subjects should not have been on treatment with anti-CMV agents (ganciclovir, valganciclovir, 
foscarnet, or letermovir) for the current CMV infection for longer than 72 hours prior to enrollment.
5.2 Concomitant Medications, Therapies, and Procedures
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. A concomitant procedure 
is any therapeutic and diagnostic intervention (eg, surgery, biopsy) or diagnostic assessment 
(eg, bacterial cultures, imaging such as X-ray, computerized tomography [CT] scans) performed 
between the dates of the first dose of the study treatment and the end of the follow-up phase, 
inclusive.
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5.2.1 Permitted Treatment
All concomitant treatment information must be recorded on the appropriate CRF page.
Additional treatment strategies may complement the use of the study treatments (eg, reducing or 
modifying the immunosuppressant drug use, or use of hemopoietic growth factors as needed for 
neutropenia).
Of note, changes in the net state of immunosuppression can influence response to treatment of 
CMV infection, therefore, whenever possible, investigators should maintain a stable regimen of 
immunosuppressant drugs during the study drug administration period, particularly through 
Study Visit 10/Week 8. Note that the sample for the assessment of immunosuppressant agent 
concentration is included in the schedule of assessments as maribavir was found to impact the 
metabolism of some immunosuppressive agents. Any changes in immunosuppression regimens 
due to the concomitant administration with maribavir or other reasons must be recorded in the 
CRF.
Maribavir is specifically intended to treat human CMV infections. Maribavir is not active in vitro 
against most non-CMV herpesvirus infections, including herpes simplex virus (HSV type 1 and 
type 2) and varicella zoster virus (VZV). At baseline, investigators will assess subjects to 
determine whether prophylaxis for these viruses is appropriate according to institutional 
guidelines or standard practices; the need for continued prophylaxis or initiation of prophylaxis 
will be assessed. If considered appropriate, permitted medications to use for this purpose include 
systemic acyclovir, valacyclovir, or famciclovir. Choice of medication, dose, and duration of 
such therapy is at the discretion of the investigator based on a given subject’s clinical condition 
(eg, net state of immunosuppression, risk factors, and other medications). These medications 
(acyclovir, valacyclovir, or famciclovir) also can be used to treat any HSV or VZV infection that 
may occur during the study. Antifungal and antibacterial medications will be allowed as deemed 
appropriate by the investigator for prophylaxis or treatment.
Although potent inhibitors of CYP 3A4 (such as ketoconazole) could increase blood levels of 
maribavir, they are likely to be associated with minimal increased risk given the safety profile of 
maribavir demonstrated at up to 1200 mg BID in Phase 2 studies.
The following concomitant medications should be taken with caution:
Maribavir has the potential to inhibit P-gp and therefore, may increase the concentration of drugs 
that are substrates of P-gp. For drugs with narrow therapeutic window, the increase in drug 
concentration may lead to toxicity. A drug interaction study showed that maribavir (400 mg 
BID) increased blood concentrations of tacrolimus (a substrate of CYP3A4 and P-gp) with Cmax
and AUC increased by 38% and 51%, respectively. 
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Therefore, monitoring tacrolimus blood concentration and tacrolimus-associated adverse events, 
and the appropriate dose adjustment of tacrolimus is recommended when maribavir and 
tacrolimus are used concomitantly. Conversely, after a period of coadministration, 
discontinuation of maribavir could lead to reduced blood levels of tacrolimus and potentially 
reduced therapeutic effect. Similarly, for drugs that are substrates of P-gp and have narrow 
therapeutic window, such as other immunosuppressants including cyclosporine, sirolimus, and 
everolimus, careful monitoring is recommended both after initiation of maribavir (when substrate 
levels may increase) and after discontinuation of maribavir (when substrate levels may decrease).
Maribavir is an inhibitor of BCRP based on in vitro data, therefore has the potential to increase 
the drug concentration of rosuvastatin which is a sensitive BCRP substrate. When initiating 
maribavir dosing in patients who are on a stable dose of rosuvastatin, patients should be closely 
monitored for the signs of myopathy and rhabdomyolysis.
5.2.2 Prohibited Treatment
Maribavir is contraindicated with valganciclovir/ganciclovir as it may antagonize ganciclovir’s 
antiviral effects due to maribavir’s inhibitory effect on HCMV UL97 encoded kinase which is 
required for activation/phosphorylation of ganciclovir.
Table 4 details the washout period for common prior treatments that are excluded medications 
for this study.
Table 4. Common Excluded Treatments and Associated Washout Period
Minimum Number of Days Before First Dose
Treatment
Prior to the first dose of 
study treatment
3
7
14
30
Ganciclovir, valganciclovira, foscarnet, artesunate
X
Letermovir
X
Cidofovir, leflunomide
X
Any investigational anti-CMV agent
X
Any unapproved agent or device
X
CMV vaccine
Any time before or during study
CMV=cytomegalovirus
a Valganciclovir will be provided by the Sponsor for this study; commercially available/prescribed valganciclovir is not 
allowed through the study and must be discontinued prior to the first dose of the study treatment.
Use of any investigational anti-CMV agents, or unapproved agents or devices during the study is not 
permitted. Infusion of T cells specific for CMV or regulatory T cells (Tregs), which is considered an 
experimental treatment, is not allowed.
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Besides the medications indicated in Table 4, concomitant use of any of the following medications is 
prohibited while the subject is receiving the study treatment (maribavir/placebo or 
valganciclovir/placebo).

Strong CYP 3A inducers: avasimibe, carbamazepine, phenytoin, rifampin, rifabutin, St. John’s 
wort (Hypericum perforatum)

Herbal medications known to have potential toxicities or drug interactions, eg, Ginkgo biloba or 
Piper methysticum (kava)
Except for ganciclovir/valganciclovir, maribavir does not antagonize the effects of other antiviral 
(anti-CMV) agents.
Potent inducers of CYP 3A4 and/or P-gp (such as rifampin, rifabutin, or phenobarbital) could reduce 
blood levels of maribavir, potentially reducing its antiviral activity. Use of alternate agents with less 
enzyme induction potential should be considered during administration of maribavir.
In vivo drug interaction studies with Valcyte have not been performed. Since valganciclovir is 
extensively and rapidly metabolized to ganciclovir; drug interactions associated with ganciclovir 
will be expected for valganciclovir (refer to the Valcyte Summary of Product Characteristics as 
documented in the Study Pharmacy Manual).
Administration of any of the prohibited treatments (except coadministration of foscarnet or 
cidofovir for indications other than CMV infection) will require discontinuation of study 
treatment.
5.2.3 Treatments Taken During the Follow-up Phase
All permitted (Section 5.2.1) and prohibited medications (Section 5.2.2) specified for the study 
treatment phase are applicable to the follow-up phase; however, in case of no viremia clearance, 
onset of tissue invasive CMV disease, a CMV recurrence, appropriate medications required for 
CMV treatment may be administered in the follow-up phase as deemed necessary by the 
investigator. The secondary prophylaxis for subjects with viral clearance is not recommended in 
the follow-up phase. All medications will be recorded on the CRF.
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6. IDENTITY OF INVESTIGATIONAL PRODUCTS
6.1 Identity of Investigational Product
The test product is maribavir, which will be provided by the sponsor in 200 mg strength tablet 
form. Additional information is provided in the current maribavir investigator’s brochure.
The reference/comparator product is valganciclovir which will be provided by the sponsor in 
450 mg strength tablet form. Refer to the local approved product information for additional 
details.
Matching placebo will be provided for both maribavir and valganciclovir.
6.2 Administration of Investigational Product(s)
6.2.1 Interactive Response Technology for Investigational Product 
Management
An IRT will be employed in this study to manage the tracking and confirmation of shipment, 
supply, inventory, ordering, expiration, randomization, site-assignments, and dose modifications 
of the study treatment. The IRT provider will provide a user manual and training to each site, 
with detailed instruction on the use of the IRT and unblinding procedures when situation arises.
6.2.2 Allocation of Subjects to Treatment
This is a double-blind, double-dummy, active-controlled study. The actual treatment given to 
individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
All eligible subjects will first be stratified based on 2 factors:
1. By last prebaseline whole blood or plasma CMV DNA concentration categorized in 
to 3 CMV DNA concentration level groups based on local or central specialty 
laboratory qPCR results:

High viral load with CMV DNA ≥27300 IU/mL to ≤273000 IU/mL in whole 
blood or ≥9100 IU/mL to ≤91000 IU/mL in plasma
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
Low viral load with CMV DNA ≥2730 IU/mL to <27300 IU/mL in whole blood 
or ≥910 IU/mL to <9100 IU/mL in plasma

Very low viral load and high risk with CMV DNA≥1365 IU/mL to 
<2730 IU/mL in whole blood OR ≥455 IU/mL to <910 IU/mL in plasma and 
high-risk infection
2. By presence or absence of acute GVHD
Following stratification, subjects will be randomized in a 1:1 allocation ratio to receive either 
double-blind maribavir or valganciclovir for 8 weeks.
The actual treatment given to individual subjects is determined by a randomization schedule 
automatically assigned by the IRT. The randomization number represents a unique number 
corresponding to study treatment allocated to the subject, once eligibility has been determined. 
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.3 Dosing
Initiation of study treatment, (ie, the first dose administration), will occur at Visit 2/Week 0 on 
Day 0 after completion of all required assessments for that visit. The first dose should be 
administered under supervision of investigator site personnel.
Depending on the time of the first maribavir/placebo or valganciclovir/placebo dose on 
Visit 2/Day 0, a second dose should be administered on Visit 2/Day 0 provided that doses can be 
separated by a minimum of 8 hours; otherwise, only 1 dose should be administered on 
Visit 2/Day 0. The second dose will then be administered (preferably) every 12 hours (q12h). 
When q12h dosing is not feasible, the doses should be separated by a minimum of 8 hours.
Maribavir 200 mg strength tablets will be utilized for the daily dosing. Subjects will take the 
maribavir 400 mg BID dose for the 8 weeks of the study treatment phase. There are no dose 
modifications for maribavir.
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Daily dosage for valganciclovir (450 mg QD to 900 mg BID as adjusted for renal function, 
based on chemistry labs at screening) will utilize 450 mg strength tablets. Subjects will take 
valganciclovir for the 8 weeks of the study treatment phase. To protect the study blind, subjects 
will be required to take 2 tablets of their assigned study treatment and 2 tablets of the placebo 
q12h in a double-dummy format as shown in Table 5.
Table 5. Study Treatment Dosing – Standard Regimen
Regimen
AM
PM
maribavir
400 mg BID
maribavir active
400 mg (2 tablets)
400 mg (2 tablets)
valganciclovir placebo
placebo (2 tablets)
placebo (2 tablets)
valganciclovir
900 mg BID
valganciclovir active
900 mg (2 tablets)
900 mg (2 tablets)
maribavir placebo
placebo (2 tablets)
placebo (2 tablets)
BID=twice daily
Valganciclovir tablets should be administered with food, and should not be broken or crushed 
(refer to the Valcyte Prescribing Information and Valcyte Summary of Product Characteristics as 
documented in the Study Pharmacy Manual). In order to maintain the blind, maribavir will also 
be administered with food and will not be broken or crushed for administration. Therefore, all 
subjects eligible for this study must be able to swallow tablets. Based on the evaluation of the 
effect of food on the PK of 200 mg tablet formulation of maribavir in Phase 1 Study 1263-104, 
only a modest effect on Cmax and no effect on AUC was observed; therefore, no clinically 
important food effect is expected with tablet formulation.
Subjects with estimated CrCl of ≥30 mL/min will be enrolled; adjustment of the valganciclovir 
dose for renal function will be allowed at entry and during the study, as deemed necessary by the 
investigator and consistent with the suggested doses in the valganciclovir label (shown in 
Table 6). The decision to modify the dose will be at investigator's discretion and it will be done 
in a manner, through IRT, so that the treatment assignment remains blinded. Placebo tablets will 
be assigned in a blinded manner to make up for adjusted dose and decrease in valganciclovir 
tablets.
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Table 6. Valganciclovir Dosing – Adjustment for Renal Function
Valganciclovir 450 mg Tablets
CrCla (mL/min)
Dose
≥60
900 mg (2 tablets) BID
40 – 59
450 mg (1 tablet) BID
25 – 39
450 mg (1 tablet) QD
10 – 24
450 mg every 2 days
BID=twice daily; CrCl=creatinine clearance; QD=once daily
a An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:
For males, eCrCl [mL/min] = (140 – age [years]) × (body weight [kg]) / (72) × (serum creatinine [mg/dL])
For females, eCrCl [mL/min] = 0.85 × (male value)
Valganciclovir administration is not recommended below CrCl of 10 mL/min.
Patients on valganciclovir are at risk for bone marrow suppression and development of 
neutropenia. In the Phase 2 study (SHP620-203) of maribavir, measured degrees of neutropenia 
were 18% versus 5% (ANC<1000/mm3) and 5% versus 2% (ANC<500/mm3) through Week 12 
study for the valganciclovir and overall maribavir groups, respectively. Based on discussions 
with regulatory authorities, dose of valganciclovir has been chosen as 900 mg BID for 8 weeks 
of study treatment period duration, given ANC ≥1000/mm3 and CrCl ≥60 mL/min. Since 
neutropenia is an identified risk with valganciclovir intake, and specifically with the induction 
dose maintained through the treatment duration, subjects will be assessed for neutropenia 
development and valganciclovir dose may be adjusted based on ANC level. It is recommended 
that ANC level and creatinine clearance is verified and taken into consideration before the study 
drug is dispensed at each study visit. Therefore, complete blood count with differential count and 
serum creatinine analysis will be performed within 2 days of each visit by the local laboratory to 
confirm ANC level and creatinine clearance (see Section 7.2.3.4). Table 7 shows predefined 
criteria for valganciclovir dose adjustment based on ANC level and CMV DNA clearance which 
may be used, as deemed necessary by the investigator and in a manner that the treatment 
assignment remains blinded, to manage treatment of subjects who experience neutropenia.
Valganciclovir should not be administered if the ANC is <500/mm3 (per the product label), the 
platelet count is <25,000/μL, or the hemoglobin is <8 g/dL. Consistent with the product label and 
peer reviewed published literature; two different ANC levels have been selected to guide 
valganciclovir dose adjustment. Three studies identifying risk factors for neutropenia reported 
ANC level <1000/mm3 (Venton et al., 2014; Tomonari et al., 2008) or <1500/mm3
(Salzberger et al., 1997). Salzberger et al. (1997) concluded that ANC level of <1000/mm3 is 
predictive of both progression of neutropenia and mortality and postulated that ganciclovir 
should be discontinued when the ANC reached 1000/mm3 rather than at an ANC level of 
750/mm3 (the threshold ANC level specified in the study). 
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In addition, in this study, a clear trend was observed between the degree of neutropenia and the 
rate of bacterial infection; for the fungal infection the increased trend was only present when 
ANC was <200/μL. Other studies (Goodrich et al., 1993; Boeckh et al., 1996) reviewed in 
Salzberger et al. (1997) showed that neutropenia with an ANC of <750/μL occurs in 30% of 
ganciclovir recipients and has been associated with increased rates of bacterial sepsis and 
invasive fungal infection in marrow transplant recipients.
Subjects who do not achieve CMV viremia clearance may need to continue treatment to resolve 
viremia, even though ANC level is between 500-1000/mm3, at the discretion of the investigator 
and with the support of hematopoietic growth factors, if needed. However, considering the 
presence of neutropenia, the dose of valganciclovir may be adjusted to 450 mg BID. For subjects 
who achieve CMV viremia clearance and have ANC level between 500-1000/mm3, benefit/risk 
assessment for continued treatment may need to be considered by the investigator, and the option 
of either valganciclovir dose adjustment or dose interruption may be chosen. In each of the 
clinical scenarios hematopoietic growth factors may be used as deemed necessary by the 
investigator to prevent/manage neutropenia in addition to other strategies such as modification of 
other treatments that may be contributing to neutropenia development (eg, mycophenolate 
mofetil, Bactrim).
Table 7. Valganciclovir Dose Adjustment Based on ANC Level and CMV DNA 
Clearance
ANC >1000/mm3
[1.0 × 109/L]
ANC based on local 
or central laboratory 
results
ANC 500/mm3 [0.5 ×109/L] 
to 1000/mm3 [1.0 × 109/L]
ANC based on local or 
central laboratory results
ANC<500/mm3 [0.5 × 109/L]
ANC based on local or 
central laboratory results
CMV DNA ≤LLOQ 
(based on local or 
central specialty 
laboratory, most 
recent result prior to 
dose assessment 
should be considered).
Continue 
valganciclovir 900 mg 
BID.
Hematopoietic growth 
factors may be used at 
investigator’s 
discretion.
May adjust valganciclovir 
dose to 450 mg BID or 
interrupt the dose and 
resume at 450 mg BID or 
900 mg BID (dose choice at 
investigator’s discretion) 
once ANC >1000/mm3
[1.0×109/L].
Hematopoietic growth 
factors may be used at 
investigator’s discretion.
May interrupt valganciclovir 
dose and resume at 450 mg 
BID or 900 mg BID (dose 
choice at investigator’s 
discretion) once ANC 
>1000/mm3 [1.0×109/L].
Permanent valganciclovir 
discontinuation and alternative 
anti-CMV treatment may be 
considered at investigator’s 
discretion.
Hematopoietic growth factors 
should be strongly considered.
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Table 7. Valganciclovir Dose Adjustment Based on ANC Level and CMV DNA 
Clearance
ANC >1000/mm3
[1.0 × 109/L]
ANC based on local 
or central laboratory 
results
ANC 500/mm3 [0.5 ×109/L] 
to 1000/mm3 [1.0 × 109/L]
ANC based on local or 
central laboratory results
ANC<500/mm3 [0.5 × 109/L]
ANC based on local or 
central laboratory results
CMV DNA ≥LLOQ 
(based on local or 
central specialty 
laboratory, most 
recent result prior to 
dose assessment 
should be considered).
Continue 
valganciclovir 900 mg 
BID.
Hematopoietic growth 
factors may be used at 
investigator’ 
discretion.
May adjust valganciclovir 
dose to 450 mg BID.
Hematopoietic growth 
factors may be used at 
investigator’s discretion.
May interrupt valganciclovir 
dose and resume at 450 mg 
BID or 900 mg BID (dose 
choice at investigator’s 
discretion) once ANC 
>1000/mm3 [1.0×109/L].
Permanent valganciclovir 
discontinuation and alternative 
anti-CMV treatment may be 
considered at investigator’s 
discretion.
Hematopoietic growth factors 
should be strongly considered.
ANC=absolute neutrophil count; BID=twice daily; CMV=cytomegalovirus; DNA=deoxyribonucleic acid; 
LLOQ=lower limit of quantitation; QD=once daily
Drug kit dispensing for dose adjustments will be managed by the IRT system in order to 
maintain the blind. Subjects that require a dose adjustment for renal function or ANC level, 
regardless of study treatment, will be assigned a new study drug kit.
Various clinical scenarios of neutropenia, as shown in Table 7, will be programmed in the IRT 
and appropriate options will be selected by the investigator. Interruptions and discontinuation of 
study treatment will be conducted in a blinded manner; therefore, it is possible that treatment 
with either valganciclovir or maribavir will be interrupted or discontinued for neutropenia 
presence. The investigator may also select to interrupt study treatment, for other adverse events, 
regardless of the treatment assignment (maribavir or valganciclovir). The interruption for a 
maximum of 7 consecutive days will not result in permanent study treatment discontinuation. 
Up to 2 study treatment interruptions for a total of up to 7 days will be allowed. If study drug is 
interrupted for any reason and subsequently resumed, the end of the study drug administration 
period would remain fixed at a maximum of 8 weeks after the date of the start of treatment. 
A third study treatment interruption will lead to permanent study treatment discontinuation; the 
subjects will complete the end of treatment procedures described for Visit 10/Study Week 8 in 
the Schedule of Assessment 1 (Table 1), and will follow a modified schedule of assessments 
through the remaining weekly visits scheduled for the study treatment phase and the regular 
schedule of assessments through the 12-week follow-up phase as described in Section 4.5.
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If valganciclovir dose adjustment is required for both renal function and neutropenia, the lowest 
dose/dose selection as specified in Table 7 will occur through the IRT.
6.2.4 Blinding Procedures
This is a randomized, double-blind, double-dummy, active-controlled study. Qualified subjects 
will be randomized in a 1:1 allocation ratio to receive maribavir or valganciclovir using a 
centralized procedure. An IRT will be used to randomize subjects and provide the treatment 
assignment to the blinded pharmacist or a blinded designated study staff member.
To accomplish the blind, exact matching placebo tablets will be provided for both maribavir and 
valganciclovir, ie, each subject will receive maribavir and placebo (identical to valganciclovir) 
tablets if randomized to maribavir treatment, or valganciclovir and placebo (identical to 
maribavir) if randomized to valganciclovir treatment To protect the study blind, subjects will be 
required to take at a maximum, 2 tablets of their assigned study treatment and 2 tablets of the 
placebo q12h in a double-dummy format as shown in Table 5.
In order to protect the study blind during the study conduct, it is imperative that the investigator, 
subjects and their families, or any member of the study team, either at the study site or that of the 
Sponsor remain blinded to the subject treatment assignments until the data base lock (after the 
last subject has completed the study). The investigator and the sponsor will also be blinded to the 
PK data. Every effort will be made to maintain the blind except in those emergency situations 
when the identification of the investigational product is required for further treatment of the 
subject.
Unblinding the Treatment Assignment
There will be a provision for unblinding to ensure adequate treatment of the subject in the case of 
an emergency (details will be provided in the study manual). The Sponsor medical monitor 
should oversee this process. An unblinded medical monitor independent from the study will be 
identified by the sponsor for any situations that may need unblinding during the study.
In order to maintain the overall quality of the clinical conduct of the trial and integrity of the 
study data, the treatment assignment must not be broken during the study except in emergency 
situations where the identification of the investigational product is required for further treatment 
decisions for the subject. The investigators are encouraged to contact the designated blinded 
study medical monitor whenever possible to discuss the circumstances and the potential need for 
unblinding. If this is not possible, in the event of emergency unblinding, the investigator must 
notify the designated blinded study medical monitor and the sponsor, as soon as possible after 
breaking the blind, taking care not to reveal the subject's randomization code (see emergency 
contact information in Section 8.2.2). 
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The date and reason for unblinding will be recorded in subject's source documents. An unblinded 
medical monitor will be contacted if needed for any matters where treatment assignment will 
need to be revealed.
The investigators will be provided by the Sponsor with a clear procedure on how to access the 
central randomization system for code-breaking for each subject, disclosing the details of the 
allocated treatment (details provided in the study manual). The code will be broken only in case 
of emergency where the further treatment of the subject is dependent on the trial medication 
he/she received. In the event that the treatment assignment is broken, the date, the signature of 
the person who broke the code, and the reason for breaking the code are recorded on the IRT and 
the source documents. Any code break that occurs must be reported to the contract research 
organization (CRO)/sponsor.
Since the PK samples for only those subjects who are taking maribavir will be analyzed while 
the study is ongoing, the bioanalysis will be conducted by unblinded staff from the bioanalysis 
laboratory/CRO to allow for the identification of the PK samples from the subjects randomized 
to the maribavir treatment arm. If needed, an interim PK analysis of maribavir PK data obtained 
from the subjects may be performed by an independent unblinded team/CRO outside of the 
blinded study team, who will also receive the reports of the drug concentrations for the interim 
population PK analysis.
 
 
 
 
 
 
 
 
 
The DMC may be unblinded as described in the DMC charter.
6.3 Labeling, Packaging, Storage, and Handling
6.3.1 Packaging and Labeling
Maribavir, valganciclovir, and matching placebos will be packaged and labeled such that the 
products will be indistinguishable from their respective match placebos by the investigator, study 
site, and subjects (refer to the pharmacy manual for further information).
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Study drug kits will be affixed with a label containing minimally the protocol number, study 
drug kit number, dosage form, storage conditions, the statements ‘For clinical trial use only’, 
and/or ‘CAUTION: New Drug – Limited by Federal (US) Law to Investigational Use’, and other 
information that may be required by the local laws.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor. Additional labels may not be added without the sponsor’s prior full 
agreement.
6.3.2 Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility for storage may be delegated to the 
pharmacy or member of the study team, but this delegation must be documented. Investigational 
products are distributed by the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique subject identifier on the investigational 
product bottle/carton labels as they are distributed.
Investigational products must be stored in accordance with labeled storage conditions which state 
“Do not store above 25°C. Do not freeze.” Temperature monitoring is required at the storage 
location to ensure that the investigational product is maintained within an established 
temperature range. The investigator is responsible for ensuring that the temperature is monitored 
throughout the duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house system, a mechanical recording device such 
as a calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s); (eg, fumigation of a 
storage room).
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6.4 Drug Accountability
Investigators will be provided with sufficient amounts of the investigational products to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. An IRT will be used to manage subject 
randomization and the investigational product.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All 
administered/dispensed medication will be documented on the CRFs and/or other investigational 
product records and may include additional information as required per applicable regulations. 
The investigator is responsible for ensuring the retrieval of all study supplies from subjects. 
Compliance will be collected in the subject's diary. The disposition of the unused supply of the 
dispensed investigational product will be documented in the accountability log.
During the COVID-19 public health emergency, alternative study drug delivery to trial 
participants may be necessary to avoid unnecessary subject visits to sites while providing needed 
study drug. Additional study drug may be dispensed during a scheduled study visit or study drug 
may be shipped directly from investigational sites to participants’ residences by a contracted 
logistics provider or distributor (direct-to-patient [DTP] shipment) in compliance with national 
laws or temporary national emergency measures and Takeda processes. When utilizing DTP, the 
investigator remains responsible for ensuring the safety of subjects and the dispensation of the 
investigational product.
No investigational product stock or returned inventory from a Takeda-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided the blind of the study is not compromised.
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With the written agreement of the sponsor, at the end of the study, or as instructed by the 
sponsor, all unused investigational product stock, subject-returned investigational product, and 
empty/used investigational product packaging will be returned to a sponsor specified 
designation. Should local, state or national laws prohibit the return of unused stock, subject 
returned investigational product, or empty/used investigational product packaging to the sponsor 
designated locations, it may be destroyed at the site or local facility once the sponsor has 
reviewed and approved the site's standard operating procedure. In this case, Certificates of 
Destruction (CoD) identifying what was destroyed, when and how, must be obtained with copies 
provided to the sponsor. Destruction of investigational products must be in accordance with 
local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5 Subject Compliance
For drug administration at the site, hospital staff or study personnel will administer all doses of 
study drug. Missed/incorrect doses will be recorded in the subject’s diary and CRF, as 
appropriate.
During the COVID-19 public health emergency, study drug may be administered by a healthcare 
professional as part of home nursing or home healthcare. If a subject participates in home 
healthcare in the treatment phase, they will receive study drug through DTP and the site will 
follow-up with the subject. When utilizing DTP, the investigator remains responsible for 
ensuring the safety of subjects and the dispensation of the investigational product.
For drug administration as outpatients, a study diary for tracking adherence to study drug dosing 
and an adequate supply of study drug will be dispensed for home use. Subjects must be 
instructed to bring their unused study drug, empty/used study treatment packaging, and the study 
diary to every visit. Drug reconciliation must be assessed for all dispensed investigational 
product. Unused investigational product will not be redispensed. Instructions will be provided in 
the pharmacy manual.
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7. STUDY PROCEDURES
7.1 Study Schedule
See Table 1 for study procedures for the double-blind study treatment phase and Table 2 for 
study procedures for the follow-up phase.
7.1.1 Screening Period 
Screening Visit (Visit 1/ Day -14 to Day 0/Week -2 to Week 0)
As specified in Table 1, the screening procedures will include:

Informed consent

Inclusion/Exclusion criteria (See Section 4.1 and Section 4.2)

Height and body weight (Section 7.2.3.1)

Vital signs (Section 7.2.3.2)

Medical history, including transplant history (eg, underlying disease that led to the HSCT, 
transplant type, other details related to transplant) and CMV history, HIV status

Prior medication, therapies, and procedures, including any prior anti-CMV medication used 
to treat the current CMV infection (Section 5.1)

Hematology/Chemistry (Section 7.2.3.4). Tests required for eligibility must be performed 
and results verified within 3 days prior to randomization.

Pregnancy test (serum) for all females of childbearing potential (Section 7.2.3.4). This must 
be performed and results verified within 3 days prior to randomization.

HIV status: Historical results for human immunodeficiency virus (HIV) tests performed 
within 3 months prior to randomization will be acceptable for screening. If no HIV test result 
within 3 months is available, the subject must have testing done locally during the screening 
period and have the results available prior to randomization (Exclusion Criterion 8).

Cytomegalovirus disease assessment (Section 7.2.2.3)

Interactive response technology (IRT; Section 6.2.1) to manage screening and site enrollment

Invasive bacterial and fungal infections/transplant relevant infection assessment (see 
Section 8.1.4)

Graft-versus-host-disease assessment
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
Cytomegalovirus DNA test (quantitation): Documentation of CMV infection in whole blood 
or plasma with a screening value of ≥1365 IU/mL to ≤273000 IU/mL in whole blood or 
≥455 IU/mL to ≤91000 IU/mL in plasma in 2 consecutive samples separated by at least 1 day 
as determined by local or central specialty laboratory qPCR or comparable quantitative CMV 
DNA results with the first sample available within 14 days prior to randomization at 
Visit 2/Week 0/Day 0. The second sample must be taken within 5 days prior to 
randomization. The 2 CMV DNA results must be ≥455 IU/mL in plasma or ≥1365 IU/mL in 
whole blood. High-risk CMV infection is defined as meeting any of the following criteria:

Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 
1 of the following 3 HLA-gene loci: HLA-A, -B or -DR;

Haploidentical donor;

Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA gene loci: 
HLA-A, -B, -C, -DRB1;

Use of umbilical cord blood as stem cell source;

Use of ex vivo T-cell-depleted grafts;

Grade 2 or greater GVHD requiring the use of systemic corticosteroids (defined as 
the use of ≥1 mg/kg/day of prednisone or equivalent dose of another corticosteroid).

Results from the same laboratory are to be used to assess subject eligibility criteria. The 
laboratory used for DNA quantification could be either local specialty laboratory or central 
specialty laboratory.
Informed consent must be obtained before any study-specific procedures are performed. All 
screening procedures will be completed within 14 days prior to randomization, with the 
exception of the following:

Clinical laboratory tests (hematology, chemistry, and pregnancy), must be performed and 
verified within 3 days prior to study treatment initiation. At screening, either central or local 
laboratory results for hematology/chemistry/pregnancy testing can be used for qualification.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered study 
treatment. Screen failures due to low platelet count, hemoglobin, and low neutrophil counts or 
liver or renal parameters can be rescreened once within the 14-day screening period at the 
investigator’s discretion when other inclusion criteria are fulfilled. Other screen failures may be 
rescreened in the future (with new informed consent and screening period) if their clinical course 
results in a change that deems them eligible for the study. 
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In addition, subjects who discontinued from screening due to COVID-19-related factors but were 
otherwise qualified to participate in the trial may be rescreened at any time if the Takeda medical 
monitor agrees.
The screening visit (Visit 1) and Visit 2/Week 0/Day 0 visits can occur in the same day.
7.1.2 Study Drug Administration Period
Visit 2/Week 0 (Baseline; Day 0) to Visit 10/Week 8 (End of Treatment)
Permissible assessment windows during the 8-week study treatment phase are: Study 
Day 4 ± 1 day, Study Week 1 + 2 days, Study Weeks 2 to 4 ± 2 days; Study Weeks 5 to 
8 ± 3 days.
As specified in Table 1 the following assessments will be performed during the study treatment 
phase:

Randomization on Visit 2/Week 0 (Day 0; baseline)

Physical examination (including weight) at Visit 2/Week 0, Visit 6/Week 4, and 
Visit 10/Week 8 (Section 7.2.3.1)

Review of medical history and prior medication at Visit 2/Week 0 (Section 5.1)

Weight at Visit 4/Week 2 and Visit 8/Week 6 (Section 7.2.3.1)

Vital signs at Visit 2/Week 0, Visit 4/Week 2, Visit 6/Week 4, Visit 8/Week 6, and 
Visit 10/Week 8 (Section 7.2.3.2)

12-lead ECG at Visit 2/Week 0, Visit 10/Week 8 (Section 7.2.3.3)

Hematology/Chemistry assessment by the central laboratory at all visits through the study 
treatment phase; potassium and magnesium at Visit 2A (Section 7.2.3.4). In addition, blood 
samples for complete blood count with differential count and serum creatinine should be 
drawn for the analysis by the local laboratory within 2 days prior to study treatment 
dispensation for any postbaseline visits so that the test results are available for review prior to 
each study treatment dispensation. Additional analysis by local laboratory may be conducted 
at the investigator's discretion.

Urinalysis at Visit 2/Week 0, Visit 4/Week 2, Visit 6/Week 4, Visit 8/Week 6, and 
Visit 10/Week 8 (Section 7.2.3.4)

Pregnancy test at Visit 2/Week 0, Visit 6/Week 4, Visit 10/Week 8 (Section 7.2.3.4)
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
Hepatitis B virus (HBV) and hepatitis C virus (HCV) test at Visit 2/Week 0 (Historical 
results available within 3 months prior to study treatment initiation will be accepted. A test 
will be performed at Visit 2/Week 0 if the historical results are not available.)

Cytomegalovirus DNA test: CMV DNA quantification in the plasma samples obtained at all 
visits (including baseline) of study treatment phase will be conducted at central specialty 
laboratory. CMV genotyping by the central specialty laboratory to assess for mutations in the 
UL97, UL27, and UL54 genes will be conducted only on the following samples: at baseline; 
 
 
 

Tissue invasive CMV disease assessment (see Appendix 4) at all visits through the study 
treatment phase
 

Immunosuppressant drug concentration measured at Visit 2/Week 0, Visit 2A/Day 4, 
Visit 3/Week 1, and Visit 10/Week 8 (see Section 7.2.3.4)

Pharmacokinetic sample collection for adult subjects ≥18 years of age will be as follows: 
at Visit 3/Day 7/Week 1 (premorning dose and between 2-4 hours postmorning dose), 
Visit 6/Week 4 (only premorning dose), and Visit 10/Week 8 (premorning dose and between 
2-4 hours postmorning dose). Pharmacokinetic sample collection for adolescent subjects 
≥16 to <18 years of age will be as follows: intensive PK sampling at Visit 3/Week 1
(premorning dose and 1, 2, 3, 4, 6, 8 [all ±5 min], and 12 hours [±15 min] postmorning dose); 
at Visit 6/Week 4 (one premorning dose PK sample); at Visit 10/Week 8 (one premorning 
dose and one between 2-4 hours postmorning dose PK samples).

Interactive response technology at all visits through the study treatment phase; except for the 
end-of-treatment visit (Visit 10/Week 8), IRT will be used for study treatment dispensing at 
all other visits through the study treatment phase.

Study drug dispensed at every visit except Visit 10/Week 8; study drug administration 
through 8 weeks of study treatment phase (Study Week 0 through Study Week 7)
 
 
 
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
Assessment of underlying disease that led to HSCT will be performed at all visits through 
study treatment phase

Invasive bacterial and fungal infections/transplant relevant infection assessed at all visits 
throughout the study treatment phase

Hepatic function grading according to the Child-Pugh classification (see Appendix 2 and 
Section 7.2.2.8) at baseline, Visit 2/Week 0

Graft-versus-host-disease assessment at all visits through the study treatment phase

Comorbidity status evaluation at baseline, Visit 2/Week 0, Visit 6/Week 4, and 
Visit 10/Week 8
 
 

Concomitant medications, therapies, and procedures through the study treatment phase

Adverse event/SAE monitoring throughout the study treatment phase
For subjects who permanently discontinue study treatment early but do not withdraw consent, 
refer to Section 4.5 regarding modified schedule of assessments.
7.1.3 Follow-up Period
Visit 11/Week 9/Follow-up Week 1 to Visit 18/Week 20/Follow-up Week 12 (End of Study)
The follow-up period for this protocol is 84 days or 12 weeks (post-treatment Visits 11 to 18). 
The permissible assessment windows for the visits are: Study Weeks 9-12 (Follow-up 
Weeks 1-4) ±2 days; Study Weeks 14-20 (Follow-up Weeks 6-12) ±3 days.
As specified in Table 2 study evaluations include:

Physical examination (including weight) at Visit 18/Week 20

Vital signs at Visit 18/Week 20

12-Lead ECG at Visit 18/Week 20

Hematology/Chemistry assessment by the central laboratory at Visit 12/Week 10, 
Visit 14/Week 12, Visit 16/Week 16, Visit 18/Week 20
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
Urinalysis at Visit 18/Week 20

Immunosuppressant drug concentration level at Visit 11/Week 9, if treatment continued until 
Week 8 (drug concentration level to be measured 1 week after the end of the study treatment)

Assessment of underlying disease that led to HSCT will be performed at all visits during the 
follow-up phase

Invasive bacterial and fungal infection assessment at all visits during the follow-up phase

Cytomegalovirus DNA test: Cytomegalovirus DNA quantification in the plasma samples 
taken at each visit of study follow-up phase will be conducted at central specialty laboratory. 
Cytomegalovirus genotyping will be conducted only on the samples:
 
 
 

Tissue invasive CMV disease assessment (see Appendix 4) at all visits during the follow-up 
phase

Graft-versus-host-disease assessment at all visits through the follow-up phase 
(Section 7.2.2.5; Appendix 8, and Appendix 9)

Comorbidity status evaluation at Visit 14/Week 12, Visit 16/Week 16, and Visit 18/Week 20
 

Monitoring of nonserious AEs not deemed related to the investigational product up to 
30 days after the last dose of study medication (all AEs deemed related to the investigational 
product are collected until Visit 18/Week 20)

SAE monitoring through the follow-up phase

Concomitant medications, therapies, and procedures collected throughout the follow-up 
phase
All SAEs not resolved at the time of end of study visit (Visit 18/Week 20 or Follow-up Week 12) 
will be followed to closure or stabilization (see Section 8.1). If a subject is withdrawn from the 
study, all Follow-up Week 12/end of study procedures must be performed as soon as possible 
after discontinuation.
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7.1.4 Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2 Study Evaluations and Procedures
All study evaluations and procedures are specified in Schedule of Assessment 1, Table 1, and 
Schedule of Assessment 2, Table 2.
7.2.1 Demographic and Other Baseline Characteristics
Age and/or year of birth, sex, race, and ethnicity will be recorded for all subjects.
7.2.2 Efficacy
7.2.2.1 CMV DNA Quantitation
Blood samples will be assessed at a central specialty laboratory for the quantification of CMV 
DNA in plasma using the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test. Central specialty 
laboratory plasma CMV DNA results will be reported to the investigator site as available. 
Additional CMV DNA testing at local specialty laboratories may be performed and collected at 
more frequent intervals or using additional assay methods at the discretion of the investigator.
Confirmed CMV viremia clearance will be defined as plasma CMV DNA concentration below 
the lower limit of quantification (<LLOQ; ie, <137 IU/mL]), when assessed by COBAS®
AmpliPrep/COBAS® TaqMan® CMV Test at a central specialty laboratory, in 2 consecutive 
postbaseline samples, separated by at least 5 days.
Confirmed Recurrence or the confirmed CMV viremia recurrence will be defined as plasma 
CMV DNA concentration ≥LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan®
CMV Test in 2 consecutive plasma samples at least 5 days apart, after being unquantifiable 
(<LLOQ) for at least 5 days in 2 consecutive samples.
7.2.2.2 CMV Genotyping and Phenotyping
Subjects with known resistance to anti-CMV agents, as determined by the local specialty 
laboratory (testing will be done as directed by the investigator) at the site, will be excluded from 
the study. At Visit 2/Day 0 plasma samples will be obtained and tested by the central specialty 
laboratory to identify mutations in the viral UL97 and UL54 genes known to confer resistance to 
anti-CMV agents. In addition, UL27 gene will be tested. Given the urgency to treat subjects, it is 
not possible to wait for this central specialty laboratory assessment prior to a subject’s
randomization. Potential for mutation conferring resistance at baseline will be limited, given that 
for the current infection, any anti-CMV treatment will not be administered for longer than 
72 hours. 
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In instances when a mutation conferring resistance to anti-CMV agents will be reported in the 
baseline sample analyzed by the central specialty laboratory these subjects will be excluded from 
the Per Protocol Set for analysis.
 
 
 
 Rebound is 
defined as increase in viral DNA load without prior clearance of viremia. The entire UL97, 
UL54, and UL27 CMV genes will be sequenced in every sample that meets the criteria for 
genotyping, including the baseline samples.
 
 
 
The list of CMV mutations known to confer resistance to valganciclovir, and other commercially 
available anti-CMV agents (ganciclovir, foscarnet, and cidofovir) is presented in Appendix 3.
7.2.2.3
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2.2.4
 
 
 
 
 
 
 
 
7.2.2.5 Underlying Disease Assessment
Hematopoietic stem cell transplant offers potentially life-saving treatment for advanced 
malignancies and other diseases of hematologic, immunologic or metabolic origin. Underlying 
disease that led to HSCT, including relapse/progression, will be assessed at all visits throughout 
the study as indicated in Table 1 and Table 2. Dates of relapse or progression of the underlying 
disease/malignancy during the study will be documented. All available methods of detection, 
such as hematological, cytogenetic, molecular, cytological/histological, organs or sites involved 
etc., will be provided as appropriate for the underlying condition.
7.2.2.6 Graft-versus-host-disease Assessments
Graft-versus-host-disease is a well-recognized complication of transplantation, and all blood 
stem cell sources can lead to this complication. Graft-versus-host-disease occurs when the donor 
cells (the “graft”) recognize the patient being transplanted (the “host”) as being foreign, 
(ie, when donor T lymphocytes respond to mismatched protein antigens expressed in host 
T cells). It presents in an acute and chronic form.
The most influential protein mismatches are human leukocyte antigens (HLAs) and the incidence 
of acute GVHD is directly related to the degree of mismatch between HLA proteins expressed by 
the HCT donor and recipient (Loiseau et al., 2007). Even in patients that receive HLA-matched 
(HLA-A/B/C/DRB1) grafts, however, GVHD arises in approximately 40% of patients due to 
differences in minor histocompatibility antigens, and requires systemic therapy. Acute GVHD 
that typically occurs in first 100 days after transplant includes: erythema, maculopapular rash, 
nausea, vomiting, anorexia, profuse diarrhea, ileus or cholestatic liver disease. A recent National 
Institute of Health classification also includes late-onset acute GVHD (after day 100) and an 
overlap syndrome with features of both acute and chronic GVHD (Cho et al., 2009).
Chronic GVHD typically occurs later (>100 days after transplant) and is manifested on skin, 
appendages, mouth, eyes, lungs, genitalia, esophagus and connective tissues. 
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Chronic GVHD diagnosis is supported by histologic evidence of GVHD from any affected site. 
The diagnosis might be difficult as negative histological findings do not exclude the existence of 
chronic GVHD, and similarity to other conditions that often occur in HSCT patients (such as 
mycophenolate mofetil [MMF] toxicity or the presence of GI tissue invasive CMV disease).
Investigators are expected to consider recommendations for diagnosis provided in guidance in 
Appendix 8 and Appendix 9 (Jagasia et al., 2015; Shulman et al., 2015). Detailed information on 
GVHD at screening, baseline or during the study will be collected in separate CRF forms.
Assessment of absence or presence of acute GVHD will be done at baseline, and if present, 
grading will be performed according to published guidelines provided in Appendix 7
(Harris et al., 2016); acute or chronic GVHD present at baseline will also be followed throughout 
the study treatment phase, at every study visit, utilizing the same diagnosis until resolution 
(during the duration of the study) as indicated in Table 1 and Table 2.
7.2.2.7 Comorbidity Status
Transplant patients often have multiple other comorbidities, resulting from their 
immunosuppressed status (co-infections, graft-versus-host-disease, transplant malfunctioning 
due to rejection), toxicities from therapies for maintenance of the transplant or reactivation of the 
baseline disease for which they had been transplanted (malignancy for example), and other 
concomitant diseases resulting in very diverse population that might be enrolled into the study. 
The comorbidity assessment will be conducted to allow for the comparison of the population 
enrolled into two treatment arms and to account for the subjects’ health status when assessing 
overall and individual subject response. Comorbidity assessment will be performed at time 
points indicated in Table 1 and Table 2. The difference between treatment arms in terms of 
baseline comorbidities might be controlled for in the analyses, if determined to be substantial.
Comorbidity assessment will utilize Karnofsky Performance Status (KPS) scale for subjects 
(Peus et al., 2013; Schag et al., 1984). Karnofsky Performance Status is a valuable tool for 
measurement of and comparison between the functional statuses of individual patients.). Refer to 
Appendix 5 for the KPS performance status scale forms.
7.2.2.8 Medical History
A medical history will be taken during the screening period and updated on 
Visit 2/Day 0/Week 0 as specified in Table 1. All medical history findings that have been 
present/active within the 2 years prior to enrollment at Visit 2/Day 0 will be recorded regardless 
of clinical relevance or presence at study start. Medical history finding that have not been 
present/active within the 2 years prior to enrollment will be recorded if deemed clinically 
relevant by the investigator to the conduct of the study. 
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Medical history related to the transplant (including the disease/diseases leading to transplant) and 
CMV infection will be recorded without a time limit. The medical history should include any 
history of allergic reactions to drugs. Refer to Section 5.1 for prior medication history.
Specific information regarding the subject’s transplant history that will be collected, including 
but not limited to, disease/condition that led to the transplant, the number of past transplants 
prior to the current transplant; the details of transplant, such as cell source and transplant type; 
the human leukocyte antigen (HLA) matching level; the date and the history of the current 
transplant including complications; transplant related infections; preparatory regimen for 
transplant; history of relevant viral serology; history of anti-viral prophylaxis; and status of the 
transplant at baseline.
Specific information regarding the subject’s CMV infection will be collected in separate CRFs. 
The collected information will include, but will not be limited to: CMV serology of donor and 
recipient and date of onset of the current CMV infection.
Subjects will be classified into 1 of the following categories with respect to hepatic function, 
based on baseline clinical and laboratory assessments (see Appendix 2). This information will 
primarily be utilized in the interpretation of the PK data for which the samples will be collected 
at the specified visits in the study:

No chronic liver disease

Chronic liver disease - Child-Pugh Class A

Chronic liver disease - Child-Pugh Class B

Chronic liver disease - Child-Pugh Class C
7.2.2.9 Subject Survival
Subject survival (yes/no) will be determined at all visits during the study. The date and cause of 
death will be recorded in the CRF.
7.2.3 Safety
7.2.3.1 Physical Examination (Including Weight)
Abnormalities identified at the screening visit (Visit 1) will be documented in the 
subject’s source documents and on the medical history CRF. Changes after the screening visit 
(Visit 1) will be captured as AEs on the AE CRF page, as deemed clinically relevant by the 
investigator.
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The investigator or designee will perform physical examinations at time points specified in 
Table 1 and Table 2. Physical examinations will be performed in accordance with standard 
practices at the investigational site. Body weight and height will be measured at time points 
specified in the schedule of assessments.
7.2.3.2 Vital Signs
Vital signs (body temperature, arterial blood pressure, and pulse) will be collected in a standard 
manner at the time points specified in Table 1 and Table 2. Any changes from baseline 
(Visit 2/Day 0/Week 0) which are deemed clinically significant in the opinion of the investigator 
are to be recorded as an AE.
7.2.3.3 Electrocardiogram
A 12-lead ECG will be performed at Visit 2/Day 0, Visit 10/Week 8 (end of treatment visit), 
Visit 18/Week 20 (end of study visit), and at any additional time during the study, if clinically 
indicated. ECG data will include heart rate, RR duration, PR duration, QT duration, QRS 
duration. The corrected QT interval (QTc) will be calculated using the Fridericia’s formula. The 
investigator will be responsible for providing the interpretation for all ECGs in terms of clinical 
significance to the subject.
7.2.3.4 Clinical Laboratory Evaluations
Clinical laboratory tests (hematology, chemistry, urinalysis, HBV, HCV, pregnancy) will be 
performed by a central laboratory at the time points, including baseline, specified in Table 1 and 
Table 2. During screening, clinical laboratory tests (hematology, chemistry parameters required 
for eligibility verification, pregnancy) must be performed and results verified within 3 days prior 
to randomization; either central or local laboratory results can be used for qualification. This also 
applies to CMV DNA quantification results. If no result of HIV testing within 3 months prior to 
screening is available, an HIV test will be performed at a local laboratory during the screening 
period for eligibility assessment. If local laboratory results are used for the assessment of 
eligibility, the reference ranges must be provided. Local laboratory results will be recorded in the 
CRF.
Historical results available within 3 months prior to study treatment initiation will be accepted 
for HBV and HCV at Visit 2/Week 0; however, a test will be performed if historical results are 
not available.
At baseline (Visit 2/Week 0) blood samples will be taken for CMV DNA quantification and 
genotyping, hematology and chemistry and tested in the central specialty laboratories. At 
assigned visits, blood samples and urine for clinical safety laboratory testing should be collected 
prior to the administration of study drug. 
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All clinical laboratory assays will be performed according to the central laboratory’s standard 
procedures. In addition, blood samples for complete blood count with differential and serum 
creatinine should be drawn and analyzed by the local laboratory within 2 days prior to study 
treatment dispensation so that results are available and reviewed prior to each study treatment 
dispensation during the treatment phase.
Reference ranges will be supplied by the central laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Clinically significant finding 
should be reported as an AE unless signs of already reported conditions exist. Abnormal clinical 
laboratory values that are unexpected or not explained by the subject’s clinical condition may, at 
the discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed:
Chemistry
Serum sodium, potassium, chloride, bicarbonate/carbon dioxide, glucose, blood urea nitrogen, 
creatinine, calcium, phosphorus, magnesium, uric acid, total protein, albumin, creatine 
phosphokinase, total bilirubin, direct bilirubin, ALT, AST, gamma glutamyltransferase (GGT), 
alkaline phosphatase (ALP), cholesterol (total and HDL/LDL ratio), and triglycerides. The 
samples for chemistry are preferred to be taken under fasting conditions, although this is not 
mandatory. The information whether samples were taken under fasting conditions will be 
collected.
A local laboratory will be used to assess potassium and magnesium levels at Visit 2A 
(Day 4±1 day for subjects receiving tacrolimus, cyclosporine, everolimus, or sirolimus at 
baseline, and at 4±1 days after initiating any of these agents for subjects starting the 
immunosuppressive therapy after baseline and during the study treatment period).
Hematology
White blood cell (WBC) and differential counts (including ANC), hemoglobin, hematocrit, red 
blood cell (RBC) count, reticulocytes, platelet count.
Urinalysis
pH, specific gravity, protein, glucose, ketones, hemoglobin, and microscopic evaluation (RBC, 
WBC, crystals, casts, bacteria), protein/creatinine ratio. Leukocyte esterase for the macroscopic 
evaluation.
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Virology

Hepatitis (hepatitis B surface antigen and/or viral DNA, hepatitis C antibody and/or viral 
RNA) at baseline only, if applicable. Historical results within 3 months of randomization are 
acceptable. If historical results are unavailable, blood will be drawn at Visit 2/Week 0 for 
hepatitis B surface antigen and hepatitis C antibody testing at the central lab. Central 
laboratory results do not need to be available prior to randomization.

Human immunodeficiency virus (HIV) test. Historical results within 3 months prior to the 
study treatment initiation will be acceptable for screening. If no result of HIV testing within 
the prior 3 months is available, the subject must have resting done locally during the 
screening period, and must have the results available prior to randomization.
Other

International normalized ratio (INR) and prothrombin time at baseline only

Immunoglobulins IgG and immunoglobulins total (a total of IgG + IgA + IgM) with no reference 
ranges associated with the immunoglobulins total value
Local Laboratory Test to Monitor Immunosuppressant Drug Concentration Levels
For subjects who are receiving tacrolimus, cyclosporine, sirolimus, or everolimus, testing of the 
blood concentration levels of these drugs will be performed at each site’s local laboratory, using each 
site’s standard assay and standard therapeutic drug monitoring practice (eg, time of sample collection 
relative to dosing). The testing will be performed at the time points outlined below, provided the 
subject is still receiving tacrolimus, cyclosporine, or everolimus on these study days.
If the subject is receiving tacrolimus, cyclosporine, sirolimus or everolimus on 
Study Visit 2/Day 0/Week 0, obtain a tacrolimus, cyclosporine, sirolimus or everolimus blood level:

At Visit 2/Day 0/Week 0 prior to initiation of study treatment

At Visit 2A/Day 4±1 day

At the Visit 3/Day 7 (±2 day)/Week 1 study visit

At Visit 10/Week 8 (±2 days) or on end of treatment visit (if earlier than Week 8)

At the Week 1 post-treatment follow-up visit (ie, 1 week [±2 days] after discontinuation of study 
treatment)
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If the subject is not receiving tacrolimus, cyclosporine, sirolimus or everolimus on Study Day 0, but 
starts any of these drugs after Day 0 while still receiving study treatment, obtain a tacrolimus, 
cyclosporine, sirolimus or everolimus blood level:

At 4±1 days after initiating treatment with tacrolimus, cyclosporine, everolimus, or sirolimus

At the next scheduled study visit after first starting the tacrolimus, cyclosporine, sirolimus, or 
everolimus, while still receiving study treatment

At Visit 10/Week 8 (+2 days) or on end of treatment (if earlier than Week 8)

At the Week 1 post-treatment follow-up visit (ie, 1 week [±2 days] after discontinuation of study 
treatment)
Pregnancy Test 
A serum β-hCG pregnancy test will be performed on all females of child-bearing potential at the 
screening visit (Visit 1), baseline (Visit 2/Week 0), Visit 6/Week 4, and at the end of study 
treatment visit (Visit 10/Week 8), or if pregnancy is suspected, or on withdrawal of the subject 
from the study. Local laboratory test results can be used for the assessment of pregnancy on 
Day 0/Week 0.
7.2.3.5 Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
All AEs are collected from the time informed consent is signed through 30 days after the last 
dose of study medication. All AEs deemed related to the investigational product and all SAEs are 
collected through the end of the study (Visit 18/Week 20 [Follow-up Week 12]).
7.2.4 Others 
7.2.4.1 Clinical Pharmacology Assessments 
Pharmacokinetic samples will be obtained for all subjects as in the Schedule of Assessments 
(Table 1), but analyzed for only those subjects who are taking maribavir. Bioanalysis of 
PK samples will be conducted while the study is ongoing. The analysis will be conducted by 
unblinded staff from the bioanalysis laboratory/CRO to allow for the identification of the 
PK samples from the subjects randomized to the maribavir treatment arm.
For subjects ≥18 years of age (Table 8), 1 or 2 PK samples will be collected on each of the study 
days specified in Table 1. The premorning dose PK sample will be obtained at all 3 PK visits. 
The postmorning dose PK samples at Visit 3/Week 1 and at Visit 10/Week 8 will be obtained 
any time between 2 to 4 hours after the morning dose. 
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Any episode of vomiting occurring within 2 to 4 hours after the morning dose at Visit3/Week 1 
and Visit 10/Week 8 must be documented. Subjects will record the date and time of the previous 
maribavir dose taken before a PK visit in their electronic diary. The instructions will be provided 
in the study manual.
Table 8. Subjects ≥18 Years Sparse PK Schedule
Week 1, Day 7 (±1d)
Week 4, Day 28 (±2d)
Week 8, Day 56 (±2d)
Study Treatment Period
Premorning dose
2-4 hours postmorning dose
One premorning dose
Premorning dose
2-4 hours postmorning dose
For subjects ≥16 to <18 years of age (Table 9), an intensive PK sampling will be performed at 
Visit 3/Week 1. Subjects will be asked to complete the 12-hour postmorning dose PK sample 
prior to taking their evening dose. Sparse PK sampling similar to adults (≥18 years) will be 
performed at Week 4 and Week 8.
Table 9. Subjects ≥16 to <18 Years Including Intensive PK (Week 1) Schedule
Week 1, Day 7 (±1d)
(Intensive PK)
Week 4, Day 28 (±2d)
Week 8, Day 56 (±2d)
Study Treatment Period
Premorning dose, 1, 2, 3, 4, 6, 8 (all 
±5 min), and 12 hours (±15 min) 
postmorning dose
One premorning dose
Premorning dose and
2-4 hours postmorning dose
The following will be recorded in the study diary and/or CRF:

Date and time of the last dose of blinded study treatment before the predose PK sample was 
taken

Date and time that the predose PK sample was taken

Date and time of the last dose of blinded study treatment before the postdose PK sample was 
taken

Date and time that the 2–4 hour postdose PK sample was taken

Date and time of vomiting within 2-4 hours after the morning dose and before the 
postmorning dose PK sample collection
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If a subject has study treatment dose interrupted for 2 consecutive days prior to the morning dose 
on a PK visit, no PK sample will be collected. If a subject has completed the premorning dose 
PK sample collection, but has missed the morning dose of blinded study treatment on the day of 
the PK visit, then no postdose PK sample will be collected.
Unscheduled PK Sample Collection
For purposes of special PK sampling, GIGVHD is defined as any of the following 
(Boeckh et al., 2003):

Biopsy-proven GVHD of the GI tract plus diarrhea (>300 mL/day)

Biopsy proven GVHD of the GI tract and nausea

Documented acute GVHD of the liver (stage II, total bilirubin >3 mg/dL or biopsy-proven) 
plus diarrhea (>500 mL/day) with no other explanation or

Biopsy-proven acute GVHD of the skin plus diarrhea (>500 mL/day) with no other 
explanation
If a subject is diagnosed with GI GVHD during the study treatment phase and therapy with study 
drug remained permissible, study drug will be continued and blood samples for the determination 
of study treatment in plasma concentrations will be collected. This unscheduled PK sampling 
will occur at the next visit after the first occurrence of a GI GVHD diagnosis, and will follow the 
schedule of sampling and recording of information as described in Table 1 (Schedule of 
Assessments).
7.2.4.2
 
 
 
 
 
 
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7.2.4.3
 
 
 
 
 
 
 
 
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7.2.5 Volume of Blood to Be Drawn from Each Subject
The volume of blood drawn from each subject per visit is shown in Table 10.
Table 10. Volume of Blood Drawn Per Study Visit
Study Visit
Blood Volume per Visit (mL)
Screening
29
Visit 2Aa
11
Visit 2
51
Visit 3
42
Visit 4, Visit 5, Visit 7, Visit 8, Visit 9
31
Visit 6
37
Visit 10
60
Visit 11
20
Visit 12, Visit 14, Visit 16
23
Visit 13, Visit 15, Visit 17
15
Visit 18
43
Additional PK
PK Blood Volume per Blood Draw (mL)
See Section 7.2.4.1
4
PK=pharmacokinetic
a To be drawn only from subjects receiving immunosuppressive agents tacrolimus, cyclosporine, everolimus, or sirolimus at 
baseline (on Day 4 ±1 day), or from subjects who initiate treatment with any of these agents after baseline (4 ±1 day after 
starting the immunosuppressant).
Note: See Schedule of Assessment 1 (Table 1) and Schedule of Assessment 2 (Table 2).
During this study, it is expected that approximately 551 mL of blood will be drawn from all 
subjects, regardless of sex. Subjects between the ages of 16 to 18 years will have an additional 
24 mL of blood drawn for intensive PK visits.
Note: The amount of blood to be drawn for each assessment at any visit is an estimate. The 
amount of blood to be drawn may vary according to the instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than 1 blood assessment is 
to be done at the time point/period, if they require the same type of tube, the assessments may be 
combined.
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8. ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1 Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(ICH Guidance E2A 1995).
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where possible, 
a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE CRF.
All SAEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1 Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates. The highest level of severity will be recorded for an event. Worsening of pretreatment 
events, after initiation of investigational product, must be recorded as new AEs (for example, if a 
subject experiences mild intermittent dyspepsia prior to dosing of investigational product, but the 
dyspepsia becomes severe and more frequent after first dose of investigational product has been 
administered, a new AE of severe dyspepsia [with the appropriate date of onset] is recorded on 
the appropriate CRF).
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The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Besides the above mentioned standard categories of severity grading for a few selected events of 
special interest (see Section 8.1.4), the severity (intensity) of AEs will also be assessed according 
to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0.
8.1.2 Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Related:
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related: The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no plausible 
temporal or biologic relationship exists between the investigational product and 
the event.
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8.1.3 Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4 Adverse Events of Special Interest
In addition, the following adverse events of special interest will be closely monitored and 
reported throughout the study regardless of seriousness or of relationship to study treatment. 
Medical assessment of severity will be determined using standard grading category (mild, 
moderate, and severe), and by using other specific severity grading for each adverse event of 
special interest (AESI) as mentioned below:
Adverse Events of Special Interest (severity grading based on CTCAE Version 4.0)
1. Tissue invasive CMV disease. Any new development or onset of tissue invasive CMV 
disease in the asymptomatic subjects (at baseline) will be monitored throughout the study. 
At each visit the investigator will provide the evaluation of the tissue invasive CMV 
disease, which will be collected on the CRF. The investigator will have the final discretion 
in determining whether or not the CMV DNA test results and other clinical data represent a 
new tissue invasive CMV disease for a given subject. When these events are entered into 
the CRF, they should be recorded using the terminology shown in Appendix 4 (eg, ‘CMV 
pneumonitis’, ‘CMV colitis’, etc.). For details on how the disease under study will be 
reported see Section 8.1.5.
2. Relapse or progression of the underlying disease (disease for which transplant was 
performed).
3. Taste disturbance (dysgeusia): If a subject reports an AE of taste disturbance, the 
investigator will record the subject’s description of the taste disturbance (when available) 
as part of the event verbatim in the CRF.
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4. Events of nausea, vomiting, and diarrhea will be recorded. These adverse events are 
common for both maribavir and valganciclovir.
5. Adverse event of neutropenia will be recorded based on laboratory results (central or local) 
considered clinically significant by the investigator. In addition, to the adverse events of 
neutropenia reported by the investigator, incidence of neutropenia defined as 
ANC <500/mm3 [0.5 x 109/L] or ANC <1,000/mm3 [1.0 x 109/L]) based on central 
laboratory data will be analyzed.
Adverse Events of Special Interest (grading based on standard severity categorization to mild, 
moderate, and severe)
1. Immunosuppressant drug concentration level increased: Immunosuppressant drug levels 
will be monitored as specified Section 7.2.3.4. High to toxic levels will be recorded as AEs.
2. Invasive fungal (aspergillus, candida, Pneumocystis jiroveci, etc.) or bacterial infections 
(Staphylococcus aureus, Streptococcus pneumonia, enterococcus, pseudomonas, etc.). 
Baseline conditions will be captured as part of medical history, while new events will be 
captured as AEs. The additional information such as diagnostic method used for the 
pathogen and the source of the sample used for the diagnosis will be collected. 
Additionally, the presence of viral infections frequently occurring in transplant population 
will also be collected (see Appendix 10).
3. Graft-versus-host-disease: GVHD will be diagnosed based on the investigator’s judgment 
(see Section 7.2.2.5). Severity of Acute GVHD (Grading I-IV) will be assessed using 
grading scale provided in Appendix 7 (Harris et al., 2016) and for chronic GVHD using 
severity grading into mild, moderate and severe according to the scoring provided in 
Appendix 8, as in the consensus project by Jagasia et al. (2015). Harris et al. (2016)
provides the confidence levels of the diagnosis (refer to Table 2 in Harris et al., 2016). For 
the purpose of this study, the disease considered 'confirmed' or 'probable' should be 
reported as GVHD. Acute or chronic GVHD present at baseline will also be followed 
utilizing the same diagnosis and severity assessments at every study visit until resolution 
(during the duration of the study) or the end of the study. The baseline presence of the 
acute or chronic GVHD will be reported on the Transplant History page.
8.1.5 Disease Under Study
Subjects will be enrolled in study after fulfilling the criteria for CMV viremia (≥1365 IU/mL to 
≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤91000 IU/mL in plasma) and their viral load 
will be monitored throughout the study. Viremia clearance, persistence, or recurrence will be 
analyzed as the part of efficacy assessment based on central laboratory result.
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It is anticipated that some subjects, although asymptomatic at baseline, may have a new onset of 
tissue invasive CMV disease during the 8 week of study treatment or in the 12-week follow-up 
phase. Since new tissue invasive CMV disease constitutes a medically important event, 
independent of hospitalization or prolongation of hospitalization required for this event, it will 
qualify to be reported as an SAE. Cytomegalovirus disease involving specific organ is to be 
reported, for example CMV disease involving liver will be reported as CMV hepatitis.
The investigator has the final discretion in determining whether or not CMV test results and 
other clinical data represent a new CMV event for a given subject.
If a CMV event crosses into different categories over time, the category of greatest severity 
should be recorded.
The terminology used for reporting should be:

Asymptomatic CMV infection

Tissue invasive CMV disease, specify organ for example CMV pneumonitis, CMV colitis
Table 11 presents the criteria for reporting tissue invasive CMV disease as an AE or as an SAE 
during its clinical course during the study.
Table 11. Criteria for Reporting Tissue Invasive CMV Disease as an AE or as an SAE
Course during the study (based 
on the investigator’s assessment)
Reportable as AE
Reportable as SAE
New onset of/
change in tissue 
invasive CMV 
disease
New onset
No
Yes
Improving
No
No
Worsening
No
Yes, but same event with 
upgraded severity
Asymptomatic 
CMV infection 
at baseline
Improving
No
No
Worsening CMV viremia (or CMV 
viremia recurrence or rebound after 
clearance)
Determined by the 
investigator based on the 
assessment of clinical 
significance; either local or 
central laboratory results to 
be used at investigator’s 
discretion.
Yes, if fulfilling 
seriousness criteria.
If the only reason for 
hospital admission or 
prolongation of 
hospitalization is the need 
for IV treatment in the 
hospital setting, then this 
will not qualify as an SAE.
Worsening to tissue invasive 
CMV disease
No
Yes
AE=adverse event; CMV=cytomegalovirus; IV=intravenous; SAE=serious adverse event
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8.1.6 Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or 
ECG values which were not present at the pretreatment value observed closest to the start of 
study treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.7 Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Takeda Global Pharmacovigilance and Risk Management Department using the Investigational 
and Marketed Products Pregnancy Report Form. The pregnant female study participant must be 
withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
postpartum. An ethics committee (EC) and Institutional Review Board (IRB) approved informed 
consent form must be signed by a pregnant partner of a study participant prior to obtaining 
pregnancy outcome information from the nonstudy participant.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Clinical Study Serious Adverse Event and 
Nonserious AEs Required by the Protocol Form. Note: An elective abortion is not considered an 
SAE.
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In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Clinical Study Serious Adverse Event and Nonserious 
AEs Required by the Protocol Form as well as the Investigational and Marketed Products 
Pregnancy Report Form. The test date of the first positive serum/urine -hCG test or ultrasound 
result will determine the pregnancy onset date.
8.1.8 Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of maribavir exceeding a 
prespecified total daily dose.
The highest dose of maribavir studied in Phase 2 treatment studies (SHP620-202 and 
SHP620-203) was 1200 mg BID. There was no significant difference in safety across all 
3 doses (400 mg BID, 800 mg BID, and 1200 mg BID) studied. Assuming a normal or only 
mildly impaired renal function and serum creatinine levels, a maximum dose of 900 mg 
valganciclovir should be administered at a time (refer to the Valcyte Prescribing Information 
and Valcyte Summary of Product Characteristics as documented in the Study Pharmacy 
Manual). Valganciclovir dose may be adjusted based on renal function and ANC level (see 
Section 6.2.3).

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
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Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. Medication errors should be collected/reported for all products under 
investigation. The administration and/or use of the unassigned treatment is/are always reportable 
as a medication error. The administration and/or use of an expired investigational product should 
be considered as a reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent(s)/legally authorized representative/caregiver.
8.2 Serious Adverse Event Procedures
8.2.1 Reference Safety Information
The reference for safety information for this study is the maribavir investigator's brochure, which 
the sponsor has provided under separate cover to all investigators.
The reference for safety information for the comparator/reference product, valganciclovir, in this 
study is the summary of product characteristics (SmPC), which the sponsor has provided under 
separate cover to all investigators.
8.2.2 Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Takeda Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event (but with no information that would unblind the study treatment assignment). 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors (see Section 8.1.8) unless they result in an SAE.
The investigator must complete, sign, and date the Clinical Study Serious Adverse Event and 
Nonserious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not
to be sent unless requested) and fax or e-mail the form to the Takeda Global Pharmacovigilance 
and Risk Management Department.
In the event of an SAE, the investigator must:
1. Fax or e-mail the clinical trial serious adverse event form within 24 hours to the 
Takeda Global Drug Safety Department. Applicable fax numbers and e-mail address 
can be found on the form (sent under separate cover) and are provided below:
Global
Fax: +1-484-595-8155 
Email: DrugSafety@shire.com
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8.2.3 Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening.
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject 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 was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.
Note: Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event.
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
1 of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization; or the development of 
drug dependency or drug abuse.
For this protocol, the following events will not be collected as SAE(s):

Pre-existing conditions that have not worsened during study participation:

Preplanned (planned prior to the initiation of the study) hospitalizations

Preplanned treatments or surgeries
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8.2.4 Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Takeda Global Drug Safety Department within 24 hours of the first awareness of the 
event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Takeda Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5 Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6 Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7 Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting
The sponsor and/or the clinical CRO is responsible for notifying the relevant regulatory 
authorities US central IRBs/European Union (EU) central ECs of related, unexpected SAEs.
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The study population is HSCT recipients with CMV infections. The following SAEs are 
common in this study population and are anticipated to occur, hence these SAEs (including fatal 
outcome) will not be considered unexpected and will not be individually reported to the 
regulatory agencies, IRBs, Ethics Committees, and investigators, provided there is no increased 
frequency of these events (Maribavir Phase 2 [Studies 1263-202 and 1263-203] data will be used 
as reference):

Any CMV infection, including CMV reactivation/recurrence, 
 

Any other viral, bacterial, or fungal infection

Acute and chronic GVHD

Reactivation/progression of the malignancy or other disease, which is an underlying disease, 
that led to the transplant
This includes fatal outcomes of the aforementioned SAEs.
However, these are AESI and will be closely monitored and recorded on the CRF. See 
Section 8.1.4 for more information on AESI.
In addition, if the event is serious (fulfilling seriousness criteria) it will be reported on SAE 
report form per Section 8.2.2. An independent DMC will be established per Section 9.5.
In addition, sponsor or the sponsor's delegate is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the maribavir 
program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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9. DATA MANAGEMENT AND STATISTICAL METHODS
9.1 Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2 Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3 Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, valganciclovir dose adjustment 
for CrCl/neutropenia, investigational product serum concentrations, CMV DNA plasma or blood
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits.
9.4 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SASVersion 9.1 2 or higher (SAS Institute, Cary, NC 27513).
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The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed 
and plan for subgroup analysis.
 
 
 The SAP will be finalized prior to 
unblinding to preserve the integrity of the statistical analysis and study conclusions. Maribavir 
PK concentrations will be analyzed by a population PK analysis approach. A separate SAP will 
be prepared for this analysis and a separate report will present the pharmacokinetic analysis 
results in addition to the primary clinical study report.
9.5 Data Monitoring Committee
An independent DMC will be established to act in an expert, advisory capacity for periodic 
assessment of the data to monitor participant safety and to ensure the validity and scientific merit 
of the study.
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of study treatment.
9.6 Sample Size Calculation and Power Considerations
The primary testing is to establish that maribavir is not inferior to valganciclovir in treatment of 
CMV infection in HSCT recipients. For ethical reasons it would not be possible to conduct a 
study of maribavir versus placebo since different treatment strategies are already used and well 
established in clinical practice to treat CMV infection. Valganciclovir has been selected as the 
active control because of its documented effectiveness for the treatment of CMV infection, 
including in patients after hematopoietic stem cell transplantation. While clinical trials of 
ganciclovir and valganciclovir versus placebo have been conducted for CMV prophylaxis, no 
placebo-controlled studies have been done to date for the treatment of CMV infection or disease. 
Therefore, the effect size of valganciclovir against placebo is not available, and treatment effect 
estimate had to be derived indirectly. Literature reports viremia clearance rate for valganciclovir 
at 70% to 100%. In the VICTOR study, a randomized controlled study to compare valganciclovir 
with ganciclovir for the treatment of CMV disease in SOT subjects (Asberg et al., 2007), the 
Week 7 viremia clearance rate was reported at 67% and the derived lower limit of the 95% CI 
was 60% for valganciclovir treatment group (n=164). 
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In Phase 2 treatment SHP620-203 study, 75% of HSCT subjects (n=61 across 3 dose groups) in 
the maribavir group and 48% in valganciclovir group (n=21) had confirmed CMV viremia 
clearance within 6 weeks. Based on these available data, the proportion of subjects who achieve 
viremia clearance after 8 weeks of treatment in the current study is assumed at 60% for the 
valganciclovir treatment group.
A 7% noninferiority (NI) margin is chosen for the current study based on the following 
considerations. First, a 7% of margin preserves at least 85% of the effect size assumed for the 
valganciclovir treatment group. Secondly, a 7% margin is less than half of 15%, a common 
NI margin used in antiviral trials and is considered very conservative. Two NI studies on 
comparing valganciclovir with ganciclovir in CMV treatment were identified after a thorough 
literature research. One study was reported by Chawla et al. (2012), and the other is VICTOR 
study (Asberg et al., 2007); both used a NI margin of 15%. Discussions with clinical experts 
confirmed that a 7% NI margin is considered a conservative choice and in clinical practice, a 
lower response rate might even be considered given the favorable safety profile of the test drug 
and where toxicities of available treatments such as valganciclovir limit their use.
Although based on the SHP620-203 study result 75% of HSCT subjects in the maribavir group 
and 48% in valganciclovir group had confirmed CMV viremia clearance within 6 weeks, it is 
expected that maribavir may be superior to valganciclovir in the treatment setting. Given the 
uncertainties regarding the differences in this study design from that of SHP620-203, literature 
reported treatment effect for valganciclovir, and practical consideration for enrollment of 
sufficient number of patients in this orphan patient population, the primary objective of this 
study is testing for noninferiority with testing for superiority to be conducted only after 
noninferiority is established.
For sample size calculation, to be conservative, it is assumed that 68% and 60% subjects will 
achieve confirmed CMV viremia clearance for the primary efficacy endpoint, in the maribavir 
and valganciclovir groups, respectively. Using the normal approximation method, a 2-sided 
95% confidence interval (CI) of the difference in the proportions of subjects with the confirmed 
CMV viremia clearance will be calculated. If the lower limit of the CI is greater than -7%, the 
noninferiority will be assumed. The sample size is estimated based on a 2-group test of 
equivalence in proportions by using nQuery Advisor 7.0. Based on the above assumptions, 
494 eligible subjects (247 per treatment group) will result in a >90% power to declare 
noninferiority of maribavir to valganciclovir for the primary efficacy endpoint. Considering 
10% dropout subjects, not included in the Per Protocol (PP) Set, 550 subjects (275 subjects per 
treatment arm) will be enrolled and randomized.
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9.7 Study Population

The Enrolled Set will consist of all subjects who have signed an informed consent and have 
begun some study procedures.

The Randomized Set will consist of all subjects in the Enrolled Set for whom a 
randomization number has been assigned.

The Modified Randomized Set will consist of all subjects in the Randomized Set who have 
taken at least 1 dose of assigned study treatment.

The Safety Set will consist of all subjects who have taken at least 1 dose of study treatment.

The PP Set will consist of all subjects in the Randomized Set who do not have major 
predefined protocol deviations that may affect the primary efficacy assessment.

The PK Set will consist of all subjects in the Safety Set who had plasma samples drawn and 
tested for maribavir concentrations.

The adolescent pharmacokinetic set will consist of all subjects of 16 to <18 years of age in 
the safety set who had plasma samples drawn and tested for maribavir concentrations.
The Modified Randomized Set and PP Sets will be used for efficacy analyses. The Safety Set 
will be used for safety analyses. Pharmacokinetic data will be analyzed using the 
Pharmacokinetic Set.
9.8 Efficacy Analyses
Efficacy measurements assessed after the initiation of prohibited anti-CMV treatment will be 
excluded from the efficacy analysis for the assigned study drug. Efficacy measurements after 
initiation of alternative anti-CMV treatment will be marked in data listings. Summary descriptive 
statistics will include the number of subjects (N), mean, standard deviation, median, minimum 
and maximum (range) values for continuous variables, and incidences and percentages for 
categorical variables. The denominator for the percentages will be based on the number of 
patients in the analysis set unless otherwise specified. Time-to-event endpoints will be 
summarized using Kaplan-Meier estimation. Ninety-five percent (95%) confidence intervals for 
the estimated 25%, 50%, and 75% times will be presented.
9.8.1 Primary Efficacy Endpoint
The primary efficacy endpoint of this study is confirmed clearance of plasma CMV DNA 
(CMV viremia clearance) at the end of Study Week 8.
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Confirmed CMV viremia clearance at the end of Study Week 8/Study Visit 10 (study treatment 
phase) is defined as plasma CMV DNA concentrations <LLOQ (ie, <137 IU/mL), when assessed by 
COBAS® AmpliPrep/COBAS® TaqMan® CMV Test at a central specialty laboratory, in 
2 consecutive postbaseline samples separated by at least 5 days, at the end of Study Week 8, 
regardless of whether either study-assigned treatment was discontinued before the end of the 
stipulated 8 weeks of therapy. This is further described with examples in Table 12. For clearance of 
CMV viremia to be declared at the end of Study Week 8 during the treatment period, the subject 
must have received exclusively study-assigned treatments.
Table 12. Assessments of Virological Responders at Study Week 8
Scenario
CMV DNA Weeks on Study
Week 6
Week 7
Week 8
Week 9a
Response
Rationale
1
+ / -
-
-
+/-/NA
Yes
2 consecutive “-” at Week 7 and Week 8
2
+ / -
-
+
+/-/NA
No
Not 2 consecutive “-” at Week 7 and Week 8
3
+ / -
+
-
+/-/NA
No
Not 2 consecutive “-” at Week 7 and Week 8
4
+ / -
-
NA
-
Yes
2 consecutive “-” as shown by available data 
and both “-” at Week 7 and Week 9 for 
missing Week 8, otherwise nonresponder
5
-
NA
-
+/-/NA
Yes
2 consecutive “-” as shown by available data 
and both ‘-‘ at Week 6 and Week 8 for 
missing Week 7, otherwise nonresponder
6
-
NA
NA
-
Yes
2 consecutive “-” as shown by available data 
at Week 6 and Week 9 and both “-”, otherwise 
nonresponder
CMV=cytomegalovirus; NA=not available for evaluation of study drug effect; reason could be not assessable by lab, or starting 
alternative anti-CMV treatment or withdrawal from study etc.
a Week 9 data, if available to evaluate effect of study drug, only to be used if Week 8 data are unavailable or missing.
Notes: Scenarios in the table above are provided as examples and may not be all-inclusive of all possibilities.
Only CMV DNA data evaluable for assessment of effect of study drug will be included (ie, prior to the start of alternative anti-CMV 
treatment if any).
"-" = CMV DNA concentration <LLOQ (<137 IU/mL)
"+" = CMV DNA concentration ≥LLOQ (ie, quantifiable)
Confirmed clearance of plasma CMV DNA (CMV viremia clearance) = 2 consecutive postbaseline assessments of CMV DNA target 
<LLOQ, separated by at least 5 days.
Statistical Methodology for Primary Efficacy Endpoint:
The proportion of subjects with confirmed CMV viremia clearance, at the end of Study Week 8 
and the corresponding 95% CIs will be calculated for each treatment group. The difference in 
proportion of subjects with confirmed CMV viremia clearance, at the end of Study Week 8, 
between treatment groups (maribavir and valganciclovir) will be obtained using 
Cochran-Mantel-Haenszel (CMH) weighted average across strata with baseline plasma CMV 
DNA concentration levels and presence or absence of acute GVHD as the stratification factors. 
The baseline plasma CMV DNA concentration will be the last central laboratory assessment 
before the first dose of study treatment. 
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The 2-sided 95% CI of the weighted average of difference across strata will be calculated using 
the normal approximation method. If the lower limit of the 95% CI is greater than -7%, it will be 
concluded that maribavir is as efficacious as valganciclovir. The noninferiority analysis will be 
performed on the PP Set as the primary analysis and on the Modified Randomized Set as a 
secondary analysis.
Sensitivity and supportive analyses of the primary endpoint of confirmed CMV viremia 
clearance at Week 8 will be conducted to evaluate the robustness of the result from the primary 
method. This will be specified in the SAP. Some examples are given below:

The primary efficacy endpoint analysis will be repeated by using the CMV DNA level used 
for the randomization rather than the CMV DNA levels based on central laboratory values as 
one of the stratification factors.

Subjects who discontinue study treatment early, with no CMV DNA measurement for 
responder evaluation of study drug effect at Study Week 8 (see Table 12), however, they 
meet the criteria of confirmed CMV viremia clearance defined as 2 consecutive postbaseline 
assessments of CMV DNA target <LLOQ, separated by at least 5 days within Study Week 8, 
will be included as responders.

Multivariate regression analysis to evaluate treatment difference after controlling for 
important demographic and baseline clinical characteristics. The list of demographic and 
baseline clinical characteristics to be considered will include but will not be limited to 
CMV viral load, CMV serostatus, immune function status, presence of acute GVHD, high 
dose steroids use at baseline, prior use of CMV prophylaxis.

Subjects with missing data due to alternative anti-CMV treatment or death due to 
CMV infection by Study Week 8 will be considered treatment failure, hence non-responder. 
Subjects with missing data due to early discontinuation from study with reason other than 
alternative anti-CMV treatment or death due to CMV infection at Study Week 8 may have 
the response data imputed.
Subject to the multiplicity adjustment method described in Section 9.8.3, the superiority 
hypothesis of the primary efficacy endpoint will be tested by comparing the lower limit of the 
95% CI of the difference with 0 in the proportion of subjects with confirmed CMV viremia 
clearance at the end of Study Week 8 between maribavir and valganciclovir. The superiority 
testing will be performed on the Modified Randomized Set.
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9.8.2 Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the maintenance of confirmed CMV viremia 
clearance achieved at the end of Study Week 8 through Week 16. Example criteria for defining 
responders at Study Week 16 are presented in Table 13.
For clearance of CMV viremia achieved at the end of Study Week 8, regardless of whether either 
study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy, 
and maintenance of such effect through Week 16, the subject must have received exclusively a 
study-assigned treatment and must also have symptom control.
Table 13. Assessments of Responders for Key Secondary Endpoint
Response (both 
Virological 
Response and 
Symptomatic 
CMV Infection 
Control) at 
Study Week 8
CMV DNA Assessment Week
Key 
Secondary 
Endpoint 
Responderb
Rationale
9
10
11
12
14
16
18a
Yes
+/-
+/-
+/-
+/-
+/-
+/-
+/-
/NA
No
Any 2 consecutive “+” in FU by 
Week 16
Yes
+/-
+/-
+/-
+/-
+/-
-
+/-
/NA
Yes
Week 16 is “-” and no 2 consecutive 
“+” during FU
Yes
+/-
+/-
+/-
+/-
+/-
+
+/-
/NA
No
Week 16 is “+” and Week 18 is “+” 
or NA, criteria of 2 consecutive “+” 
is met
Yes
+/-
+/-
+/-
+/-
+/-
+
-
Yes
Week 16 is “+”, and 2 consecutive 
“+” criteria is not met based on 
Week 18 data
Yes
+/-
+/-
+
-
-
NA
-
Yes
Week 16 is missing, 2 consecutive 
“+” criteria is not met based on 
Week 14 and 18 data
Yes
+/-
+/-
+
-
-
NA
+/NA
No
Week 16 is missing, 2 consecutive 
“+” criteria may be met based on 
available Week 18 data
Yes
+/-
/NA
+/-
/NA
+/-
/NA
+/-
/NA
NA
NA
+/-
/NA
No
Lack of data to show maintaining 
effect through Week 16
No
No
CMV=cytomegalovirus; FU=follow-up; NA=not available for evaluation of study drug effect; reason could be starting alternative 
anti-CMV treatment, withdrawal from study, etc.
a Week 18 data will be used only if Week 16 data are unavailable or missing.
b Must also meet the criterion of CMV infection symptom control to be a responder.
Notes: Scenarios in the table above are provided as examples and may not be inclusive of all possibilities.
Only CMV viremia data prior to receiving nonstudy CMV treatment or rescue treatment will be included in the assessment.
Statistical Methodology for Key Secondary Efficacy Endpoint:
The proportion of subjects who achieve response, as defined for the key secondary efficacy 
endpoint, and the corresponding 95% CIs will be calculated for each treatment group. 
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The difference in proportion between treatment groups (maribavir and valganciclovir) will be 
obtained using CMH weighted average across strata with baseline plasma CMV DNA 
concentration level (based on the last central laboratory assessment before the first dose of study 
treatment) and presence or absence of acute GVHD as the stratification factors. The 2-sided 
95% CI of the weighted average of difference across strata will be calculated using the normal 
approximation method. Sensitivity analyses for the key secondary endpoint will also be 
performed.
Subject to the multiplicity adjustment method described in Section 9.8.3, the noninferiority 
testing will be done by comparing the lower limit of the 95% CI with the same NI margin as the 
primary efficacy endpoint. If the lower limit of the 95% CI is greater than -7%, it will be 
concluded that maribavir is as efficacious as valganciclovir in maintaining treatment effect. The 
noninferiority analysis will be performed on the PP Set as the primary analysis and on the 
Modified Randomized Set as a secondary analysis.
Subject to the multiplicity adjustment method described in Section 9.8.3, the superiority in key 
secondary efficacy endpoint will be tested by comparing the lower limit of the 95% CI of the 
difference with 0 in the proportion of subjects who achieve response as defined for the key 
secondary efficacy endpoint between maribavir and valganciclovir. The superiority testing will 
be performed on the Modified Randomized Set.
9.8.3 Multiplicity Adjustment
The hypothesis testing of the primary and key secondary efficacy endpoints will be adjusted for 
multiple comparisons using a gatekeeping testing procedure to control the family-wise Type 1 
error rate at 2-sided α=5% level. The testing will be done in the order of primary efficacy 
endpoint NI testing (H11) first, the primary efficacy endpoint superiority testing (H12) and the 
key secondary efficacy endpoint NI testing (H21) second, and lastly the key secondary efficacy 
endpoint superiority testing (H22).

First, the NI testing of the primary efficacy endpoint will be assessed based on the 
2-sided 95% CI of the adjusted difference in proportion of subjects who have CMV 
viremia clearance at the end of Study Week 8 stratified by baseline CMV DNA level 
and presence/absence of acute GVHD at baseline. This analysis will be conducted 
using Per Protocol Set as the primary and Modified Randomized Set as secondary. If the 
lower limit of the 95% CI is above the predefined NI margin of -7%, NI is considered 
established.
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
If and only after the NI of the primary efficacy endpoint is established, the superiority 
hypothesis of the primary efficacy endpoint and the NI hypothesis of the key secondary 
endpoint will be tested in parallel. Hochberg procedure will be used to control family-wise 
Type 1 error rate at 2-sided α=5% level.

If and only if the superiority of the primary efficacy endpoint and NI of key secondary 
efficacy endpoint are established, the superiority hypothesis of the key secondary efficacy 
endpoint will be tested.
9.8.4 Subgroup Analyses
The proportion of responders and the corresponding 95% CI will be summarized for primary and 
key secondary endpoints by treatment group for the following subgroups (inclusive, but not 
limited to):

Cytomegalovirus DNA viral load (high, low, very low/high-risk)

Acute GVHD presence/absence at baseline

Adolescents ≥16 to <18 years of age (exploratory analysis: may be conducted if sample size 
is adequate)

Enrolling regions (enrolling centers will be grouped by geographic locations to explore 
homogeneity of treatment effect across regions).
9.8.5 Secondary Efficacy Endpoints
The other secondary endpoints of this study are:

The achievement of the confirmed CMV viremia clearance after 8 weeks of receiving 
study-assigned treatment.

The proportion of subjects achieving the confirmed CMV viremia clearance after 
receiving 8 weeks of study-assigned treatment, and the corresponding 95% CIs will 
be calculated for each treatment group separately. The difference in each respective 
proportion between treatment groups and the associated 95% CI will be calculated 
using the same approach as the primary efficacy endpoint, and will be assessed using 
CMH test with acute GVHD and baseline CMV DNA concentration as 2 stratification 
factors.
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
The maintenance of the confirmed CMV viremia clearance after completion of 8 weeks of 
receiving study-assigned treatment, through Study Weeks 12 (4 weeks post-treatment 
period), 16 (8 weeks of post-treatment/follow-up phase), and 20 (12 weeks post-treatment).

The proportion of subjects who maintained the confirmed CMV viremia clearance 
achieved after receiving 8 weeks of study-assigned treatment, through 
Study Weeks 12, 16, and 20, and the corresponding 95% CIs will be calculated for 
each treatment group separately. The difference in each respective proportion 
between treatment groups and the associated 95% CI will be calculated using the 
same approach as the primary efficacy endpoint, and will be assessed using CMH test 
with acute GVHD and baseline CMV DNA concentration as 2 stratification factors.

The maintenance of the CMV viremia clearance achieved at the end of Study Week 8 
through Study Weeks 12, and 20, regardless of whether either study-assigned treatment was 
discontinued before the end of the stipulated 8 weeks of therapy. For maintenance effect to 
be achieved at a time point, the subjects must have received exclusively study-assigned 
treatments up to that time point and also must have symptom control.

The proportion of subjects maintaining the CMV viremia clearance from the end of 
Study Week 8 through Study Weeks 12 and 20 and the corresponding 95% CIs will 
be calculated for each treatment group separately. The difference in each respective 
proportion between treatment groups and the associated 95% CI will be calculated 
using the same approach as the primary efficacy endpoint, and will be assessed using 
CMH test with baseline CMV DNA concentration and presence or absence of acute 
GVHD as 2 stratification factors.

The recurrence of CMV viremia during the first 8 weeks of the study, in the follow-up period 
of 12 weeks, and at any time during the 20 weeks of the study, regardless of whether either 
study-assigned treatment was discontinued before the end of the stipulated 8 weeks of 
therapy.

The proportion of subjects with confirmed recurrence of viremia during the first 
8 weeks of the study, when off treatment in the 12-week follow-up phase, at any time 
during the 20 weeks of the study will be calculated.

The recurrence of confirmed CMV viremia in the 2 study treatment arms when subjects are 
on treatment and off treatment.

The proportion of subjects with confirmed recurrence of viremia while on study 
treatment and when off treatment will be calculated.
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
The incidence of grade 3 or 4 neutropenia (defined as ANC <1,000/mm3 [1.0×109/L]) or 
ANC <500/mm3 [0.5×109/L], respectively)

The proportions of subjects with neutropenia while receiving study treatment will be 
calculated for each treatment group.
The time to first neutropenia while receiving study treatment will be summarized using the 
Kaplan-Meier method. The analysis of the secondary efficacy endpoints will be conducted using 
the Modified Randomized Set and PP Set unless otherwise specified. Secondary efficacy 
endpoints will be summarized by treatment arm, and, if indicated, analyzed statistically at 
α=0.05 (2-sided), without adjustment for multiple comparisons.
9.8.6 Exploratory Efficacy Endpoints
 
9.9 Safety Analyses
The safety analyses will include evaluation and procedures to meet the secondary objective of 
assessing the safety and tolerability of the study treatments.
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Statistical Methodology for Safety Endpoints
Safety evaluation will be made during the periods as illustrated in Figure 1, ie, Screening Phase, 
Treatment Phase, and Follow-up Phase.
Two observation periods are defined for the purpose of analyses:
1. The on-treatment observation period starts at the time of study treatment initiation 
through 7 days after the last dose of study treatment. For subjects who transfer from the 
study treatment to a nonstudy anti-CMV treatment, the on-treatment observation period 
starts at the time of the study treatment initiation through 7 days after the last dose of 
study treatment, or until the nonstudy anti-CMV treatment initiation, whichever is earlier. 
This will serve as the primary analysis of safety.
2. The overall-study observation period starts at the time of the start of the study 
treatment through the end of the study. 
An AE (classified by preferred term) that has a start date on or after the first dose of study 
treatment, or that has a start date before the date of first dose of study treatment but increases in 
severity after the first dose of study treatment, will be considered a treatment-emergent AE 
(TEAE).
The overall study AEs are those occurring during the overall-study observation period.
Safety endpoints will be summarized descriptively for the on-treatment period, and overall study 
period, as appropriate. Baseline assessments will be the last assessment before the first dose of 
study treatment. The Safety Set population will be used to analyze the safety data.
The safety endpoints for this study are as follows:

TEAEs and treatment-emergent SAEs, overall study AEs and overall study SAEs

Clinical laboratory evaluations (including incidence of neutropenia defined as ANC 
<500/mm3 [0.5 × 109/L] or ANC <1,000/mm3 [1.0 × 109/L] at any time during the study [on 
treatment and overall study period], time to neutropenia development), and study treatment 
dose adjustment due to AEs

Safety assessments will also include vital sign measurements, physical examination, and 
ECG.
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The number of events, incidence, and percentage of TEAEs and overall-study AEs will be 
displayed for each treatment group by preferred terms using the Medical Dictionary for 
Regulatory Activities (MedDRA®). Summaries in terms of severity and relationship to study 
medication will also be provided.
Treatment-emergent SAEs will be summarized separately in a similar fashion. Summaries of 
AEs causing discontinuation of study medication, withdrawals, AEs leading to death, SAEs and 
AESIs will be provided.
Adverse events of special interest as defined in Section 8.1.4, will be analyzed according to 
primary system organ classes (SOCs) and preferred terms (PTs). Standardized MedDRA queries 
(SMQs) may be used, as applicable. Summary tables with SOCs and PTs will be generated 
presenting the number and percentage of subjects by AE, severity, seriousness, and relationship 
to study medication. Invasive bacterial and fungal infections, if any, will be noted.
Usage of concomitant medications will be summarized descriptively for each of the treatment 
groups for the on-treatment period and overall study period. Additionally, summary of 
hematopoietic growth factors, blood, and blood products transfusions will be provided.
Change from Baseline in vital signs and clinical laboratory test s will be summarized for each 
treatment group with descriptive statistics at each assessment visit. Additional shift tables may be 
produced for selected laboratory parameters using severity grades based on National Cancer 
Institute (NCI) common terminology criteria for adverse events (CTCAE v4.0) or using 
normal/above normal/below normal range. Analyses of shifts in NCI CTC toxicity grades from 
baseline to maximum grade postbaseline for the on-treatment period and the overall-study period 
will be provided. Potentially clinically important findings will also be summarized.
Treatment-emergent grade 3 or 4 neutropenia (defined respectively as ANC <1,000/mm3
[1.0 × 109/L]) or ANC <500/mm3 [0.5 × 109/L]) will be summarized as shifts in laboratory
results from lower grade to maximum grade of either 3 or 4 postbaseline for the on-treatment 
period and the overall-study period. Time to neutropenia development will be evaluated.
Study treatment dose adjustment, specifically valganciclovir dose adjustment and interruptions 
for neutropenia or renal function impairment or other AE, and maribavir dose interruptions for 
any AE, will be summarized.
Abnormal physical examination findings will be listed.
Summary of ECG findings will be provided by treatment groups.
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An independent DMC will be established to assess the data for safety and to ensure the validity 
and scientific merit of the trial. Detailed plans for the DMC’s purpose and responsibilities will be 
described in the DMC charter and the SAP.
9.10 Other Analyses
9.10.1
 
 
9.10.2
 
9.10.3 Pharmacokinetic and Pharmacokinetic/pharmacodynamic Analyses
The PK Population will be used to analyze the PK endpoints. Since this is a double-blind study, 
PK samples will be obtained for all subjects as in the Schedule of Assessments (Table 1), but 
analyzed for only those subjects who are taking maribavir.
Pharmacokinetic endpoints for this study are as follows:
Secondary endpoint:
For all subjects:

Maribavir Cmin (predose maribavir concentration)
For adolescent subjects who provided intensive PK samples at Visit 3/Week 1:

AUC(0-tau): area under the concentration-time curve over the 12-hour dosing interval at steady 
state

Cmax: maximum concentration

Tmax: time when maximum concentration is observed

CL/F: apparent oral clearance

Vz/F: apparent volume of distribution
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Blood samples will be analyzed for plasma maribavir concentration levels. Maribavir concentrations
will be summarized by visit and planned sampling time. A scatter plot of all reportable maribavir 
concentration vs actual sampling time will be generated. A listing of subjects with maribavir 
concentration below the quantitation limit will be provided along with the Week 8 efficacy response. 
In a separate analysis and report, maribavir concentrations will be analyzed by population PK 
analysis approach using nonlinear mixed effect model approach using NONMEM Version 7 or 
above. Post hoc maribavir PK parameters such as AUC, Cmax, and Cmin will be generated and 
summarized by identified covariates; 
 
 This 
analysis maybe conducted by combining maribavir PK data from other Phase 2 and Phase 3 studies.
If needed, an interim population PK analysis of maribavir PK data obtained from the study 
subjects will be performed. Interim population PK analysis will be performed by an independent 
unblinded team or CRO who will have no involvement in the conduct of the study. Results from 
this analysis will not be shared with any members of the study team until after database lock. 
Rules governing this process are detailed in the sponsor’s (or designee’s) standard operating 
procedures.
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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, International 
Conference on Harmonisation (ICH), EU Directive 2001/20/EC and its revisions/updates, and 
local ethical and legal requirements.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1 Sponsor’s Responsibilities
10.1.1 Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), 
EU Directive 2001/20/EC, Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical 
Practice E6 (R2) Current Step 4 version dated 09 November 2016, as well as all applicable 
national and local laws and regulations, and any updates and/or revisions.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2 Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO/investigator as necessary.
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10.1.3 Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4 Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5 Reporting of COVID-19 Cases During the Study
The sponsor will, complying with local laws and regulations, notify relevant health authorities of 
any participant who contracts COVID-19 during the study.
10.1.6 Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2 Investigator’s Responsibilities
10.2.1 Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, Integrated Addendum to ICH E6 (R1): Guideline for Good 
Clinical Practice E6 (R2) Current Step 4 version dated 09 November 2016, applicable regulatory 
requirements and guidelines, and any updates or revisions.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
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The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study and request any medical 
history of the subject (with the subject's consent).
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995).
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study tasks conducted at the trial site. If the investigator/institution retains the services 
of any party to perform study tasks they should ensure this party is qualified to perform those 
study tasks, received study-specific training and should implement procedures to ensure the 
integrity of the study tasks performed and any data generated.
10.2.2 Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
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10.2.3 Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms are supplied by the sponsor/CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
The investigator should maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial subjects. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry and should be explained if necessary 
(eg, via an audit trail).
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) will check or will verify 
the CRF entries against the source documents. The consent form includes a statement by which 
the subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Nonstudy site personnel will not 
disclose any personal information or personal medical information. Due to the COVID-19 public 
health emergency, remote source document verification can be utilized where allowed by local 
laws and regulations. 
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These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency [EMA], United Kingdom Medicines 
and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
US national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor.
The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
10.3 Ethical Considerations
10.3.1 Informed Consent
It is the responsibility of the investigator to obtain written informed consent, and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments; parents will sign the assent form, as applicable. All consent and assent 
documentation must be in accordance with applicable regulations and GCP. 
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Each subject or their parent(s)/subject’s legally authorized representative, as applicable, is 
requested to sign and date the subject informed consent form or a certified translation if 
applicable, after the subject has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by a parent or both parents/legally authorized representative/caregiver of the safe, responsible 
storage and administration of investigational product to the study subject.
10.3.2 Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/CRO has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
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10.4 Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market maribavir; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique number for identification.
The results of studies containing subjects’ unique identifying number and relevant medical 
records will be recorded. They may be transferred to, and used in, other countries which may not 
afford the same level of protection that applies within the countries where this study is 
conducted. The purpose of any such transfer would include: to support regulatory submissions, 
to conduct new data analyses to publish or present the study results, or to answer questions asked 
by regulatory or health authorities.
10.5 Study Results/Publication Policy
Takeda will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative.
Additionally, Takeda adheres to external guidelines (eg, Good Publication Practices 2) when 
forming a publication steering committee, which may be done for large, multicenter 
Phase 2-4 and certain other studies as determined by Takeda. The purpose of the publication 
steering committee is to act as a noncommercial body that advises or decides on dissemination of 
scientific study data in accordance with the scope of this policy. 
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The sponsor and/or its representatives accessing the records and data will take all reasonable 
precautions in accordance with applicable laws, regulations, and guidelines to maintain the 
confidentiality of subjects’ identities.
All publications relating to Takeda products or projects must undergo appropriate technical and 
intellectual property review, with Takeda agreement to publish prior to release of information. 
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Takeda, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
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Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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Cordonnier, C. 2001. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell 
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Maffini, E., Giaccone, L. and Festuccia, M. 2016. Treatment of CMV infection after allogeneic 
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K., Ziemer, M., Pavletic, S. Z., Lee, S. J., Flowers, M. E., Schultz, K. R., Jagasia, M., 
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APPENDIX 1 PROTOCOL HISTORY
Amendment 8 was made to update the sponsor name and address from Shire ViroPharma, Inc 
(Shire) to Takeda Development Center Americas, Inc (TDC Americas; Takeda) and to clarify the 
secondary endpoints. Other minor editorial revisions (including changes for consistency and 
clarity) are not described in the table below.
Protocol Amendment
Summary of Changes Since Protocol Version 8.0 (Protocol Amendment 7)
Amendment Number
8
Amendment Date
02 Jul 2021
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated the sponsor (name and address) from Shire 
ViroPharma, Inc (Shire) to Takeda Development 
Center Americas, Inc (TDC Americas; Takeda) as 
the legal entity will change 01 July 2021.
Document headers; Title/Cover; Protocol Signature Page; 
Product Quality Complaints; Synopsis; Section 3.4, 
Changes to Study Procedures Due to COVID-19 
Pandemic; Section 4.5, Discontinuation and/or 
Withdrawal of Subjects; Section 6.4, Drug 
Accountability; Section 7.1.1, Screening Period; 
Section 8.1.7, Pregnancy; Section 8.2.2, Reporting 
Procedures; Section 8.2.4, Serious Adverse Event 
Collection Time Frame; Section 10.5, Study 
Results/Publication Policy
Document
Date
Global/Country/Site Specific
Original Protocol
04 Aug 2016
Global
Amendment 1
02 Mar 2017
Global
Amendment 2
01 Jun 2017
Global
Amendment 3
01 Sep 2017
Global
Amendment 4
05 Feb 2019
Global
Amendment 5
12 Feb 2020
Global
Amendment 6
07 Dec 2020
Global
Amendment 6.1
10 Mar 2021
Country (CHN)
Amendment 7
25 Mar 2021
Global
Amendment 7.1 (CHN)
17 May 2021
Country (CHN)
Amendment 8
02 Jul 2021
Global
Amendment 8.1 (CHN)
02 Jul 2021
Country (CHN)
Amendment 9
15 Sept 2021
Global
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Protocol Amendment
Summary of Changes Since Protocol Version 8.0 (Protocol Amendment 7)
Amendment Number
8
Amendment Date
02 Jul 2021
Global
Description and Rationale for Change
Section(s) Affected by Change
Clarified the secondary efficacy endpoints on 
maintenance of viremia clearance achieved at 
Week 8 through Week 16 (key), 12, and 20 
regardless if either study-assigned treatment was 
discontinued before the end of the stipulated 8 weeks 
of therapy, the subject must also have symptom 
control.
Synopsis; Section 9.8.2, Key Secondary Efficacy 
Endpoint; Section 9.8.5, Secondary Efficacy Endpoints
Amendment 7 to Protocol SPH620-302 incorporated agency concerns.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Changes Since Protocol Version 7.0 (Protocol Amendment 6)
Amendment Number
7
Amendment Date
25 Mar 2021
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Removed language extending measures to other situations beyond the 
COVID-19 pandemic (“or other future similar unexpected public 
health concerns” as this section applies only to the current COVID-19 
pandemic.
Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic
Updated the guidance on management of clinical trials during the 
COVID-19 pandemic. Clarified that the site must contact the sponsor 
for approval of the alternative method for obtaining informed consent 
prior to implementation.
Synopsis; Table 1, Schedule of 
Assessment 1: Screening Phase and 
Study Treatment Phase; Section 3.4, 
Changes to Study Procedures Due to 
COVID-19 Pandemic; Section 4.1, 
Inclusion Criteria
Clarified the recording of abuse, misuse, overdose, and medication 
errors on the AE CRF.
Section 8.1.8, Abuse, Misuse, 
Overdose, and Medication Error
Amendment 6 to Protocol SHP620-302 incorporated the following major changes: 

The protocol was amended to maintain subject safety, confidentiality, and study integrity in 
the context of healthcare delivery challenges presented by the COVID-19 pandemic. 
Amendment 6 provided flexibility to study participants to opt for home healthcare (HHC) 
solutions as permitted by local regulations. This “hybrid study design” would offer study 
participants the option of in clinic or HHC for all study visits in the treatment phase.
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
Guidance was provided regarding changes to the study procedures that could be implemented 
for study participants or study sites affected by the COVID-19 Public Health Emergency. 
The guidance took references from the FDA Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public Health Emergency - Guidance for Industry, 
Investigators, and Institutional Review Boards, March 2020, updated 03 June 2020, and the 
EMA Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) 
Pandemic, Version 3 (28 April 2020).

As the COVID-19 pandemic could peak in different regions at different times and restrictions 
implemented by local laws and recommendations could vary, any decision on procedural 
changes was to be made on a case-by-case basis by the principal investigator in consultation 
with the study team and the medical team as needed, while maintaining patient safety and 
confidentiality as the priority
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Changes Since Protocol Version 6.0 (Protocol Amendment 5)
Amendment Number
6
Amendment Date
07 Dec 2020
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated Sponsor Approval on Protocol Signature Page.
Protocol Signature Page
Updated number of completed Phase 1 studies from 15 to 17.
Section 1.2.2, Efficacy
Updated number of completed Phase 1 studies from 16 to 17.
Section 1.2.3, Safety
Included language regarding home healthcare services/remote visits 
for the treatment phase.
Study Schedules; Section 3.1, Study 
Design and Flow Chart; Section 3.4, 
Changes to Study Procedures Due to 
COVID-19 Pandemic; Section 6.4, 
Drug Accountability
Included language regarding Direct-to-Patient study drug services 
where allowed per local regulations.
Section 3.1, Study Design and Flow 
Chart; Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic; Section 6.4, Drug 
Accountability
Implementation of remote source document verification where allowed 
per local laws and regulations.
Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic; Section 10.2.3.2, Recording, 
Access, and Retention of Source Data 
and Study Documents
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Protocol Amendment
Summary of Changes Since Protocol Version 6.0 (Protocol Amendment 5)
Amendment Number
6
Amendment Date
07 Dec 2020
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Included language to cover subjects who discontinued due to 
COVID-19.
Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic; Section 4.5, Discontinuation 
and/or Withdrawal of Subjects
Included language to cover subjects who discontinued due to 
COVID-19.
Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic; Section 4.5, Discontinuation 
and/or Withdrawal of Subjects
Included language concerning the notification of relevant health 
authorities about participants who contract COVID-19 during the 
study.
Section 3.4, Changes to Study 
Procedures Due to COVID-19 
Pandemic; Section 10.1.5, Reporting of 
COVID-19 Cases During the Study
Maribavir tablet strength corrected to 200 mg, which was previously 
inadvertently stated as 20 mg.
Section 3.1, Study Design and Flow 
Chart
Added the possibility of valganciclovir dose adjustments for subjects 
with moderate renal impairment to Figure 1, Study Design Flow Chart.
Section 3.1, Study Design and Flow 
Chart
Replaced cidofovir with letermovir in the list of anti-CMV agents that 
must not be taken for current CMV infection for longer than 72 hours.
Section 3.1, Study Design and Flow 
Chart; Section 4.2, Exclusion Criteria; 
Section 5.1, Prior Medications, 
Therapies, and Procedures
Reinserted the clinical laboratory assessment for immunoglobulins 
under the heading labeled “Other”, which was inadvertently removed 
from Protocol Amendment 5.
Section 7.2.3.5, Clinical Laboratory 
Evaluations
Changed the assessment of severity (intensity) of adverse events 
according to version 4.0 of the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE).
Section 8.1.1, Severity Categorization; 
Section 8.1.4, Adverse Events of 
Special Interest
Clarified the recording of abuse, misuse, overdose, and medication 
errors on the AE CRF.
Section 8.1.8, Abuse, Misuse, 
Overdose, and Medication Error
For subjects with CMV DNA ≤910 IU/mL in plasma or ≤2730 IU/mL 
in whole blood with high-risk CMV infection, the requirement was 
removed that the second result must be higher or decrease no more 
than 30% relative to the first result.
Section 7.1.1, Screening Period
Corrected value for inclusion criteria 4 from ≥730 IU/mL in whole 
blood to ≥2730 IU/mL in whole blood under changes for Protocol 
Amendment 4, which was inadvertently not stated correctly in 
Protocol Amendment 5.
Appendix 1, Protocol History
Updated data and sources in Table A-2 and Table A-3 listing CMV 
genetic mutations associated with resistance to anti-CMV drugs.
Appendix 3, CMV Genetic Mutations 
Associated with Resistance to Anti 
CMV Drugs
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
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Amendment 5 to Protocol SHP620-302 incorporated the following major changes:

Added Modified Randomized Set, consisting of all subjects in Randomized Set who take at 
least 1 dose of assigned study treatment.
.

Updated comorbidity status evaluation.

To align with the investigator’s brochure, updated the Cmax and AUC values for the increased 
tacrolimus when concomitantly administered with maribavir (400 mg BID) (33% changed to 
38% and 54% changed to 51%, respectively) and changed 2D6 substrate to CYP2C19 
substrate.

Updated number of completed for Phase 1 studies in Section 1.2.3 from 15 to 16.

Removed references to an electronic diary (e-diary) due to the introduction of paper back-up 
diaries.

Updated the versions of the Valcyte Prescribing Information and Summary of Product 
Characteristics (SmPC) to specify the current version as documented in the Study Pharmacy 
Manual.

Corrected the unit of measure for hemoglobin from mg/dL to g/dL.

Clarified that timing of comorbidity status evaluation is at Visit 6/Week 4 and 
Visit 10/Week 8.

Clarified follow-up to closure of unresolved serious adverse events (SAEs) rather than AEs 
at end of study.

Corrected pregnancy reporting information to indicate that it is the investigator’s 
responsibility to obtain pregnancy outcome/infant condition information within 
approximately 30 calendar days and 1 year postpartum. Removed requirement for a copy of 
the Investigational and Marketed Products Pregnancy Report Form being sent to the CRO/ 
Shire medical monitor using details specified in the emergency contact information section of 
protocol.
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
Corrected information regarding reporting of SAEs.

Removed confidence intervals from 3 secondary efficacy endpoints as they are not clinically 
meaningful for these analyses.

Removed the Ljungman 2002 reference, updated the Ljungman reference from 2016 
(e-publication date) to 2017 (final publication date), and added a statement to refer to the 
citation for full details on the definition of CMV disease.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Changes Since Protocol Amendment 4 (Version 5.0)
Amendment Number
5
Amendment Date
12 Feb 2020
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated Sponsor Approval on Protocol Signature Page.
Protocol Signature Page
Updated study period dates to 2017-2021.
Synopsis
Added Modified Randomized Set, consisting of all subjects in 
Randomized Set who take at least 1 dose of assigned study treatment.
Synopsis; Section 9.7, Study 
Population; Section 9.8.1, Primary 
Efficacy Endpoint; Section 9.8.2, 
Key Secondary Efficacy Endpoint; 
Section 9.8.3, Multiplicity 
Adjustment; Section 9.8.5, 
Secondary Efficacy Endpoints; 
 
 
 
 
 
 
 
Updated comorbidity status evaluation.
Study Schedules, Table 1, Schedule 
of Assessment 1: Screening Phase 
and Study Treatment Phase
To align with the investigator’s brochure, updated the Cmax and AUC 
values for the increased tacrolimus when concomitantly administered 
with maribavir (400 mg BID) (33% changed to 38% and 54% changed to 
51%, respectively) and changed 2D6 substrate to CYP2C19 substrate.
Section 1.2.1, Pharmacokinetics, 
Metabolism, and Drug-Drug 
Interactions; Section 5.2.1, Permitted 
Treatment
Updated number of completed Phase 1 studies from 15 to 16.
Section 1.2.3, Safety
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Protocol Amendment
Summary of Changes Since Protocol Amendment 4 (Version 5.0)
Amendment Number
5
Amendment Date
12 Feb 2020
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Removed references to an electronic diary (e-diary) due to the 
introduction of paper back-up diaries.
Section 6.4, Drug Accountability; 
Section 6.5, Subject Compliance
Updated the versions of the Valcyte Prescribing Information and 
Summary of Product Characteristics (SmPC) to specify the current 
version as documented in the Study Pharmacy Manual.
Section 2.2, Rationale for the Study 
Design; Section 4.4.1, Female 
Contraception; Section 5.2.2, 
Prohibited Treatment; Section 6.2.3, 
Dosing; Section 8.1.8, Abuse, 
Misuse, Overdose, and Medication 
Error
Corrected the unit of measure for hemoglobin from mg/dL to g/dL.
Section 6.2.3, Dosing
Clarified timing of comorbidity status evaluation is at Visit 6/Week 4 and 
Visit 10/Week 8.
Section 7.1.2, Study Drug 
Administration Period
Clarified follow-up to closure of unresolved serious adverse events 
(SAEs) rather than AEs at end of study.
Section 7.1.3, Follow-up Period; 
Section 8.1, Definition of Adverse 
Events, Period of Observation, 
Recording of Adverse Events
Corrected pregnancy reporting information to indicate that it is the 
investigator’s responsibility to obtain pregnancy outcome/infant condition 
information within approximately 30 calendar days and 1 year 
postpartum. Removed requirement for a copy of the Shire Investigational 
and Marketed Products Pregnancy Report Form being sent to the 
CRO/Shire medical monitor using details specified in the emergency 
contact information section of the protocol.
Section 8.1.7, Pregnancy
Corrected information regarding reporting of SAEs.
Section 8.2.2, Reporting Procedures
Removed confidence intervals from 3 secondary efficacy endpoints as 
they are not clinically meaningful for these analyses.
Section 9.8.5, Secondary Efficacy 
Endpoints
Updated Appendix 1, Protocol History to include Protocol Amendment 5 
and added the summary of change information from Protocol 
Amendment 4.
Appendix 1, Protocol History
 
 
 
 
Amendment 4 to Protocol SHP620-302 incorporated the following major changes:

Expanded eligibility criteria for viral load and creatinine clearance rate (CrCl).
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
Added a third viral-load stratum for subjects with very low viral load (CMV DNA 
≥1365 IU/mL to <2730 IU/mL in whole blood or ≥455 IU/mL to <910 IU/mL in plasma at 
baseline) and high-risk infection, in addition to the existing low viral-load (CMV DNA 
≥2730 IU/mL to <27300 IU/mL in whole blood or ≥910 IU/mL to <9100 IU/mL in plasma) 
and high viral-load (CMV DNA ≥27300 IU/mL in whole blood or ≥9100 IU/mL in plasma) 
strata.

Added a study visit at Study Day 4 (±1) for subjects taking a narrow therapeutic index 
immunosuppressive agent (ie, tacrolimus, cyclosporine, everolimus, sirolimus) at baseline to 
align the protocol with a recent recommendation from the Data Monitoring Committee 
(DMC) for Study SHP620-303.

Added a visit 4 days after starting new therapy with a narrow therapeutic index 
immunosuppressive agent for subjects who begin new therapy during the course of the 
treatment period to align the protocol with a recent recommendation from the DMC for 
Study SHP620-303.

Updated contact list, including removal of contacts for sites in Latin America.

Updated safety reporting contacts to a single Shire Global Safety e-mail and fax contact per 
revised safety reporting procedures.

Added exclusion for concomitant letermovir and specified required washout period.

Clarified end of period for collecting nonserious AEs as up to 30 days after the last dose of 
study medication.

Modified the definition of overall study AEs to include events during the overall study period 
through the end of study observation, regardless of initiation of alternative anti-CMV 
treatment.

Modified criteria for reporting of CMV as an AE or SAE to harmonize with the reporting 
format used in Study SHP620-303.

Updated Table 12 Assessments of Responders for Key Secondary Endpoint (confirmed 
CMV viremia clearance at the end of Study Week 8 through Week 16) to ensure assessment 
of responder rates consistent with assessment specified in Study SHP620-303.

Eliminated the Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) assessment and 
deleted Appendix 5 containing the index.

Clarified language regarding starting dosage regimens, as updated entry criteria require 
expansion of starting doses.
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
Added GVHD assessment criteria forms from publications cited in new Appendix 8 
(formerly Appendix 9, containing only citation references) and added tables for GVHD 
diagnosis criteria to new Appendix 9 (formerly Appendix 10, containing only citation 
references).
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
05 Feb 2019
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated Sponsor representative to 
, MD.
Protocol Signature Page
Removed HCT CI from list of abbreviations.
Abbreviations
Updated Emergency Contact Information, including removal of hotline 
numbers for Latin America, and removal of specific medical monitor 
contacts.
Emergency Contact Information
Updated product quality complaint reporting contact to a single e-mail 
and phone contact.
Product Quality Complaints
Removed Latin America from listed Sites and Regions.
Synopsis, Section 3.3 Sites and 
Regions
Modified inclusion criterion 4 for viral load from ≥910 IU/mL in plasma 
or ≥2730 IU/mL in whole blood to ≥455 IU/mL in plasma or 
≥1365 IU/mL in whole blood to include a very low viral-load stratum for 
high-risk subjects, in addition to the existing high and low viral load 
strata.
Synopsis, Table 1, Section 3.1 Study 
Design and Flow Chart;
Section 4.1 Inclusion Criteria; 
Section 8.1.5 Disease Under Study; 
Section 9.8.4 Subgroup Analyses
Modified inclusion criterion 7d for CrCl from 60 mL/min to 30 mL/min.
Synopsis, Section 4.1 Inclusion 
Criteria
Added letermovir to exclusion criterion 5 and specified washout.
Synopsis, Section 4.2 Exclusion 
Criteria
Removed details of washout for anti-CMV agents from exclusion 
criterion 6.
Synopsis, Section 4.2 Exclusion 
Criteria
Added requirement for negative result of HIV testing within 3 months 
prior to start of study treatment to exclusion criterion 17.
Synopsis, Table 1, Section 3.1 Study 
Design and Flow Chart; Section 4.2 
Exclusion Criteria; Section 7.2.3.5
Specified that starting dosage of valganciclovir could be adjusted for 
renal function at screening; removed statement of assumption of only 
mild renal impairment.
Synopsis; Section 3.1 Study Design 
and Flow Chart
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
05 Feb 2019
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Removed additional table listing valganciclovir dose adjustments for 
subjects with both neutropenia and renal impairment as redundant with 
table describing dose adjustment for renal impairment.
Synopsis; Section 6.2.3 Dosing
(previous Table 8)
Modified Study Flow Chart, Schedule, and Procedures to include new 
visit 2A for subjects receiving tacrolimus, cyclosporine, everolimus, or 
sirolimus at baseline, added description of local lab testing of potassium 
and magnesium.
Synopsis, Table 1, Section 3.1 Study 
Design and Flow Chart; 
Section 7.2.3.5 Clinical Laboratory 
Evaluations
Modified the definition of the overall study period for the summary of 
overall study AEs as including the entire study period through the end of 
study observation, regardless of initiation of alternative anti-CMV 
treatment.
Synopsis; Section 9.9
 
Added minimum washout window of 3 days prior to first dose of study 
medication for letermovir.
Section 5.2.2 Prohibited Treatment, 
Table 4
Updated event reporting procedure to specify a single e-mail and fax 
contact for reporting of SAEs and pregnancies and updated department 
name to Global Drug Safety.
Section 8.2.2 Reporting Procedures; 
Section 8.2.4 Serious Adverse Event 
Collection Time Frame
Added a column for additional visit 2A to collect the following 
assessments: Hematology/Chemistry, Immunosuppressant drug 
concentration levels, Adverse events, Study diary, Concomitant meds, 
Therapies, and Procedures.
Table 1; Section 7.1.2 Study Drug 
Administration Period
Added new footnote and text explanation that Visit 2A is required only 
for subjects receiving tacrolimus, cyclosporine, everolimus, or sirolimus, 
and will occur at Day 4±1 day for subjects receiving agent at baseline or 
4±1 day after initiating for those subjects who start after baseline.
Table 1, Footnotes; Section 7.1.2
Study Drug Administration Period
Clarified that local laboratory will assess potassium and magnesium 
levels at Visit 2A (Day 4±1 day for subjects receiving tacrolimus, 
cyclosporine, everolimus, or sirolimus at baseline, and 4±1 day after 
initiation of treatment for subjects initiating treatment with any of these 
agents after baseline during the treatment period).
Table 1; Footnote h; Section 7.2.3.5 
Clinical Laboratory Evaluations
Clarified that nonserious AEs occurring only during the study or within 
30 days of last dose of study medication will be collected.
Table 2; Section 7.1.3 Follow-up 
Period; Section 7.2.3.6 Adverse 
Event Collection
Updated timeframe for collection of medical history data from 5 years to 
2 years.
Section 7.2.3.1 Medical History
Specified requirements for prior hepatitis testing within 3 months before 
randomization.
Section 7.2.3.5 Clinical Laboratory 
Evaluations
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
05 Feb 2019
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated the blood volume expected to be drawn from each subject to 
include additional volumes for subjects receiving tacrolimus, 
cyclosporine, everolimus, or sirolimus.
Section 7.2.5 Volume of Blood to Be 
Drawn from Each Subject, Table 8
Clarified criteria for reporting CMV infection as an AE or as an SAE.
Section 8.1.5 Disease Under Study, 
Table 9
Clarified that the Safety Set will be used for analyses of safety endpoints.
Section 9.7 Study Population
 
 
Clarified that the primary analysis of safety will be based on the 
on-treatment observation period.
Section 9.9 Safety Analyses
Redefined treatment-emergent adverse events to include events with start 
dates before initiation of study treatment that increase after the first dose 
of study treatment, as well as events with start dates after the first dose.
Section 9.9 Safety Analyses
Specified that clinical laboratory evaluations would be assessed for 
on-treatment and overall study periods.
Section 9.9 Safety Analyses
Added study treatment dose adjustments due to AEs as a single safety 
endpoint, and removed specific endpoints of valganciclovir dose 
adjustment/interruptions and maribavir dose interruptions for AEs.
Section 9.9 Safety Analyses
Removed specific examples of adverse events of special interest, and 
referred instead to Section 8.1.4.
Section 9.9 Safety Analyses
Removed blood product transfusions and invasive bacterial or fungal 
infections as separate safety endpoints, and noted inclusion of invasive 
bacterial and fungal infections with discussion of analyses of adverse 
events of special interest.
Synopsis, Section 9.9 Safety 
Analyses
Combined vital sign measurements, physical examination, and ECG as 
safety assessments.
Synopsis, Section 9.9 Safety 
Analyses
Removed statement that a shift table summarizing changes from normal 
and vice versa for all laboratory tests, and added a statement that shifts in 
National Cancer Institute Common Toxicity Criteria toxicity grades from 
baseline to maximum grade postbaseline will be analyzed for the 
on-treatment and overall study periods.
Section 9.9 Safety Analyses
Added statement that transfusions of hematopoietic growth factors, blood, 
and blood products will be summarized.
Section 9.9 Safety Analyses
Specified that treatment-emergent shifts to grade 3 or grade 4 neutropenia 
from lower grade to maximum grade will each be summarized for the 
on-treatment period and the overall study period, and that time to 
development of neutropenia will be evaluated.
Section 9.9 Safety Analyses
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
05 Feb 2019
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Added statement that study treatment dose adjustment, specifically 
valganciclovir dose adjustment and interruptions for neutropenia or renal 
function impairment or other AE, and maribavir dose interruptions for 
any AE, will be summarized.
Section 9.9 Safety Analyses
Revised assessment of responders for the key secondary endpoint to be 
aligned with assessment methods used in Study SHP620-303.
Synopsis; Table 11
Deleted previous Appendix 5, The Hematopoietic Cell Transplant 
Comorbidity Index; renumbered subsequent appendices 6 to 11 as 
Appendices 5 to 10.
(previous) Appendix 5; (new) 
Appendices 5 to 10.
Restored figure attachments for new Appendix 8, Recommendations for 
Chronic GVHD Diagnosis and Grading; restored tables to Appendix 9, 
Diagnostic Criteria for Chronic GVHD.
(new) Appendix 8, (new) 
Appendix 9
Amendment 3 to Protocol SHP620-302 incorporated the following major changes:

Storage conditions of investigational product were revised.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Added reference to the pharmacy manual
Section 6.3.1
Revised storage conditions:

The investigator has overall responsibility for ensuring that 
investigational product is stored in a secure, limited-access 
location. Maribavir and corresponding placebo tablets will be 
stored at room temperature (15°C 30°C 86°F). Valganciclovir 
tablets do not require any special storage conditions and should 
be stored in a similar condition as maribavir tablets to maintain 
the blind. Limited responsibility for storage may be delegated to 
the pharmacy or member of the study team, but this delegation 
must be documented. Investigational products are distributed by 
the pharmacy or nominated member of the study team. The 
pharmacist/nominated team member will enter the unique 
subject identifier on the investigational product bottle/carton 
labels as they are distributed.
Section 6.3.2
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change

Investigational products must be stored in accordance with 
labeled storage conditions of up to 25°C or 77°F.
Added sentence after final bullet point:
For subjects who permanently discontinue study treatment early but 
do not withdraw consent, refer to Section 4.5 regarding modified 
schedule of assessments.
Section 7.1.2
Amendment 2 to Protocol SHP620-302 incorporated the following major changes:

Stated “CMV central nervous system (CNS) infection” as one of the reasons for 
discontinuation and/or withdrawal.

Added basic descriptive statistics generally for all endpoints.

Added sensitivity analysis for investigation of homogeneity of treatment effect across 
centers/regions.

Added rules for conducting the interim population PK analysis.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
01 Jun 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Revised definition of the terms:

Resistant to “Documented failure to achieve >1 log10 decrease 
in CMV DNA level in whole blood or plasma after of 2 or more 
weeks of treatment with IV ganciclovir, oral valganciclovir, IV 
foscarnet, or IV cidofovir (or any combination thereof).
Documentation of 1 or more CMV genetic mutations associated 
with resistance to ganciclovir, valganciclovir, foscarnet, and/or 
cidofovir.”

Symptomatic subjects to: “Transplant recipients with refractory 
CMV infections, including CMV infections with confirmed 
resistance to 1 of the anti-CMV agents (ganciclovir, 
valganciclovir, foscarnet, or cidofovir), who have tissue invasive 
CMV disease, as initially determined by the investigator at 
baseline. HSCT recipients who have tissue-invasive CMV 
Definitions
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
01 Jun 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
disease as determined by the investigator according to the 
criteria specified by Ljungman et al. 2016.”

Asymptomatic subjects to “Transplant recipients with 
refractory CMV infections, including CMV infections with 
confirmed resistance to 1 of the anti-CMV agents (ganciclovir, 
valganciclovir, foscarnet, or cidofovir), who do not have tissue 
invasive CMV disease as diagnosed by the investigator at 
baseline. HSCT recipients who do not have tissue-invasive 
CMV disease as determined by the investigator according to the 
criteria specified by Ljungman et al. 2016.”
Added rationale for dosing of adolescents:
Currently available maribavir pharmacokinetics, PK modeling and 
extrapolation of systemic exposure from adults, and safety and 
tolerability data in adults support the administration of the 400 mg BID 
dose in adolescents who weigh ≥35 kg and are able to swallow tablets. 
Per Lu and Rosenbaum (2014), the expression of CYP3A4 and CYP 
2C19, which are primary enzymes for maribavir metabolism in the liver, 
occurs during the first weeks of life. The expression of CYP1A2, which is 
also involved with maribavir metabolism, the last enzyme to develop, is 
present by 1 to 3 months of life. By 1 to 2 years of age, all the isoenzyme 
activities are similar to those of adults. Therefore, the bioavailability and 
systemic exposure of maribavir in adolescent subjects (≥16 and <18 years 
of age) is not expected to be different from adults at the same oral dose.
Section 2.3
Moved CMV central nervous system (CNS) infection as a reason for 
discontinuation and/or withdrawal from Section 5.2.2 (Prohibited 
Treatment) to Section 4.5.1 (Reasons for Discontinuation and/or 
Withdrawal).
Section 4.5.1
Changed pharmacokinetic sample collection for adolescent subjects from 
≥12 to <18 years of age to ≥16 to <18 years of age
Section 7.1.2
Moved description of summary statistical methods from “Exploratory 
Efficacy Endpoints” to “Efficacy Analyses”:
Summary descriptive statistics will include the number of subjects (N), 
mean, standard deviation, median, minimum and maximum (range) 
values for continuous variables, and incidences and percentages for 
categorical variables. The denominator for the percentages will be based 
on the number of patients with nonmissing information in the randomized
analysis set unless otherwise specified. Time-to-event endpoints will be 
summarized using Kaplan-Meier estimation. Ninety-five percent (95%) 
confidence intervals for the estimated 25%, 50%, and 75% times will be 
presented.
Section 9.8, Section 9.8.6
Added another example of a sensitivity analysis of the primary endpoint 
of confirmed CMV viremia clearance at Week 8:

The primary efficacy endpoint analysis will be repeated by using 
the CMV DNA level used for the randomization rather than the 
CMV DNA levels based on central laboratory values as one of 
the stratification factors.
Section 9.8.1
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
01 Jun 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Revised description of subgroup analyses as follows:
The primary and key secondary endpoints will be examined for the 
following subgroups The proportion of responders and the corresponding 
95% CI will be summarized for primary and key secondary endpoints by 
treatment group for the following subgroups (inclusive, but not limited
to):

Cytomegalovirus DNA viral load (high, low)

Acute GVHD presence/absence at baseline

Adolescents ≥16 to <18 years of age (exploratory analysis: may 
be conducted if sample size is adequate)

Enrolling regions (enrolling centers will be grouped by 
geographic locations to explore homogeneity of treatment effect 
across regions).
Section 9.8.4
Added more information regarding interim analyses:
If needed, an interim population PK analysis of maribavir PK data 
obtained from the study subjects will be performed. by an independent 
unblinded team/CRO. Interim population PK analysis will be performed 
by an independent unblinded team or CRO who will have no involvement 
in the conduct of the study. Results from this analysis will not be shared 
with any members of the study team until after database lock. Rules 
governing this process are detailed in the sponsor’s (or designee’s) 
standard operating procedures.
Section 9.10.3
Amendment 1 to Protocol SHP620-302 incorporated the following major changes:

Modification of primary, key secondary, and secondary objectives to include subjects 
who discontinue study treatment early and meet the criteria of confirmed CMV viremia 
clearance as responders in the primary efficacy analysis.

Modified Inclusion Criterion 5 to indicate that the current CMV infection must be the 
first episode of CMV viremia after HSCT, either primary or reactivation.

Clarified Inclusion Criterion 8 to indicate that urine pregnancy tests may be done per 
institutional requirements in addition to serum; however, they are not sufficient for 
eligibility determination.

Added a new Exclusion Criterion 3 to exclude subjects with recurrent CMV infection.

Amended Exclusion Criterion 6 to indicate that subjects must not be on treatment with 
anti-CMV agents (ganciclovir, valganciclovir, foscarnet or cidofovir) for the current 
CMV infection for longer than 72 hours.
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Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Note: A subject who is receiving these anti-CMV agents must discontinue their use before the 
first dose of study treatment. A subject who may be receiving cidofovir must discontinue this 
antiviral at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study 
treatment.
Note: Subjects who were administered these anti-CMV agents for prophylaxis should have these 
treatments completed at least 2 weeks prior to the study entry or start of the treatment for current 
infection, whichever comes first, and have undetectable CMV DNA (based on local laboratory) 
for at least 2 weeks between the completion of the anti-CMV prophylaxis and onset of the 
current infection.

Clarified in Exclusion Criterion 13 that subjects who have received an unapproved agent 
or device within 30 days before initiation of study treatment will not be eligible.

Clarified Exclusion Criterion 16 indicating that known (previously documented) HIV 
historical results will be accepted and no additional study testing will be required.

Added an intensive PK sampling schedule for adolescents.

An additional pregnancy test at 4 weeks (Visit 6/Week 4) to obtain a monthly testing 
interval.

Addition of highly effective method of female and male contraception per the 
recommendations related to contraception and pregnancy testing in clinical trials by 
clinical trial facilitation group (CTFG).

Emphasis on potent inducers of Cytochrome P450 (CYP) 3A4 and/or P-glycoprotein 
(P-gp) and caution for concomitant use of potent inhibitors of CYP 3A4, in alignment 
with the guidance to the investigators provided in the maribavir investigator’s brochure.

Caution and recommendation for careful monitoring of concentration levels of 
concomitant medications that are substrates of CYP2C19 and P-gp both after initiation of 
maribavir (when substrate levels may increase) and after discontinuation of maribavir
(when substrate levels may decrease), in alignment with the guidance to the investigators 
provided in the maribavir investigator’s brochure.
Noteworthy changes to the protocol are captured in the table below. Other minor editorial 
revisions (including changes for consistency and clarity) are not described in this table.
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
02 Mar 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Updated signatory to Obiamiwe Umeh, MD, MSc.
Protocol Signature Page
Added “FU = follow-up” to the abbreviations list.
Abbreviations
Created a list of definitions pertaining to evaluations/analysis for the 
study for easy access and convenience.
Definitions
Added clarifying text to indicate that initiation of study treatment (ie, first 
dose) will only occur after completion of all required Visit 2/Day 0 
procedures, confirmation of eligibility, and completion of randomization.
Synopsis, Table 1 (footnote “c”), 
Section 3.1
Modification of primary objective and corresponding endpoint and 
analysis to clarify that subjects who discontinue study treatment early and 
meet the criteria of confirmed CMV viremia clearance at Study Week 8 
will be considered as responders in the primary efficacy analysis.
Synopsis, Section, 2.4.1, 
Section 9.8.1
Modification of key secondary objective and corresponding endpoints 
and analyses to clarify that subjects who discontinue study treatment 
early and meet the criteria of confirmed CMV viremia clearance at Study 
Week 8 will be considered as responders in the efficacy analysis.
Synopsis, Section, 2.4.2, 
Section 9.8.2
Modification of secondary objectives and corresponding endpoints and 
analyses as follows.
Added the former primary and key secondary objectives as secondary 
objectives:
• “To compare the efficacy of maribavir to valganciclovir in CMV 
viremia clearance after 8 weeks of treatment of asymptomatic CMV 
infection in HSCT recipients.”
• “To compare the efficacy of maribavir and valganciclovir on 
maintenance of CMV viremia clearance, achieved after completion 
of 8 weeks of treatment, through Study Weeks 12 (4 weeks 
post-treatment period), 16 (8 weeks of post-treatment/follow-up 
phase), and 20 (12 weeks post-treatment).”
Added the secondary objectives:
• “To assess the maintenance of CMV viremia clearance achieved at 
the end of Study Week 8, through Weeks 12 (4 weeks 
post-treatment) and 20 (12 weeks post-treatment).”
• “To evaluate the incidence of recurrence of confirmed CMV viremia 
in the 2 study treatment arms during the first 8 weeks of the study, 
during the 12 weeks of the follow-up study phase, and at any time 
during the study.”
• “To evaluate the incidence of recurrence of confirmed CMV viremia 
in the 2 study treatment arms when subjects are on treatment and off 
treatment.”
Synopsis, Section 2.4.3, 
Section 9.8.5
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
02 Mar 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Deleted the following objective and the corresponding endpoint since it 
became redundant with the modified primary objective:
• “To assess the two study treatment arms for maintenance of CMV 
viremia clearance achieved while on study treatment, irrespective of 
its duration, at 8 weeks of study”
 
 
 
 
 
Updated the published article Ljungman 2002 with Ljungman 2016 
where relevant.
Section 1.1, Section 3.1, 
Section 7.2.23
Modified Inclusion Criterion 5 to exclude subjects with recurrent CMV 
infection:
“The current CMV infection must be the first episode of CMV viremia 
after HSCT, either primary or reactivation.”
Synopsis, Section 4.1
Clarified Inclusion Criterion 8 to indicate that urine pregnancy tests may 
be done per institutional requirements; however, they are not sufficient 
for eligibility determination.
Synopsis, Section 4.1
Added a new Exclusion Criterion 3 to exclude subjects with recurrent 
CMV infection:
“Be presenting with recurrent CMV infection (defined as a new detection 
of CMV infection) in a subject who had at least one previously 
documented episode of CMV infection post-transplant, and who has had
at least 2 weeks of undetectable CMV DNA between the episodes (during 
active surveillance, based on same local laboratory and same sample 
type). The subject must also have been off any anti-CMV treatment 
between the current and prior infection. Otherwise, the current infection 
may be considered continuation of the prior infection.”
Synopsis, Section 4.2
Amended Exclusion Criterion 6 to indicate that subjects must not “be on 
treatment” with anti-CMV agents (ganciclovir, valganciclovir, foscarnet 
or cidofovir) for the current CMV infection for longer than 72 hours.
Note: A subject who is receiving these anti-CMV agents must 
discontinue their use before the first dose of study treatment. A subjects 
who may be receiving cidofovir must discontinue this antiviral at least 
14 days prior to randomization at Visit 2/Day 0 and the first dose of 
study treatment.
Synopsis, Section 4.2
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
02 Mar 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Note: Subjects who were administered these anti-CMV agents for 
prophylaxis should have these treatments completed at least 2 weeks 
prior to the study entry or start of the treatment for current infection, 
whichever comes first, and have undetectable CMV DNA (based on 
local laboratory) for at least 2 weeks between the completion of the 
anti-CMV prophylaxis and onset of the current infection.”
Clarified in Exclusion Criterion 13 that subjects who have received an 
unapproved agent or device within 30 days before initiation of study 
treatment will not be eligible.
Synopsis, Section 4.2, Section 5.2.2 
(Table 4)
Clarified Exclusion Criterion 16 indicating that known historical results 
will be accepted and no additional study testing will be required.
“Have known (previously documented) positive results for human 
immunodeficiency virus (HIV).”
Synopsis, Table 1 (footnote “i”), 
Section 3.1, Section 4.2, 
Section 7.1.1, Section 7.2.3.5 
(Virology)
Removed text indicating that PK samples collected from subjects 
receiving valganciclovir would be discarded:
“Pharmacokinetic samples collected from subjects receiving 
valganciclovir will be discarded prior to analysis.”
Synopsis, Section 7.2.4.1
Clarified that the Randomized Set rather than the FAS will be used for 
efficacy analysis along with the Per-Protocol Set and that the 
Randomized Set would be used for the primary analysis and the Per-
Protocol Set would be used as the supportive analysis.
Synopsis, Section 9.7
Added the definition of adolescent pharmacokinetic set.
Synopsis, Section 9.7
Updated Table 11 and Table 12 to include additional scenarios for 
responder determination.
Synopsis, Section 9.8.1, 
Section 9.8.2
Updated the primary, key secondary, secondary, and exploratory 
endpoints to align with updates made to the objectives.
Synopsis, Section 9.8.1, 
Section 9.8.2, Section 9.8.5, 
Section 9.8.6
Added an additional subgroup analysis for adolescents:

Adolescents ≥16 to <18 years of age (exploratory analysis: may be 
conducted if sample size is adequate)
Synopsis, Section 9.8.4
Added PK parameters assessed as secondary endpoints for adolescent 
subjects who provided intensive PK sample at Visit 3/Week 1. The 
secondary PK endpoint for all subjects who received maribavir will be 
maribavir Cmin (predose maribavir concentration).
Synopsis, Section 9.10.3
Per CTFG requirements, added an additional pregnancy test at 4 weeks 
(Visit 6/ Week 4) so that tests are performed at a regular interval. 
Table 1, Section 7.1.2
Added intensive PK sampling schedule for adolescents.
Table 1 (footnote “o”), 
Section 7.2.4.1
Added text for the study rationale regarding pediatric subjects.
Section 2.2
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Maribavir 
Clinical Study Protocol: SHP620-302 Protocol Amendment 9
15 Sep 2021
Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
02 Mar 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Added recommendations related to contraception in clinical trials, per the 
clinical trial facilitation group (CTFG). Elaborated on highly effective 
method of contraception for sexually active females of childbearing 
potential participating in the study. Added that vasectomized male partner 
is a highly effective birth control method provided that partner is the sole 
sexual partner of the female trial participant who is of childbearing 
potential and that the vasectomized partner has received medical 
assessment of the surgical success.
Section 4.4.1
Added the following to male contraception per the Clinical Trial 
Facilitation Group requirements (CTFG):
“Male subjects will be required to use a condom in conjunction with a 
highly effective method of birth control for their female partners of 
childbearing age. Both male participants and their female partners must 
use this form of birth control from the time prior to first dosing until 90 
days after the last dose of study treatment (ie, maribavir or 
valganciclovir). For male subjects, sexual intercourse with pregnant 
partners should also be avoided during the course of the study unless 
condoms are used from the time prior to the first dose until 90 days after 
the last dose of study treatment. Male subjects must not donate sperm 
until 90 days after the last dose of study treatment”.
Section 4.4.2
Added caution and recommendation for careful monitoring of 
concentration levels of concomitant medications that are substrates of 
CYP2C19 and P-gp both after initiation of maribavir (when substrate 
levels may increase) and after discontinuation of maribavir (when 
substrate levels may decrease), in alignment with the guidance to the 
investigators provided in the maribavir investigator’s brochure.
Section 5.2.1
Added caution for concomitant use of potent inhibitors of CYP 3A4 and 
emphasized prohibition of potent inducers of Cytochrome P450 (CYP) 
3A4 and/or P-glycoprotein (P-gp), in alignment with the guidance to the 
investigators provided in the maribavir investigator’s brochure.
Section 5.2.1, Section 5.2.2
Corrected error in cited week number for end of study visit.
Section 7.1.3
Added additional clinical laboratory evaluations for:
Hematology: manual differential results for band neutrophils, basophils, 
eosinophils, lymphocytes, monocytes, segmented neutrophils, and total 
neutrophils.
Urinalysis: leukocyte esterase in the microscopic evaluation.
Other: immunoglobulins IgG and immunoglobulins total (a total of IgG + 
IgA + IgM) with no reference ranges associated with the 
immunoglobulins total value.
Section 7.2.3.5
 
 
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Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
02 Mar 2017
Global/Country/Site Specific
Global
Description and Rationale for Change
Section(s) Affected by Change
Added the additional blood draw volume required for intensive PK 
sampling for adolescents:
“Subjects between the ages of 12 to <18 years will have an additional 
24 mL of blood drawn for intensive PK visits.”
Section 7.2.5, Table 8
Amended Section 8.2.7 to include fatal outcomes:
“The study population is HSCT recipients with CMV infections. The 
following SAEs are common in this study population and are anticipated 
to occur, hence these SAEs (including fatal outcome) will not be 
considered unexpected and will not be individually reported to the 
regulatory agencies, IRBs, Ethics Committees, and investigators, 
provided there is no increased frequency of these events*:

Any CMV infection, including CMV reactivation/recurrence, 

Any other viral, bacterial, or fungal infection

Acute and chronic GVHD”

Reactivation/progression of the malignancy or other disease, 
which is an underlying disease, that led to the transplant
This includes fatal outcomes of the aforementioned SAEs.
*Maribavir Phase 2 (studies 1263-202 and 1263-203) data will be used as 
reference.
Section 8.2.7
Added reference to updated industry regulation: Integrated Addendum to 
ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2) Current Step 
4 version dated 09 November 2016.
Section 10.1.1, Section 10.2.1
Updated the table in Appendix 3 with the following pUL97 substitutions: 
D456N, M460L, C480R, P521L, C592F, L595T, N597D/I, G598D/V, 
and C603Y and the following pUL54 substitutions: L862F, D879G, and 
A972V.
Section 12 
Applied editorial changes throughout the document for clarity.
Synopsis and Sections, as needed
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APPENDIX 2 CHILD-PUGH CLASSIFICATION OF CHRONIC LIVER DISEASE
Table A1
Child-Pugh Classification of Chronic Liver Disease
Score
Bilirubin
(mg/dL)
Albumin
(gm/dL)
INR
Hepatic Encephalopathy
(grade)
Ascites
(grade)
1
<2
>3.5
<1.7
None
None
2
2-3
2.8-3.5
1.7-2.2
Mild
(controlled medically)
Mild
(controlled medically)
3
>3
<2.8
>2.2
Marked
(poor control)
Marked
(poor control)
Child-Pugh Class:
A
Score of 5-6
B
Score of 7-9
C
Score >9
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APPENDIX 3 CMV GENETIC MUTATIONS ASSOCIATED WITH RESISTANCE TO 
ANTI CMV DRUGS
Specific mutations in the UL97 and/or UL54 human cytomegalovirus (HCMV) genes are 
associated with resistance to certain anti-CMV drugs (ganciclovir/valganciclovir, foscarnet, or 
cidofovir). The UL97 gene encodes a viral protein kinase, while the UL54 gene encodes a viral DNA 
polymerase.
Ganciclovir (administered intravenously, orally, or through its oral prodrug valganciclovir) is a 
guanosine analog that acts as a chain terminator once incorporated into the elongating viral DNA 
chain. In order for the drug to be incorporated into the viral DNA chain, ganciclovir first needs to be 
monophosphorylated by the UL97 HCMV protein kinase. Cellular kinases then di- and 
tri-phosphorylate the drug into a form that can be incorporated into the viral DNA chain. Mutations 
in the UL97 gene that inactivate the UL97 kinase prevent the monophosphorylation step and result in 
resistance to ganciclovir/valganciclovir. Foscarnet is a pyrophosphate analog that blocks the release 
of pyrophosphate by the UL54 viral polymerase. Cidofovir is a cytosine monophosphate analog that 
is dependent on diphosphorylation by cellular kinases for its inhibition of viral DNA synthesis.
The tables below list the mutations in UL97 that are proven to confer resistance to 
ganciclovir/valganciclovir and the mutations in UL54 that confer resistance to one or multiple anti-
CMV agents, mostly based on the phenotyping, except in the case of deletions, that do not need to be 
confirmed due to the location of the deleted residues.
Since foscarnet and cidofovir do not require phosphorylation by the viral UL97 kinase for their 
activity, they are unaffected by mutations in the UL97 gene. Mutations in the UL54 gene that 
inactivate the viral DNA polymerase prevent incorporation of ganciclovir/valganciclovir and/or 
cidofovir into the elongating viral DNA chain, leading to resistance to the drug(s). Similarly, 
mutations in the UL54 gene can lead to foscarnet resistance.
The tables below are the reference for the investigators while the full list of reportable mutations 
should they be found in the clinical study analyses will be provided in the resistance analysis plan.
The following mutations have been determined to confer resistance to ganciclovir/valganciclovir or 
cross-resistance to foscarnet, cidofovir or maribavir (Campanini et al., 2012; 
Cherrier et al., 2018; Chou, 2020; Chou and Bowlin, 2011; Fischer et al., 2016; 
Gilbert et al., 2011; Harada et al., 1997; Van Leer Buter et al., 2019; Viracor, n.d.; 
Wong et al., 2019). The PRS and MRS populations will be defined by the presence of one or more of 
these mutations at study baseline genotypic results performed by the central specialty laboratory.
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Table A2
Known Ganciclovir/Valganciclovir Resistance Mutations
UL97 Mutation
Ganciclovir/Valganciclovir
F342S
R (also MBV-R) 
F342Y
R (also MBV-R)
V356G
R (also MBV-R) 
K359E
R 
K359Q
R
L405P
R
D456N
R (also MBV-R)
M460I
R
M460T
R
M460V
R
M460L
R*
V466G
R (also MBV-R)
C480F
R (also MBV-R)
C480R
R (also MBV-R)
C518Y
R
H520Q
R
P521L
R (also MBV-R)
A590T
Ra
del590 to 600
Ra
del590 to 603
Ra
del591 to 594
R
del591 to 607
R
A591D
Ra
A591V
R
C592G
Rb
C592F
Ra
del594 to 601
Ra
A594E
R
A594G
R
A594P
R
A594S
R
A594T
R
A594V
R
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Table A2
Known Ganciclovir/Valganciclovir Resistance Mutations
UL97 Mutation
Ganciclovir/Valganciclovir
L595F
R
L595S
R
L595W
R
L595T
Ra
del595
R
del595 to 603
R
del596
R
E596G
R
E596Y
R
del597 to 598
R
del597 to 599
R
del597 to 600
Ra
del597 to 603
Ra
N597I
Ra
G598S
R
G598V
Ra
del599
R
K599M
Ra
K599T
R
del599 to 603
Ra
del600
R
del601
R
del600 to 601
R
del601 to 602
R
del601 to 603
R
C603R
R
C603S
R
C603W
R
C603Y
Ra
A606D
Ra
C607F
R
C607S
Ra
C607Y
R
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Table A2
Known Ganciclovir/Valganciclovir Resistance Mutations
UL97 Mutation
Ganciclovir/Valganciclovir
I610T
R
A613V
R
del617
R (also MBV-R)
MBV=maribavir; R=resistance
a Clinical isolates but unconfirmed by Marker transfer.
b Alone confers modest resistance. When found in conjunction with UL54 del 981 to 982, there is a much higher level of 
resistance.
Note: Mutations in bold letters are the most common mutations.
Table A3
UL54 Resistance Mutations, Including Cross-resistance
UL54 Mutation
Cidofovir
Foscarnet
Ganciclovir
S290R
S
R
S
D301N
R
S
R
E303Da
R
S
R
E303Ga
R
S
R
N408D
R
S
R
N408K
R
S
R
N408S
R
S
R
N410K
R
S
R
F412C
R
S
R
F412L
R
S
R
F412S
R
S
R
F412V
R
S
R
D413A
R
S
R
D413E
R
S
R
D413N
R
S
R
D413Ya
R
S
R
P488R
R
S
R
K493N
R
R
R
N495K
S
R
R
P497S
R
S
R
K500N
R
S
R
L501F
R
S
R
L501I
R
S
R
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Table A3
UL54 Resistance Mutations, Including Cross-resistance
UL54 Mutation
Cidofovir
Foscarnet
Ganciclovir
T503I
R
S
R
A505Va
R
S
R
K513N
R
S
R
K513E
R
S
R
K513R
R
S
R
K513T
R
S
R
D515E
S
S
R
D515Y
R
S
R
L516R
R
S
R
L516P
R
S
R
L516W
R
S
R
I521T
R
S
R
P522A
R
S
R
P522S
R
S
R
del524
R
S
R
V526L
R
S
R
C539G
R
S
R
C539R
R
S
R
D542Ea
R
S
S
A543P
R
S
R
L545S
R
S
R
L545W
R
S
R
T552N
S
R
R
L565V
R
R
R
Q578H
R
R
R
Q578L
S
R
S
S585A
S
R
S
D588E
S
R
S
D588N
S
R
R
F595I
S
R
S
T700A
S
R
S
V715A
S
R
S
V715M
S
R
S
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Table A3
UL54 Resistance Mutations, Including Cross-resistance
UL54 Mutation
Cidofovir
Foscarnet
Ganciclovir
I726T
S
S
R
I726Vb
R
S
R
E756K
R or Sb
R
R
E756D
S
R
S
E756Q
S
R
S
L773V
R
R
R
L776M
S
R
R
V781I
S
R
Rb
V787A
S
R
R
V787E
R
R
R
V787L
S
R
R
L802M
S
R
R or Sb
K805Q
R
S
S
A809V
S
R
R
V812La
R
R
R
T813S
R
R
R
T821I
S
R
R
V823A
R
S
R
P829S
S
S
R
A834P
R
R
R
T838A
S
R
S
G841A
R
R
R
G841S
S
R
R
M844T
S
R
S
M844V
S
R
R
V946L
S
R
S
E951D
S
R
R
L957F
S
S
R
del981 to 982
R
R
R
A987G
R
S
R
A987V
S
R
S
R=resistant; S=sensitive
a Also confers resistance to brincidofovir.
b Low grade or variable resistance.
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APPENDIX 4 DEFINITIONS OF TISSUE INVASIVE CMV DISEASE
The following definitions of CMV disease are based on a commonly cited reference that was 
intended for application to transplant recipients (Ljungman et al., 2017; please refer to the 
citation for full details on the definitions of CMV disease). Definitions often require clinical 
judgment regarding compatible symptoms or other factors. The investigator should utilize his/her 
best clinical judgment for this categorization, and apply these definitions whenever possible for 
consistency. When reporting CMV disease, the presence of any co-pathogens that may be 
contributing to the organ disease must be reported as well.
Pneumonia: “CMV pneumonia” is defined by the presence of signs and/or symptoms of 
pulmonary disease combined with the detection of CMV in bronchoalveolar lavage fluid or lung 
tissue samples. Detection of CMV should be performed by virus isolation, histopathologic 
testing, immunohistochemical analysis, or in situ hybridization. Detection of CMV by 
polymerase chain reaction (PCR) alone may be too sensitive for the diagnosis of CMV 
pneumonia and is therefore insufficient for this purpose. The presence of fungal copathogens, 
such as Aspergillus species, together with radiologic signs typical of Aspergillus pneumonia (eg, 
a halo sign or a crescent sign) indicates fungal pneumonia rather than CMV pneumonia. CMV 
documented by culture from BAL might be used as the evidence in the absence of other 
preferred assays.
Gastrointestinal disease: “CMV gastrointestinal disease” is defined by the identification of a 
combination of clinical symptoms from the upper or lower gastrointestinal tract, findings of 
macroscopic mucosal lesions on endoscopy, and demonstration of CMV infection (by culture, 
histopathologic testing, immunohistochemical analysis, or in situ hybridization) in a 
gastrointestinal tract biopsy specimen. Detection of CMV by PCR alone is insufficient for the 
diagnosis of CMV gastrointestinal disease. Patients with CMV disease that involves the 
intestinal tract usually have mucosal abnormalities that can be seen by the endoscopist, but the 
appearance of some of these lesions is subtle. The spectrum of endoscopic lesions is variable and 
ranges from patchy erythema, exudates, and microerosions to diffusely edematous mucosa, to 
multiple mucosal erosions, to deep ulcers and pseudotumors. The diagnostic yield for CMV is 
higher when mucosal abnormalities are targeted for study. If CMV is detected in normal mucosa 
near a lesion consistent with those typical of CMV infection, this can be accepted as CMV 
gastrointestinal disease.
Cytomegalovirus documented in blood by PCR or antigenemia or CMV documented by PCR 
from tissue biopsies might be used in the absence of other preferred methods of diagnosis.
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Hepatitis: “CMV hepatitis” is defined by the findings of elevated bilirubin and/or enzyme levels 
during liver function testing, absence of any other documented cause of hepatitis, and detection 
of CMV infection (by culture, histopathologic testing, immunohistochemical analysis, or in situ 
hybridization) in a liver biopsy specimen. Detection of CMV by PCR alone is insufficient for the 
diagnosis of CMV hepatitis because it can imply the presence of transient viremia. 
Documentation of CMV (ie, by immunohistochemical analysis) within the liver tissue is needed. 
Other pathogens, such as hepatitis C virus, may be present without excluding the diagnosis of 
CMV hepatitis.
Central Nervous System disease: Cytomegalovirus “CNS disease” is defined by the 
identification of CNS symptoms together with the detection of CMV in cerebrospinal fluid 
samples, by culture or PCR, or in brain biopsy specimens, by culture, histopathologic testing, 
immunohistochemical analysis, or in situ hybridization.
Retinitis: The diagnosis of disease requires typical ophthalmological signs judged by an 
ophthalmologist experienced with the diagnosis of CMV retinitis. If the presentation is atypical 
or an experienced ophthalmologist is not available, it is recommended that the diagnosis is 
supported by CMV documented in vitreous fluid by PCR. The images or retina taken during 
ophthalmological exam should be provided.
Nephritis: Cytomegalovirus nephritis can be defined by the detection of CMV infection (by 
culture, immunohistochemical analysis, or in situ hybridization) together with the identification 
of histologic features of CMV infection in a kidney biopsy specimen obtained from a patient 
with renal dysfunction.
Cystitis: Cystitis is defined by the detection of CMV infection (by culture, 
immunohistochemical analysis, or in situ hybridization) together with the identification of 
conventional histologic features of CMV infection in a bladder biopsy specimen obtained from a 
patient with cystitis.
Myocarditis: Myocarditis is defined by the detection of CMV infection (by culture, 
immunohistochemical analysis, or in situ hybridization) together with the identification of 
conventional histologic features of CMV infection in a heart biopsy specimen obtained from a 
patient with myocarditis.
Pancreatitis: The definition of CMV pancreatitis requires the detection of CMV infection (by 
culture, immunohistochemical analysis, or in situ hybridization) together with the identification 
of conventional histologic features of CMV infection in a pancreatic biopsy specimen obtained 
from a patient with pancreatitis.
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Other CMV disease categories: Cytomegalovirus can also cause disease in other organs, and 
the definitions of these additional disease categories include the presence of compatible 
symptoms and signs, and documentation of CMV by biopsy (detection of CMV by PCR alone is 
insufficient), with other relevant causes excluded.
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APPENDIX 5 KARNOFSKY PERFORMANCE STATUS SCALE
The Karnofsky Performance Scale Index (Table A4) allows patients to be classified as to their 
functional impairment. This can be used to compare effectiveness of different therapies and to 
assess the prognosis in individual patients. The lower the Karnofsky score, the worse the survival 
for most serious illnesses.
Table A4
Karnofsky Performance Scale Index
Able to carry on 
normal activity and 
to work; no special 
care needed.
100
Normal no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of 
disease.
Unable to work; 
able to live at home 
and care for most 
personal needs; 
varying amount of 
assistance needed.
70
Cares for self; unable to carry on normal activity or to do active 
work.
60
Requires occasional assistance, but is able to care for most of 
his personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for 
self; requires 
equivalent of 
institutional or 
hospital care; 
disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospital admission is indicated although 
death not imminent.
20
Very sick; hospital admission necessary; active supportive 
treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead
Sources:
Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining outcomes and risk in geriatric 
outpatients. J Gerontol. 1991; 46: M139-44.
de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993; 24:320-7.
Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. 
Cancer. 1994; 73: 2087-98.
O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 1991; 155:384-7.
Oxford Textbook of Palliative Medicine, Oxford University Press. 1993; 109.
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin 
Oncology. 1984; 2:187-93.
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APPENDIX 6
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APPENDIX 7 ACUTE GRAFT-VERSUS-HOST DISEASE: CLINICAL STAGING AND 
GRADING
The clinical staging and grading of acute GVHD is done through evaluation of the skin, liver, 
and gastrointestinal tract (upper and lower) (Harris et al., 2016).
Table A6
GVHD Target Organ Staging
Stage
Skin (Active Erythema Only)
Liver
(Bilirubin)
Upper GI
Lower GI (stool 
output/day)
0
No active (erythematous) GVHD 
rash
<2 mg/dL
No or intermittent 
nausea, vomiting, 
or anorexia
Adult: <500 mL/day or 
<3 episodes/day
Child: <10 mL/kg/day or 
<4 episodes/day
1
Maculopapular rash
<25% BSA
2-3 mg/dL
Persistent nausea, 
vomiting or 
anorexia
Adult: 500-999 mL/day or 
3-4 episodes/day
Child: 10-19.9 mL/kg/day or 
4-6 episodes/day
2
Maculopapular rash
25-50% BSA
3.1-6 mg/dL
Adult: 1000-1500 mL/day or 
5-7 episodes/day
Child: 20-30 mL/kg/day or 
7-10 episodes/day
3
Maculopapular rash
>50% BSA
6.1-15 mg/dL
Adult: >1500 mL/day or 
>7 episodes/day
Child: >30 mL/kg/day or 
>10 episodes/day
4
Generalized erythroderma
(>50% BSA) plus bullous 
formation and desquamation >5% 
BSA
>15 mg/dL
Severe abdominal pain with 
or without ileus or
grossly bloody stool 
(regardless of stool volume)
BSA=body surface area; GI=gastrointestinal; GVHD=graft-versus-host disease
Overall clinical grade (based on most severe target organ involvement):
Grade 0: No stage 1-4 of any organ.
Grade I: Stage 1-2 skin without liver, upper GI, or lower GI involvement.
Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI.
Grade III: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI.
Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI.
Source: Table 1, Harris et al., 2016
The differences in GVHD diagnosis make it challenging to conduct multicenter trials because of 
the difﬁculty determining whether a patient truly experienced GVHD. To address these varying 
practices, Harris et al. (2016) developed a structure for collecting granular GVHD data and 
assigning conﬁdence levels for the attribution of symptoms to GVHD based on the treatment 
decisions made by the clinician.
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Table A7
Confidence Level Criteria
Confidence 
Level
Pathologic 
Evidence
Clinical Assessment
Treatment for 
Acute GVHD
Comments
Confirmed
Unequivocal 
pathologic 
evidence of GVHD
GVHD is the 
etiology for 
symptoms
Not applicable
GVHD is clearly present even 
if other etiologies may coexist 
simultaneously.
Probable
Not required
GVHD most likely 
etiology for 
symptoms (as 
evidenced by 
treatment being 
provided)
Yes
GVHD is most likely present, 
but other etiologies may also 
explain the symptoms, and 
there is insufficient evidence to 
make a confirmed diagnosis.
Possible
Not required
GVHD in 
differential diagnosis
(but no treatment is 
being provided)
No
GVHD may be present, but 
other etiologies are favored to 
the degree that GVHD 
treatment is not initiated.
Negative
Unequivocal 
evidence of a 
diagnosis other 
than GVHD (eg, 
drug rash)
GVHD is not 
considered as an 
explanation for the 
symptoms
No and the 
symptoms 
resolve without 
GVHD 
treatment
A “negative” biopsy (eg, 
normal skin) is not unequivocal 
evidence of a diagnosis other 
than GVHD.
Source: Table 2, Harris et al., 2016
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APPENDIX 8 RECOMMENDATIONS FOR CHRONIC GVHD DIAGNOSIS AND 
GRADING
A.
Organ Scoring of Chronic GVHD as published in NIH GVHD Consensus for GVHD 
Consensus for Clinical Trials: I. The 2014 Diagnosis and Staging Working Group Report, 
Jagasia et al., 2015 (Figure 1).
Figure A-1. Organ Scoring of Chronic GVHD
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Figure A-1. Organ Scoring of Chronic GVHD (continued)
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Figure A-1. Organ Scoring of Chronic GVHD (continued)
ADL=activities of daily living; ALT=alanine aminotransferase; AP=alkaline phosphatase; BSA=body surface area; 
ECOG=Eastern Cooperative Oncology Group; FEV1=forced expiratory volume in 1 second; GVHD=graft-versus-host-disease; 
KPS=Karnofsky Performance Status; LFTs=liver function tests; LPS=Lansky Performance Status; ULN=normal upper limit.
*
Weight loss within 3 months.
†
Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a 
discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, OR if 
superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher 
level should be used for the final skin scoring.
‡
To be completed by specialist or trained medical providers (see Supplementary Figure: Figure A-2).
**
Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used 
in the final lung scoring where there is discrepancy between symptoms and FEV1 scores.
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Figure A-2. Supplemental Genital Tract Chronic GVHD Scoring and Supplemental Skin 
GVHD Scoring (supplemental material for Jagasia et al. [2015], Figure 1.)
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B.
NIH Severity Grading of Chronic GVHD as published in NIH GVHD Consensus for 
GVHD Consensus for Clinical Trials: I. The 2014 Diagnosis and Staging Working Group 
Report (Table 2 in the supplemental material for Jagasia et al. [2015])
Table A8
NIH Global Severity of Chronic GVHD
Mild chronic GVHD
1 or 2 organs involved with no more than score 1 plus
Lung score 0
Moderate chronic GVHD
3 or more organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
OR
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global severity.
If the entire abnormality in an organ is noted to be unequivocally explained by a non-GVHD 
documented cause, that organ is not included for calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other 
causes) the scored organ will be used for calculation of the global severity regardless of the 
contributing causes (no downgrading of organ severity score).
Source: Table 2, Jagasia et al., 2015
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APPENDIX 9 DIAGNOSTIC CRITERIA FOR CHRONIC GVHD
A.
Signs and Symptoms of Chronic GVHD (Table 1 in Jagasia et al., 2015)
Table A9
Signs and Symptoms of Chronic GVHD
Organ or Site Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD)
Distinctivea (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis)
Other Features or 
Unclassified Entitiesb
Commonc (Seen 
with Both Acute 
and Chronic 
GVHD)
Skin
Poikiloderma
Lichen planus–like 
features
Sclerotic features 
Morphea-like 
features
Lichen sclerosus–
like features
Depigmentation
Papulosquamous lesions
Sweat impairment
Ichthyosis
Keratosis pilaris
Hypopigmentation
Hyperpigmentation
Erythema
Maculopapular 
rash
Pruritus
Nails
Dystrophy
Longitudinal ridging, 
splitting or brittle features
Onycholysis
Pterygium unguis
Nail loss (usually 
symmetric, affects most 
nails)
Scalp and body 
hair
New onset of scarring or 
nonscarring scalp 
alopecia (after recovery 
from chemoradiotherapy)
Loss of body hair
Scaling
Thinning scalp hair, 
typically patchy, coarse 
or dull (not explained 
by endocrine or other 
causes)
Premature gray hair
Mouth
Lichen planus–like 
changes
Xerostomia
Mucoceles
Mucosal atrophy
Ulcers
Pseudomembranes
Gingivitis
Mucositis
Erythema
Pain
Eyes
New onset dry, gritty, or 
painful eyes
Cicatricial conjunctivitis
KCS
Confluent areas of 
punctate keratopathy
Photophobia
Periorbital 
hyperpigmentation
Blepharitis (erythema of 
the eyelids with edema)
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Table A9
Signs and Symptoms of Chronic GVHD
Organ or Site Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD)
Distinctivea (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis)
Other Features or 
Unclassified Entitiesb
Commonc (Seen 
with Both Acute 
and Chronic 
GVHD)
Genitalia
Lichen planus–like 
features
Lichen sclerosus–
like features
Erosions
Fissures
Ulcers
Females
Vaginal scarring or 
clitoral/labial 
agglutination
Males
Phimosis or 
urethral/meatus 
scarring or stenosis
GI Tract
Esophageal web
Strictures or stenosis 
in the upper to mid 
third of the 
esophagus
Exocrine pancreatic 
insufficiency
Anorexia
Nausea
Vomiting
Diarrhea
Weight loss
Failure to thrive 
(infants and 
children)
Liver
Total bilirubin, 
alkaline 
phosphatase 
>2 × upper limit of 
normal
ALT >2 × upper 
limit of normal
Lung
Bronchiolitis 
obliterans diagnosed 
with lung biopsy
BOSd
Air trapping and 
bronchiectasis on chest 
CT
Cryptogenic organizing 
pneumonia
Restrictive lung 
diseasee
Muscles, 
fascia, joints
Fasciitis
Joint stiffness or 
contractures 
secondary to 
fasciitis or sclerosis
Myositis or polymyositisf Edema
Muscle cramps
Arthralgia or arthritis
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Table A9
Signs and Symptoms of Chronic GVHD
Organ or Site Diagnostic 
(Sufficient to 
Establish the 
Diagnosis of 
Chronic GVHD)
Distinctivea (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis)
Other Features or 
Unclassified Entitiesb
Commonc (Seen 
with Both Acute 
and Chronic 
GVHD)
Hematopoietic 
and Immune
Thrombocytopenia
Eosinophilia
Lymphopenia
Hypo- or hyper-
gammaglobulinemia
Autoantibodies (AIHA, 
ITP)
Raynaud's phenomenon
Other
Pericardial or pleural 
effusions
Ascites
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction 
abnormality or 
cardiomyopathy
AIHA=autoimmune hemolytic anemia; ALT=alanine aminotransferase; BOS=bronchiolitis obliterans syndrome; 
GVHD=graft-versus-host disease; ITP=idiopathic thrombocytopenic purpura.
a In all cases, infection, drug effect, malignancy, or other causes must be excluded.
b Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is confirmed.
c Common refers to shared features by both acute and chronic GVHD.
d Bronchiolitis obliterans syndrome can be diagnostic for lung chronic GVHD only if distinctive sign or symptom 
present in another organ (see text).
e Pulmonary entities under investigation or unclassified.
f
Diagnosis of chronic GVHD requires biopsy.
Source: Table 1, Jagasia et al., 2015
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B.
Histological Criteria for GVHD by Organ System according to NIH Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 
Disease: II. The 2014 Pathology Working Group Report (Table 1 in 
Shulman et al., 2015). Chronic GVHD is supported by histologic evidence of GVHD 
from any affected site. Investigators are expected to consider recommendations for 
chronic GVHD diagnosis including not only clinical but histological evidence.
Table A10
Histological Criteria for GVHD by Organ System
Organ or System
Minimal Criteria for 
Acute/Active GVHDa
Specific Criteria for Chronic GVHDb
Liver
Global assessment of 
dysmorphic or destroyed small 
bile ducts ± cholestasis, lobular 
and portal inflammation
Ductopenia, portal fibrosis, chronic 
cholestasis reflect chronicity but are not 
specific for chronic GVHD
GI
Variable apoptotic criteria 
(≥1/piece) in crypts
Destruction of glands, ulceration or 
submucosal fibrosis may reflect severe or 
long-standing disease but are not specific for 
chronic GVHD
Skin, in general
Apoptosis in epidermal basal 
layer or lower Malphigian layer 
or infundibulum/outer root 
sheath/hair bulge of hair follicle 
or acrosyringium/sweat 
ducts ± lichenoid 
inflammation ± vacuolar 
change ± lymphocytic satellitosis
Skin, lichen 
planus–like
Combination of epidermal 
orthohyperkeratosis, hypergranulosis and 
acanthosis resembling lichen 
planus ± lichenoid inflammation and/or 
vacuolar changes of eccrine units
Skin morpheic 
(localized or 
diffuse)
Thickening and homogenization of collagen 
bundles throughout reticular dermis or 
pandermal sclerosis with overlying interface 
changes ± thickening and homogenization of 
subcutaneous septa
Skin, lichen 
sclerosus–like
Homogenization ± sclerosis of papillary 
dermal collagen with overlying interface 
changes including melanophages in the 
papillary dermis and sparse lymphocytic 
infiltrate
Skin, fasciitis
Thickening of fascial septa with adjacent 
inflammation ± sclerosis of subcutis
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Table A10
Histological Criteria for GVHD by Organ System
Organ or System
Minimal Criteria for 
Acute/Active GVHDa
Specific Criteria for Chronic GVHDb
Oral/oropharyngeal
mucosa and 
conjunctiva
Lichenoid interface lymphocytes 
with infiltration of mucosa 
(exocytosis) and variable 
apoptosisc
Minor salivary or 
lacrimal gland
Periductal lymphocytic infiltrate with 
infiltration and damaged intralobular ducts, 
fibroplasia in periductal stroma, mixed 
lymphocytic and plasmacytic inflammation 
with destruction of acinar tissued
Lung
CBO: dense eosinophilic scarring beneath the 
respiratory epithelium, resulting in luminal 
narrowing or complete fibrous obliteration. 
May be preceded by lymphocytic bronchiolitis 
without intraluminal fibrosise
Kidney
Membranous nephropathy, minimal change 
disease
Lesions of Uncertain Pathogenesis
Lung
COP
Skeletal Muscle
Myositis
CBO=constrictive bronchiolitis obliterans; COP=cryptogenic organizing pneumonia; 
GVHD=graft-versus-host-disease
a Conditions that result in lesser degrees of change include immunosuppressive treatment, biopsy very soon after 
onset of signs, suboptimal or small tissue sample, insufficient serial sectioning, confounding infection, drug 
reaction, or inflammatory conditions.
b After the diagnosis of chronic GVHD has been established or following immunosuppressive treatment, the 
histological manifestations of active disease may meet only minimal diagnostic criteria for activity. Different 
manifestations of cutaneous chronic GVHD may all be present together in 1 biopsy or in separate but concurrent 
biopsies.
c Inflammation of the oral mucosa and within the minor salivary glands may persist from prior chemo-irradiation or 
prior inflammation. The distinction between acute and chronic GVHD requires the addition of distinctive oral 
manifestations.
d The distinction of past acinar destruction and fibrosis from ongoing chronic GVHD activity can be difficult and 
relies on assessing lobules that are not completely fibrotic. Acinar and periductal inflammation with features of 
damage to ducts, such as vacuolar change, lymphocytic exocytosis nuclear dropout, dyspolarity or apoptosis, and 
resultant fibroplasia indicate chronic GVHD activity.
e Constrictive bronchiolitis obliterans should be distinguished from cryptogenic organizing pneumonia, which is 
also associated with GVHD but has a different clinicopathologic presentation and a more favorable outcome.
Source: Table 1, Shulman et al., 2015
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C.
Recommendations for Final Diagnosis Categories of GVHD (Table 2 in 
Shulman et al., 2015)
Table A11
Recommendation for Final Diagnosis Categories
Category
Definition
Examples
Comments
Not GVHD No evidence for GVHD
Possible 
GVHD
Evidence of GVHD but other 
possible explanations

Obvious CMV enteritis with 
inclusions near the apoptotic changes

Focal colonic ulcers with marked 
apoptotic cryptitis and destruction of 
crypts associated with use of MMF

Coinfection with known active viral 
hepatitis

Clinical features which suggest or 
favor a drug reaction
Indicate possible 
alternate 
diagnoses and 
reasons for 
suspicion
Likely 
GVHD
Clear evidence of GVHD 
without a competing cause of 
injury
OR
Clear evidence of GVHD with 
mitigating factors
OR
GVHD most likely diagnosis but 
relevant clinical information is 
limited
OR
GVHD is validated by 
sequential biopsy or by absence 
of competing diagnosis

Abundant epithelial apoptosis 
without clinical or histological 
evidence of drug injury or infection

Evidence of CMV yet abundant 
apoptotic epithelial changes that are 
not associated with CMV infected 
cells by immunostaining

Single or rare apoptotic epithelial 
changes without other features of 
active GVHD and no alternative 
explanations

Limited sample or minimal or focal 
findings

Proximity to recent chemotherapy or 
radiotherapy
Included old 
categories of 
“consistent with” 
and 
“unequivocal” 
GVHD
CMV=cytomegalovirus; GVHD=graft-versus-host-disease; MMF=mycophenolate mofetil
Source: Table 2, Shulman et al., 2015
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APPENDIX 10 BACTERIAL AND FUNGAL INFECTIONS ASSESSMENT
In Hematopoietic Stem Cell Transplant (HSCT) population post-transplant infection remains a 
significant cause of morbidity and mortality, particularly after allogeneic transplantation. While 
the expected period of profound neutropenia after HSCT usually occurs during the pre-
engraftment stage, normal neutrophil recovery is not always possible as neutrophil count is 
adversely affected by other risk factors and comorbidities, such as graft failure or rejection, 
GVHD, relapse of the underlying neoplasm, drug-induced myelosuppression and concomitant 
infections (Klumpp, 1993).
Due to the gradual immune system reconstitution HSCT recipients are vulnerable to various 
opportunistic viral, bacterial or fungal pathogens at different stages after the transplant 
(Tomblyn et al., 2009). Opportunistic infection is defined as any infection that occurs with 
increased frequency or severity in HSCT population (Dykewicz, 2001).
Figure A-3. Phases of Opportunistic Infections Among Allogeneic HSCT Recipients
EBV=Epstein-Barr virus; HHV=human herpes virus; HSCT=Hematopoietic Stem Cell Transplant; 
PTLD=post-transplant lympho-proliferative disease
Phase I: <15-45 days post-transplant; Phase II: 30-100 days post-transplant; Phase III: >100 days after HSCT.
Source: Figure 1, Tomblyn et al., 2009.
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Infectious complications are most frequent in the pre-engraftment period due to cytopenias and 
immune ablation and immune suppression but may continue for months or years in HSCT 
recipients with delayed immune reconstitution (Majhail et al., 2012). During the early 
post-transplant period HSCT recipients are susceptible to bacteremia and fungal infections with 
Candida and Aspergillus species, along with herpes simplex virus (HSV) reactivation. Candida 
often causes superficial skin infection (thrush), with rare occasions of invasive disease 
manifested as esophagitis, endocarditis or hepatosplenic disease.
During the early postengraftment phase infections relate primarily to impaired cell-mediated 
immunity, which is influenced by a history of GVHD and the requirement for ongoing 
immunosuppression. The predominant organisms in this phase are herpesviruses, along with 
Pneumocystis jiroveci and Aspergillus species. In the late postengraftment period common 
pathogens include CMV, VZV and infections with encapsulated bacteria, such as Streptococcus 
pneumonia, Haemophilus influenzae (Tomblyn et al., 2009; Majhail et al., 2012).
Prolonged neutropenia in the pre-engraftment phase results is a substantial risk for bacterial and 
fungal infections, and has been the most important risk factor for invasive aspergillosis 
(Schwartz et al., 1984; Salzberger et al., 1997; Marr et al., 2002).
The most common bacterial infections in neutropenia are provided in the table below.
Table A12
Common Bacterial Pathogens in Neutropenic Patients
Common gram-positive pathogens
Coagulase-negative staphylococci
Staphylococcus aureus, including methicillin-resistant strains
Enterococcus species, including vancomycin-resistant stains
Viridans group streptococci
Streptococcus pneumoniae
Common gram-negative pathogens
Escherichia coli
Klebsiella species
Enterobacter species
Pseudomonas aeruginosa
Citrobacter species
Acinetobacter species
Stenotrophomonas maltophilia
Source: Table 1; Freifeld et al., 2011
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Fever during neutropenia in immunocompromised patients may be the only indication of a 
severe underlying infection, because signs and symptoms of inflammation typically are 
attenuated; pulmonary infection may have no signs on infiltrates on radiographs, CSF 
pleocytosis might be low or absent in the setting of meningitis. The guidance document for 
management of neutropenic patients with fever (Freifeld et al., 2011) also provides the details of 
the evidence to be used for the confirmation of the relevant bacterial or viral infection.
In this study, a history of infections, including ongoing infections at baseline, will be 
documented as part of the subject’s medical history. Any new infections that occur during the 
course of the study will be recorded as adverse events. It is recommended that bacterial and 
fungal infections diagnosed as possible/probable or proven per the criteria described by 
Boeckh et al. (2015) are reported.
FUNGAL INFECTIONS
A. Aspergillus spp. or other mold infection:
Proven: Clinical signs and symptoms plus a tissue biopsy revealing growth of an 
organism or positive histopathology.
Probable: Clinical signs and symptoms with bronchoalveolar lavage (BAL) yielding 
positive growth or positive histopathology.
Possible: at least 3 clinical signs or symptoms and growth of an organism from 
nonsterile fluid (ie, sputum).
B. Candida spp. or other yeast (eg, T. glabrata):

Proven fungemia: Any single positive blood culture that is culture positive for 
Candida spp. or T. glabrata. [Note: Removal of indwelling catheters is strongly 
encouraged.]

Tissue documented: Clinical signs and symptoms compatible with invasive yeast 
infection and a positive culture from a normally sterile site with histologic evidence of 
tissue invasion (definite) or positive culture from sterile site without histologic 
evidence of invasion (probable).
BACTERIAL INFECTIONS
A. Bacteremia:

Any single positive blood culture that is culture positive for bacterial pathogens 
consistent with a serious bloodstream infection.

Urinary tract infections will not be captured as opportunistic infections of interest.
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B. Invasive Bacterial Tissue Infection:

Clinical signs and symptoms compatible with disease (sinusitis, pneumonia, 
intra-abdominal abscess)
and

Radiographic evidence of disease and pure or predominant culture or pathogen 
detection from a sterile site biopsy.

Pathogen detection in respiratory secretion or sinus aspirates or CSF specimens will be 
considered if they are predominant and compatible with the clinical picture.
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SAP_001.pdf: 
NCT Number: 
Study Title: 
Study Number: 
NCT02927067
A Phase 3, Multicenter, Randomized, Double-blind, 
Double-dummy, Active-controlled Study to Assess the 
Efficacy and Safety of Maribavir Compared to Valganciclovir 
for the Treatment of Cytomegalovirus (CMV) Infection in 
Hematopoietic Stem Cell Transplant Recipients
SHP620-302
STATISTICAL ANALYSIS PLAN 
SAP version and Date: 
Version 2.0: 27 April 2022
For non-commercial use only


Study Title: A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, 
Active-controlled Study to Assess the Efficacy and Safety of Maribavir Compared to 
Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem 
Cell Transplant Recipients
Phase: 3
Version: 2.0
Date: 27-APR-2022
Prepared by: 
Based on:
Protocol Version: Amendment 9 (Version 10.0)
Protocol Date: 15 September 2021
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda.
STATISTICAL ANALYSIS PLAN
Study Number: SHP620-302
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Statistical Analysis Plan V2.0
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27 Apr 2022
REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
Draft 0.1
31-Mar-2020
First stable version
1.0
23 Jul 2021
Transfer to new SAP template and update based on protocol 
amendment 8
2.0
27 Apr 2022
Incorporate FDA comment on SAP, clarify and add analysis details 
planning for final report. 
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Statistical Analysis Plan V2.0
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27 Apr 2022
TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................3
LIST OF IN-TEXT TABLES ..........................................................................................................7
LIST OF IN-TEXT FIGURES.........................................................................................................7
ABBREVIATIONS .........................................................................................................................8
1.
OBJECTIVES, ENDPOINTS AND ESTIMANDS...............................................................10
1.1
Objectives.................................................................................................................10
1.1.1
Primary Objective..................................................................................................10
1.1.2
Secondary Objectives.............................................................................................10
1.1.3
Exploratory Objectives ..........................................................................................10
1.2
Endpoints..................................................................................................................11
1.2.1
Primary Endpoint...................................................................................................11
1.2.2
Secondary Endpoints .............................................................................................11
1.2.2.1
Key Secondary Endpoint........................................................................11
1.2.2.2
Other Secondary Endpoints....................................................................11
1.2.3
Exploratory Endpoints ...........................................................................................12
1.2.4
Safety Endpoints....................................................................................................12
1.2.5
Pharmacokinetic Endpoints ...................................................................................13
1.2.6
13
1.2.7
13
1.3
Estimand(s)...............................................................................................................13
2.
STUDY DESIGN ...................................................................................................................15
2.1
Study Design and Flow Chart ..................................................................................15
2.2
Blinding....................................................................................................................16
3.
STATISTICAL HYPOTHESES AND DECISION RULES .................................................17
3.1
Statistical Hypotheses ..............................................................................................17
3.1.1
Non-inferiority for the Primary Endpoint..............................................................17
3.1.2
Superiority for the Primary Endpoint ....................................................................18
3.1.3
Non-inferiority for the Key Secondary Endpoint ..................................................18
3.1.4
Superiority for the Key Secondary Endpoint.........................................................18
3.2
Statistical Decision Rules.........................................................................................19
3.3
Multiplicity Adjustment ...........................................................................................19
4.
SAMPLE-SIZE DETERMINATION.....................................................................................21
5.
ANALYSIS SETS ..................................................................................................................22
6.
STATISTICAL ANALYSIS ..................................................................................................23
6.1
General Considerations ............................................................................................23
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6.1.1
Handling of Treatment Misallocations ..................................................................23
6.2
Disposition of Subjects.............................................................................................23
6.2.1
Disposition.............................................................................................................23
6.2.2
Protocol Deviations................................................................................................24
6.3
Demographic and Other Baseline Characteristics....................................................24
6.3.1
Demographics ........................................................................................................24
6.3.2
Baseline Characteristics.........................................................................................24
6.4
Medication History and Concomitant Medications .................................................26
6.4.1
Medical History .....................................................................................................26
6.4.2
Prior, Concomitant, and Post-Treatment Medications...........................................26
6.4.3
Prior, Concomitant, and Post-Treatment Procedures.............................................27
6.5
Efficacy Analysis .....................................................................................................27
6.5.1
Primary Endpoint(s) Analysis................................................................................28
6.5.1.1
Derivation of Endpoint(s).......................................................................28
6.5.1.2
Main Analytical Approach.....................................................................31
6.5.1.3
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint .................................................................................................32
6.5.2
Secondary Endpoints Analysis ..............................................................................40
6.5.2.1
Key Secondary Endpoint Analysis.........................................................40
6.5.2.2
Main Analytical Approach.....................................................................44
6.5.2.3
Sensitivity and Supplementary Analyses of the Key Secondary 
Endpoint .................................................................................................44
6.5.3
Other Secondary Endpoints Analysis ....................................................................45
6.5.3.1
Achievement of confirmed CMV viremia after 8 weeks of receiving 
study assigned treatment ........................................................................46
6.5.3.2
The maintenance of CMV viremia clearance after completion of 8 
weeks of receiving study-assigned treatment, through Study Weeks 
12, 16, and 20 .........................................................................................47
6.5.3.3
The maintenance of CMV viremia clearance and symptom control 
achieved at the end of study Week  8 through Study Weeks 12 and 
20, regardless of whether either study assigned treatment was 
discontinued before the stipulated 8 weeks of therapy ..........................47
6.5.3.4
The recurrence of CMV viremia during the first 8 weeks of the 
study, in the follow-up period of 12 weeks, and at any time during 
the 20 weeks of the study, regardless of whether either study-
assigned treatment was discontinued before the stipulated 8 weeks 
of therapy................................................................................................48
6.5.3.5
The recurrence of confirmed CMV viremia in the 2 study treatment 
arms when subjects are on treatment and off treatment.........................48
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6.5.3.6
The incidence of grade 3 or 4 neutropenia (defined as 
ANC<10000/mm3 or ANC<500/mm3) while on treatment....................48
6.5.4
Analyses of Exploratory Endpoints .......................................................................49
6.5.4.1
49
6.5.4.2
49
6.5.4.3
49
6.5.4.4
50
6.5.4.5
51
6.5.4.6
51
6.5.4.7
51
6.5.4.8
51
6.5.4.9
51
6.5.4.10
52
6.5.4.11
52
6.5.5
Subgroup Analyses ................................................................................................52
6.6
Safety Analysis.........................................................................................................53
6.6.1
Adverse Events ......................................................................................................54
6.6.1.1
Renal Disorder TEAEs...........................................................................56
6.6.2
Adverse Events of Special Interest ........................................................................56
6.6.2.1
Time to Resolution for Dysgeusia and Similar Terms While on 
Treatment and When Off Treatment ......................................................57
6.6.2.2
Time to Resolution of Neutropenia While on Treatment and When 
Off Treatment.........................................................................................58
6.6.2.3
Immunosuppressant Drug Concentration Level Increased ....................58
6.6.3
Subgroup Analysis of TEAE and AESIs ...............................................................58
6.6.4
Clinical Laboratory Data........................................................................................59
6.6.5
Vital Signs..............................................................................................................60
6.6.6
Electrocardiogram (ECG)......................................................................................61
6.6.7
Other Safety Data...................................................................................................62
6.6.8
Extent of Exposure.................................................................................................62
6.6.9
Measurement of Treatment Compliance................................................................63
6.7
Pharmacokinetic and Pharmacodynamic Analyses..................................................64
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6.7.1
Pharmacokinetic Analysis......................................................................................64
6.7.1.1
Drug Concentration................................................................................64
6.7.1.2
Handling Below Lower Limit of Quantitation Values...........................65
6.7.1.3
Analysis of Pharmacokinetic Endpoints ................................................65
6.7.1.4
Population PK and PK/PD Analysis ......................................................66
6.8
66
6.8.1
66
6.8.2
 
67
6.9
68
6.10
Interim Analyses ......................................................................................................68
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data 
Review Committees]................................................................................................68
7.
REFERENCES .......................................................................................................................69
8.
CHANGES TO PROTOCOL PLANNED ANALYSES .......................................................70
9.
APPENDIX.............................................................................................................................71
9.1
Study Schedule.........................................................................................................71
9.2
Data Handling Conventions .....................................................................................71
9.2.1
Repeated or Unscheduled Assessments of Safety Parameters...............................71
9.2.2
Handling of Missing, Unused, and Spurious Data.................................................71
9.2.2.1
Missing Date of Investigational Product................................................71
9.2.2.2
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)...........................................................................71
9.2.2.3
Missing Date Information for Adverse Events ......................................73
9.2.2.4
Missing Severity Assessment for Adverse Events.................................73
9.2.2.5
Missing Relationship to Investigational Product for Adverse Events....74
9.2.2.6
Character Values of Clinical Laboratory Variables ...............................74
9.2.3
Definition of Visit Windows..................................................................................74
9.2.4
Derivation of Maintenance for Secondary Endpoints............................................77
9.2.5
Baseline for Efficacy and Safety Endpoints ..........................................................77
9.3
Analysis Software ....................................................................................................78
9.4
Changes from the Previous Version of the SAP ......................................................78
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LIST OF IN-TEXT TABLES
Table 1
List of Estimands...........................................................................................14
Table 2
Assessments of Virological Response at Study Week 8 ...............................30
Table 3
Assessments of Virological Response at Study Week 8 in Subjects 
with missing data between Week 6 and Week 9 due to COVID 19 
(Modified Algorithm of Table 2) ..................................................................37
Table 4
Assessments of Responders for Key Secondary Endpoint............................43
Table 5
Criteria for Potentially Clinically Significant Vital Signs.............................61
Table 6
Criteria for Potentially Clinically Significant ECG Values ..........................62
LIST OF IN-TEXT FIGURES
Figure 1
Study Design Flow Chart ..............................................................................16
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ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ATC
anatomical therapeutic chemical
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration versus time curve
AUC(0-tau)
area under the plasma concentration versus time curve over the 12-hour 
dosing interval at steady state
-HCG
beta-human chorionic gonadotropin
BID
twice daily
bpm
beats per minute
Cmax
maximum observed plasma concentration 
Cmin
minimum observed plasma concentration
CI
confidence interval
CL/F
apparent oral clearance
CMH
Cochran-Mantel-Haenszel
CMV
cytomegalovirus 
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CrCl
creatinine clearance
CTCAE
Common Terminology Criteria for Adverse Events 
DMC
data monitoring committee
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eDiary
electronic Diary
ECG
electrocardiogram
FU
follow-up
GGT
gamma-glutamyltransferase
GI
gastrointestinal
GVHD
graft-versus-host disease
HBV
hepatitis B virus
HCV
hepatitis C virus
HLA
human leukocyte antigen
HSCT
hematopoietic stem cell transplant
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INR
international normalized ratio
IRT
interactive response technology
ITT
intention-to-treat
LLOQ
lower limit of quantification
NCI 
National Cancer Institute 
NI
noninferiority
MedDRA
Medical Dictionary for Regulatory Activities
OC
observed cases
PCS
potentially clinically significant
PD
Pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
PT
preferred term 
Q1
25th Percentile
Q3
75th Percentile
QTc
corrected QT interval
QTcF
QT Interval Corrected for Heart Rate using Fridericia’s Formula
RAP
resistance analysis plan
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation 
SMQ
Standardized MedDRA® Query
SOC
system organ class
SOT
solid organ transplant
TEAE
treatment-emergent adverse event
Tmax
time when maximum concentration is observed
Vz/F
apparent volume of distribution
WHO
World Health Organization
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1.
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
The primary objective of the study is to compare the efficacy of maribavir to valganciclovir in 
CMV viremia clearance at the end of Study Week 8 in asymptomatic CMV infection in HSCT 
recipients.
1.1.2
Secondary Objectives
The key secondary objective of this study is to compare the efficacy of maribavir and 
valganciclovir on maintenance of CMV viremia clearance, achieved at the end of Study Week 8 
through Study Week 16 (8 weeks of post-treatment/follow-up phase).
The other secondary objectives of this study are:

To compare the efficacy of maribavir to valganciclovir in CMV viremia clearance after 
completion of 8 weeks of treatment for asymptomatic CMV infection in HSCT 
recipients.

To compare the efficacy of maribavir and valganciclovir on maintenance of CMV 
viremia clearance, achieved after completion of 8 weeks of treatment, through Study 
Weeks 12 (4 weeks of post-treatment period), 16 (8 weeks of post-treatment/follow-up 
phase), and 20 (12 weeks post-treatment).

To assess the maintenance of CMV viremia clearance, achieved at the end of Study 
Week 8, through Weeks 12 (4 weeks of post-treatment period), and 20 (12 weeks 
post-treatment).

To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study 
treatment arms during the first 8 weeks of the study, during the 12-weeks of the 
follow-up study phase, and at any time during the study.

To evaluate the incidence of recurrence of confirmed CMV viremia in the 2 study 
treatment arms when subjects are on treatment and off treatment.

To evaluate the incidence of treatment-emergent grade 3 or 4 neutropenia (defined as 
ANC<1000/mm3 or ANC<500/mm3) while on treatment.

To assess the safety and tolerability of maribavir compared to valganciclovir.

To characterize the PK of maribavir.
1.1.3
Exploratory Objectives
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1.2
Endpoints
1.2.1
Primary Endpoint
The primary efficacy endpoint of this study is confirmed clearance of plasma CMV DNA (CMV 
viremia clearance) at the end of Study Week 8. The detail of definition is in Section 6.5.1.1.
1.2.2
Secondary Endpoints
1.2.2.1
Key Secondary Endpoint
The key secondary efficacy endpoint is defined as the maintenance of confirmed CMV viremia 
clearance and symptom control achieved at the end of Study Week 8 through Week 16. The 
detail of definition is in Section 6.5.2.1.
1.2.2.2 
Other Secondary Endpoints
The other secondary endpoints of this study specified in Section 6.5.3 are:

The achievement of the confirmed CMV viremia clearance after 8 weeks of receiving
study-assigned treatment.

The maintenance of the confirmed CMV viremia clearance after completion of 8 weeks
of receiving study-assigned treatment, through Study Weeks 12 (4 weeks post-treatment
period), 16 (8 weeks of post-treatment/follow-up phase), and 20 (12 weeks
post-treatment).

The maintenance of the CMV viremia clearance achieved at the end of Study Week 8
through Study Weeks 12, and 20, regardless of whether either study-assigned treatment
was discontinued before the end of the stipulated 8 weeks of therapy. For maintenance
effect to be achieved at a time point, the subjects must have received exclusively
study-assigned treatments up to that time point and also must have symptom control.

The recurrence of CMV viremia during the first 8 weeks of the study, in the follow-up
period of 12 weeks, and at any time during the 20 weeks of the study, regardless of
whether either study-assigned treatment was discontinued before the end of the stipulated
8 weeks of therapy.
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
The recurrence of confirmed CMV viremia in the 2 study treatment arms when subjects
are on treatment and off treatment.

The incidence of grade 3 or 4 neutropenia (defined as ANC <1,000/mm3 [1.0 x 109/L]) or
ANC <500/mm3 [0.5 x 109/L], respectively).
1.2.3
Exploratory Endpoints
 
 
1.2.4
Safety Endpoints

Treatment-emergent AEs and treatment-emergent SAEs, overall study AEs and overall
study SAEs.

Clinical laboratory evaluations (including incidence of neutropenia defined as ANC
<500/mm3 [0.5 x109/L] or ANC <1,000/mm3 [1.0 x 109/L] at any time during the study
[on treatment and overall study period] and time to neutropenia development), and study
treatment dose adjustments due to AEs.

Safety assessments will also include vital sign measurements, physical examination, and
ECG.
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1.2.5
Pharmacokinetic Endpoints
Pharmacokinetic samples will be obtained for all subjects as in the Schedule of Assessment 1 
(Table 1, SHP620-302 protocol), but analyzed for only those subjects who are taking maribavir.

Maribavir Cmin (pre-dose maribavir concentration).
For adolescent subjects who provided intensive PK samples at Visit 3/Week 1:

AUC(0-tau): area under the concentration time curve over the 12-hour dosing interval at
steady state.

Cmax: maximum concentration.

Tmax: time when maximum concentration is observed

CL/F: apparent oral clearance.

Vz/F: apparent volume of distribution.
In a separate analysis and report, maribavir concentration data (pre-dose and post-dose) will be 
analyzed by population PK analysis approac
 
1.2.6
1.2.7
1.3
Estimand(s)
The primary and key secondary estimands that are to support regulatory decisions are described 
in Table 1.
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Table 1
List of Estimands
Estimand
Definition
Attributes
A: Population
B: Variable (or 
endpoint)
C: Strategy for addressing 
intercurrent event
D: Population-
level summary
Primary
The primary estimand 
of this study is the 
effect of SHP620 
compared to 
valganciclovir in 
treatment of CMV 
infection at the end of 
Study Week 8.
HSCT recipients 
with first episode 
of asymptomatic 
CMV infection
Proportion of 
responders, defined as 
subjects with confirmed 
viremia clearance at 
Study Week 8 and no 
alternative anti-CMV 
treatment
The following intercurrent events are 
considered:
1.
If a subject takes alternative anti-
CMV treatment before Study
Week 8, assume non-response
2.
If a subject drops out of study
before Study Week 8 without data to
confirm viremia clearance at Study
Week 8, assume non-response
Difference in 
proportion of 
responders at Study 
Week 8 between 
SHP620 and 
valganciclovir 
treatment groups
Key 
Secondary
The key secondary 
estimand is the 
maintenance effect of 
SHP620 compared to 
valganciclovir in 
treatment of CMV 
infection achieved at 
the end of Study 
Week 8 through Study 
Week 16    
HSCT recipients 
with first episode 
of asymptomatic 
CMV infection
Proportion of 
responders, defined as 
subjects who achieved 
confirmed viremia 
clearance and CMV 
infection symptom 
control at Study Week 8 
and maintain through 
Study Week 16 and no 
alternative anti-CMV 
treatment 
The following intercurrent events are 
considered:
1.
If a subject takes alternative anti-
CMV treatment before Study
Week 16, assume non-response
2.
If a subject drops out of study
before Study Week 16 without data
to confirm the maintenance of
viremia clearance and CMV
infection symptom control at Study
Week 16, assume non-response
Difference in 
proportion of 
responders for the key 
secondary endpoint 
between SHP620 and 
valganciclovir 
treatment groups
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2.
STUDY DESIGN
2.1
Study Design and Flow Chart 
This is a multicenter, randomized, double-blind, double-dummy, active-controlled study of 
maribavir compared to valganciclovir for the treatment of asymptomatic CMV infection in 
HSCT recipients. "Asymptomatic subjects” at baseline will be defined as HSCT recipients who 
do not have tissue invasive CMV disease as determined by the investigator according to the 
criteria specified by Ljungman et al (2016). The study will assess the efficacy of maribavir by 
measuring the plasma CMV DNA clearance. To be eligible for the study, subjects must have a 
documented asymptomatic CMV infection with a screening value of CMV DNA ≥1365 IU/mL 
to ≤273000 IU/mL in whole blood or ≥455 IU/mL to ≤91000 IU/mL in plasma in 2 consecutive 
assessments, separated by at least 1 day, as determined by local or central specialty laboratory 
quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. 
Results for CMV and, in subjects with very low viral load, evaluations for high-risk CMV 
infection (study protocol Section 7.1.1) should be available before the subject is randomized to 
verify subject eligibility for the study. Both samples should be taken within 14 days prior to 
randomization with the second sample obtained within 5 days before randomization. The same 
laboratory and sample type should be used for these assessments. Subjects must not have CMV 
tissue invasive disease (symptomatic CMV infection), must not have a CMV infection that is 
known to be genotypically resistant to anti-CMV drugs and must meet the remaining specified 
eligibility criteria. Subjects treated with ganciclovir, valganciclovir, foscarnet or letemovivir for 
the current CMV infection should not be treated with these anti-CMV agents for longer than 
72 hours prior to enrolling in the study.
All eligible subjects will be stratified based on last pre-baseline whole blood or plasma CMV 
DNA concentration (high viral load with CMV DNA ≥27300 IU/mL in whole blood or 
≥9100 IU/mL in plasma, low viral load with CMV DNA ≥2730 IU/mL to <27300 IU/mL in 
whole blood or ≥910 IU/mL to <9100 IU/mL in plasma, and in subjects with high-risk infection, 
very low viral load with CMV DNA <2730 IU/mL in whole blood or <910 IU/mL in plasma) as 
determined by the local or central specialty laboratory qPCR. Subjects will also be stratified 
based on acute GVHD status (presence or absence at baseline). Subjects in each stratum will then 
be randomized in a 1:1 allocation ratio to receive double-blind maribavir 400 mg BID or 
valganciclovir 900 mg BID, 450 mg BID, or 450 mg QD, based on subject's CrCl at eligibility, 
for 8 weeks. Valganciclovir dose may be adjusted during the study for renal function impairment 
or neutropenia.
An independent Data Monitoring Committee (DMC) will be established to assess the data at 
specified periodic intervals for safety and to ensure the validity and scientific merit of the trial. 
Detailed plans for the DMC’s purpose and responsibilities will be described in the DMC charter 
and this statistical analysis plan.
As shown in the study schematic in Figure 1 (Study Design Flow Chart) below, the study will 
have 3 phases: (1) Up to a 2-week screening phase; (2) 8-week double-blind study treatment 
phase; and (3) 12-week follow-up phase. Subjects will be required to visit the site up to 18 times 
for up to a 22-week period.
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Figure 1
Study Design Flow Chart
BID: twice daily; BL: baseline; Rand: randomized; wks: weeks
a Visit 2A is required only for subjects receiving tacrolimus, cyclosporine, everolimus, or sirolimus at baseline.
2.2
Blinding
This is a double-blind, double-dummy, active controlled study. The blind will be accomplished 
by use of identical looking placebo formulations of maribavir and valganciclovir. The subject 
will receive maribavir and placebo (identical to valganciclovir) tablets if randomized to the 
maribavir treatment arm, or valganciclovir and placebo (identical to maribavir) if randomized to 
the comparator arm (valganciclovir).
The investigators, subjects and their families, or any member of the study team, either at the 
study site or with the Sponsor, will remain blinded to the treatment assignments until the routine 
un-blinding occurs after completion of the last subject’s last visit and data base lock.
Bioanalysis of PK samples will be conducted by un-blinded staff from the bioanalysis 
laboratory/CRO. If needed, an interim population PK analysis of maribavir PK data obtained 
from the subjects receiving maribavir may be performed by an independent un-blinded 
team/CRO outside of the blinded study team.
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3.
STATISTICAL HYPOTHESES AND DECISION RULES
3.1
Statistical Hypotheses
The following four hypotheses for the primary and key secondary endpoints are to be tested.  
•
Primary endpoint
–
Null hypothesis H11 (Non-inferiority assessment)
–
Null hypothesis H12 (Superiority assessment)
•
Key Secondary endpoint
–
Null hypothesis H21 (Non-inferiority assessment)
–
Null hypothesis H22 (Superiority assessment)
3.1.1
Non-inferiority for the Primary Endpoint
The non-inferiority (NI) margin of the primary efficacy endpoint is 7%. A 7% NI margin was 
chosen based on the following considerations:

It preserves at least 85% of the effect size assumed for the valganciclovir treatment group

It is less than half of 15%, a common NI margin in antiviral trials

Discussions with clinical experts confirmed it as a conservative choice.
The null hypothesis and alternative hypothesis for the non-inferiority analysis of the primary 
endpoint (H11) are:
H110: P1T – P1C ≤ -0.07 
vs
H111: P1T – P1C > -0.07
P1T: proportion of responders in maribavir treatment group who achieve confirmed viremia 
clearance at the end of Study Week 8 
P1C: proportion of responders in valganciclovir group who achieve confirmed viremia clearance 
at the end of Study Week 8 
The difference in the proportion of responders (i.e., subjects with confirmed CMV viremia 
clearance at the end of Study Week 8 regardless of whether study-assigned treatment was 
discontinued before the end of the stipulated 8 weeks of therapy) will be calculated for each 
treatment group after adjusting for baseline viral load and acute GVHD at baseline.
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3.1.2
Superiority for the Primary Endpoint
The null hypothesis and alternative hypothesis for the superiority analysis of the primary 
endpoint (H12) are:
H120: P1T – P1C = 0 
vs
H121: P1T – P1C ≠ 0
P1T: proportion of responders in maribavir treatment group who achieve confirmed viremia 
clearance at the end of Study Week 8 
P1C: proportion of responders in valganciclovir group who achieve confirmed viremia clearance 
at the end of Study Week 8 
3.1.3
Non-inferiority for the Key Secondary Endpoint
The key secondary efficacy endpoint will use the same 7% NI margin as the primary endpoint 
for the same reasons.
The null hypothesis and alternative hypothesis for the non-inferiority analysis of the key 
secondary endpoint (H21) are:
H210: P2T – P2C ≤ -0.07 
vs
H211: P2T – P2C > -0.07
P2T: proportion of responders in maribavir treatment group who achieve confirmed viremia 
clearance and CMV infection symptom control at the end of Study Week 8 and maintain the 
effect through Study Week 16.
P2C: proportion of responders in valganciclovir group who achieve confirmed viremia clearance 
and CMV infection symptom control at the end of Study Week 8 and maintain the effect through 
Study Week 16.
3.1.4
Superiority for the Key Secondary Endpoint
The null hypothesis and alternative hypothesis for the superiority analysis of the key secondary 
endpoint (H22) are:
H220: P2T – P2C = 0 
vs
H221: P2T – P2C ≠ 0
P2T: proportion of responders in maribavir treatment group who achieve confirmed viremia
clearance and CMV infection symptom control at the end of Study Week 8 and maintain the 
effect through Study Week 16.
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P2C: proportion of responders in valganciclovir group who achieve confirmed viremia clearance 
and CMV infection symptom control at the end of Study Week 8 and maintain the effect through 
Study Week 16.
3.2
Statistical Decision Rules
The difference in proportion of responders (i.e., subjects who achieve confirmed viremia 
clearance and CMV infection symptom control at end of Study Week 8 and maintain the effect 
through Study Week 16) between treatment groups will be obtained using 
Cochran-Mantel-Haenszel (CMH) weighted average across all strata, with baseline plasma CMV 
DNA concentration (high, low, very low) and acute GVHD (present, absent) as two stratification 
factors. The difference in the proportion of responders will be calculated for each treatment 
group after adjusting for baseline CMV DNA concentration and acute GVHD at baseline. The 
95% confidence intervals (CI) of the weighted average of difference across strata will be 
provided using the normal approximation. If the lower limit of the 95% CI is greater than -7%, 
non-inferiority of maribavir to vanganciclovir will be declared and it will be concluded that 
maribavir is as efficacious as valganciclovir. If non-inferiority of maribavir to vanganciclovir is 
declared then the superiority of maribavir to vanganciclovir will be tested as part of the 
procedure described in Section 3.3. If the lower limit of the 95% CI is greater than 0, it will be 
concluded that maribavir is more efficacious than valganciclovir. 
The primary analysis for both NI and superiority testing will be performed in the Modified 
Randomized Set. Both NI and superiority analyses will also be performed in the per protocol (PP 
Set) as supportive.
3.3
Multiplicity Adjustment
The hypotheses testing will be adjusted for multiple comparisons using the gatekeeping testing 
procedure as specified below to control the family-wise Type 1 error rate at 2-sided α=5% level. 
The testing will be done in the order of primary efficacy endpoint NI testing (H11) first, the 
primary efficacy endpoint superiority testing (H12) and the key secondary efficacy endpoint NI 
testing (H21) second, and lastly the key secondary efficacy endpoint superiority testing (H22).
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
First, the NI hypothesis of the primary efficacy endpoint (H11) will be tested based on the
2-sided 95% CI of the adjusted difference in proportion of subjects who have CMV viremia
clearance at Study Week 8 stratified by baseline CMV DNA level and presence/absence of
acute GVHD at baseline. If the lower limit of the 95% CI is above - 7%, NI of the primary
efficacy endpoint is considered established, i.e. H11is rejected.

If and only after the NI of the primary efficacy endpoint is established, i.e. H11 is rejected,
the superiority hypothesis of the primary efficacy endpoint (H12) and the NI hypothesis of
the key secondary endpoint of maintenance of response through Study Week 16 (H21) will
be tested in parallel. Hochberg procedure will be used to control family-wise Type 1 error
rate at α=5% level.

If and only if the superiority of the primary efficacy endpoint and NI of key secondary
efficacy endpoint are established, i.e. H12 and H21 are both rejected, the superiority
hypothesis of the key secondary efficacy endpoint (H22) will be tested based at the two-sided
0.05 level.
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4.
SAMPLE-SIZE DETERMINATION
For sample size calculation, to be conservative, it is assumed that 68% and 60% subjects will 
achieve confirmed CMV viremia clearance for the primary efficacy endpoint, in the maribavir 
and valganciclovir groups, respectively. Using the normal approximation method, a 2-sided 95%
confidence interval (CI) of the difference in the proportions of subjects with the confirmed CMV 
viremia clearance will be calculated. If the lower limit of the CI is greater than -7%, the 
noninferiority will be assumed. The sample size is estimated based on a 2-group test of
equivalence in proportions by using nQuery Advisor 7.0. Based on the above assumptions, 
494 eligible subjects (247 per treatment group) will result in a >90% power to declare 
noninferiority of maribavir to valganciclovir for the primary efficacy endpoint. Considering 10% 
dropout subjects, not included in the Per Protocol (PP) Set, 550 subjects (275 subjects per 
treatment arm) will be enrolled and randomized.
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5.
ANALYSIS SETS

The Enrolled Set will consist of all subjects who have signed an informed consent and
have begun some study procedures.

The Randomized Set will consist of all subjects in the Enrolled Set for whom a
randomization number has been assigned.

The Modified Randomized Set will consist of all subjects in the Randomized Set who
have taken at least 1 dose of assigned study treatment.

The Safety Set will consist of all subjects who have taken at least 1 dose of study
treatment.

The Per-protocol (PP) Set consists of all subjects in the Randomized Set who do not have
relevant major protocol deviations that may affect the primary efficacy assessment.
The major protocol deviations that lead to exclusion from the PP Set include but are not limited 
to the following
o
Taking wrong study treatment or receiving no study treatment
o
Early discontinuation defined as discontinuation from study treatment within
72 hours of first dose of study assigned treatment
o
Violations of inclusion criteria 2-6 or 8
o
Violations of exclusion criteria 1-6 or 12
o
Received prohibited concomitant anti-CMV medications for more than one day
while on treatment

The pharmacokinetic (PK) Set will consist of all subjects in the Safety Set who received
maribavir treatment and had plasma samples drawn and tested for maribavir
concentrations.

The adolescent PK set will consist of all subjects of ≥16 to <18 years of age in the safety
set who received maribavir treatment and had plasma samples drawn and tested for
maribavir concentrations.

The supportive PK Set will consist of all subjects in PK Set who are also in the PP Set.
The Modified Randomized Set and PP Sets will be used for efficacy analyses. If there is more 
than 10% difference in the number of subjects between the Modified Randomized Set and 
Randomized Set, then the analysis for the primary and key secondary endpoints will be 
performed for the Randomized Set. The Safety Set will be used for safety analyses. 
Pharmacokinetic data will be analyzed using the PK Set as well as supportive PK set. If there is 
more than 10% difference in the number of subjects between the PK Set and supportive PK Set 
then pharmacokinetic data will be analyzed using the supportive PK Set as well.
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6.
STATISTICAL ANALYSIS
6.1
General Considerations
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, interquartile ranges (Q1, Q3), minimum, maximum. Categorical and 
count variables will be summarized by the number and the percent of subjects in each category. 
The denominator for the percentages will be based on the number of subjects in the analysis set 
unless otherwise specified. Time-to-event endpoints will be summarized using Kaplan-Meier 
estimation. 95% confidence intervals for the estimated 25%, 50%, and 75% times will be 
presented.
The baseline value for efficacy variables is defined as the last available value before or on the 
first dose date of study drug on Visit 2/Day 0.
Baseline safety analyses is defined as the last value for the assessment prior to taking the first 
dose of study treatment. 
Unless otherwise specified, time part will be excluded from the baseline calculation when 
comparing the dates
6.1.1
Handling of Treatment Misallocations
For summary or analysis of safety set, the actual treatment is used, otherwise, the randomized 
treatment is used. The efficacy analysis will be based on the randomized treatment unless 
otherwise specified.
6.2
Disposition of Subjects
6.2.1
Disposition
A listing of all Screen Failures (i.e. subjects who were screened but not randomized) will be 
presented along with reasons for screen failure and details of any AEs.  
The number of subjects included in each analysis set (i.e., Enrolled Set, Randomized Set, 
Modified Randomized Set, Safety Set, PP Set, Pharmacokinetic Set, and adolescent PK Set) will 
be summarized by treatment group and for the overall population. Percentages will be provided 
(except for the Enrolled Set) using the Randomized Set as the denominator.
The number and percentage (calculated using the Randomized Set as denominator) of subjects in 
the following categories will be presented by treatment group and overall.

Completed 8-week study-assigned treatment or discontinued study treatment early and by
reason for early discontinuation of study treatment early

Completed the 8-week treatment phase (regardless of number of weeks of treatment) or
discontinued from the study during the 8-week treatment phase, and by reason if
discontinued treatment early during the 8-week treatment-phase early.
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
Final status (i.e. study completer vs discontinued early). Completed the study at the end
of study, and by reason if discontinued from the study discontinuation
In addition, the number of subjects enrolled and randomized , will be tabulated by region, 
country and site. The number of subjects completed  for the Modified Randomized Set will be 
tabulated by region, country and site .
6.2.2 
Protocol Deviations
Protocol deviations (PDs) will be recorded. Protocol deviations related to COVID-19 pandemic 
will be captured. The CRO/Sponsor will classify major/significant and minor/non-significant 
protocol deviations per the agreed study Deviations Rules Document. The study team will review 
the protocol deviations and their classification throughout the study. 
For any criteria for protocol deviations that can be completely implemented by a computer 
program, the detailed algorithm will be agreed upon. Details of such algorithms will be included 
in the derived dataset specifications and finalized before treatment unblinding. Non-programable 
protocol deviations identified by medical monitoring will be incorporated into the datasets.
Confirmed major and minor protocol deviations will be documented in the Protocol Deviation 
tracker for the study. 
The number of subjects and number of events with major/minor protocol deviations will be 
summarized for the Randomized Set by category and site for each treatment group overall and by 
time. Major/minor protocol deviations will be listed for the Randomized Set. A summary of the 
number and percentage of subjects with any COVID-19 related deviations, major and minor, will 
be produced using Randomized Set.
6.3 
Demographic and Other Baseline Characteristics
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the efficacy and safety sections (refer to Section 6.5 
and Section 6.6). 
6.3.1 
Demographics
Demographic and baseline characteristics will be determined using the screening visit or last 
observation on or prior to first dose of study drug, whichever is later. 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the Randomized Set, the Modified Randomized Set and PP Set.
The following demographic characteristics will be summarized: age, age group (<18, 18-44, 
45-64, and ≥65 years old), sex, ethnicity, race, weight, height, and BMI.
6.3.2 
Baseline Characteristics
The following baseline characteristics including HSCT history and CMV history will be 
summarized. The following baseline characteristics will be treated as categorical variables:
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
HSCT history
o
Number of HSCT transplants prior to current transplant
o
Underlying disease for current transplantation
o
Is this recurrence of underlying disease
o
Type of transplant (autologous, allogeneic)

If allogenic haploidentical (yes/no)

If allogenic HLA, match type
o
Stem cell source for current HSCT
o
Current graft status at baseline
o
Type of preparative conditioning regimen
o
T-cell depletion modality
o
Was a donor T-cell infusion given post-HSCT

CMV serostatus

CMV DNA category (high, low, very low) used in randomization from IRT

CMV DNA category (high, low, very low) based on baseline central laboratory results

Does subject have resistance mutation according to central laboratory result (yes/no)
o
If yes, region (UL97, UL54, UL27)

Is net immunosuppression reduced prior to start of study treatment, specifically due to
current CMV infection (yes/no)
o
If yes, strategies used

Use of T-cell depletion agent

Acute GVHD status at baseline (presence/absence)

Chronic GVHD status at baseline (presence/absence)

History  of CMV prophylaxis

CD69+CD4+ cells from immune function assay (<0.5%, ≤0.5% and <2%, ≥2%)

CD69+CD8+ T cells from immune function assay (<0.5%, ≤0.5% and <2%, ≥2%)

Baseline leukocyte (<2.7, ≤2.7 and <7, ≥7 10^9/L)

Hepatic impaired subjects ( no impairment, impairment and by grade)

Renal impaired subjects (no, mild, moderate, severe)

Karnofsky score
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Baseline characteristics treated as continuous variable:

The nucleated cell number transplanted in 106 for the current transplant

The number of CD34+ transplanted in 106 for the current transplant

Days from onset of current CMV infection to first dose of study assigned treatment

Days from the current transplant to the first dose of study assigned treatment

Baseline CMV DNA levels from central laboratory

Most recent screening CMV DNA levels from local laboratory for eligibility

Baseline leukocyte count
6.4
Medication History and Concomitant Medications  
6.4.1
Medical History
The medical history will be summarized by system organ class (SOC) and preferred term (PT) 
for each treatment group for the Safety Set.
6.4.2
Prior, Concomitant, and Post-Treatment Medications
World Health Organization (WHO) Drug Dictionary dated March 2019 or in effect at the time 
will be used for coding prior and concomitant medications, classified by Anatomical Therapeutic 
Chemical (ATC) class and preferred drug name. 
Prior medication is defined as any medication (therapies/procedures) with the start date prior to 
the date of the first dose of study treatment. 
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of study treatment and continuing after the first dose of study treatment or with a start 
date and time after the study treatment initiation and before the end of the on-treatment period; 
the on-treatment period is defined in Section 9.2.3. 
Post-treatment medication is defined as any medication with a start date during the on-treatment 
period and continuing into the follow-up period or with a start date after the end of the 
on-treatment period through the end of follow-up period.
Prior and concomitant medication usage will be summarized by the number and proportion of 
subjects in each treatment group receiving each medication by ATC Level III and preferred term 
by treatment group using the Safety Set. Medications can be counted both as prior and 
concomitant medication.  Multiple medication usage by a subject in the same category will be 
counted only once.
Additionally, growth factors product uses will be summarized for baseline, on-treatment period, 
off-treatment period and overall post-baseline study period. Immunosuppression drug use will be 
summarized for baseline, during treatment phase, after treatment phase, on-treatment period, 
off-treatment period and overall post baseline study period. Anti-CMV drugs use will be 
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summarized for during treatment phase, after treatment phase, on-treatment period, off-treatment 
period and overall post-baseline study period. Blood products use will be summarized for the on-
treatment period and overall study period. 
All prior, concomitant, and post-treatment medication will be provided by subject in the listings. 
Additionally, immunosuppression regimen and treatment with blood derived products or blood 
transfusions will be provided in separate data listings.
6.4.3 
Prior, Concomitant, and Post-Treatment Procedures
A concomitant procedure is any therapeutic and diagnostic intervention (e.g., surgery/biopsy) or 
diagnostic assessment (bacterial cultures, imaging such as X-ray, CT scans) performed between 
the dates of the first dose of the study treatment and the end of the follow-up phase, inclusive.
Prior procedure is defined as any procedure with a start date prior to the date of the first dose of 
study treatment. 
Concomitant procedure during the on-treatment period is defined as any procedure with a start 
date prior to the date of the first dose of study treatment and continuing after the first dose of 
study treatment or with a start date and time after the study treatment initiation and before the 
end of the on-treatment period. 
Post-treatment procedure is defined as any procedure with a start date during the on-treatment 
period and continuing into the follow-up period or with a start date after the end of the on-
treatment period through the end of follow-up period. 
All prior, concomitant, and post-treatment procedures will be provided in a by-subject listing.
6.5 
Efficacy Analysis
All efficacy analyses will be conducted on the PP Set and the Modified Randomized Set, unless 
stated otherwise.  
All efficacy analyses will be conducted according to the treatment assigned.
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise. Control of Type I error is discussed in Section 3.3 in detail. 
Efficacy measurements assessed during the treatment phase and follow-up phase before 
non-study anti-CMV treatment initiation for more than one day, are included in the efficacy 
analysis to assess effect of the study assigned treatments unless otherwise specified. Efficacy 
measurements after initiation of alternative anti-CMV treatment for more than one day will be 
marked in data listings.
All definitions and specifications described below will apply to all subsections. 
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Unless otherwise specified, all efficacy analyses of CMV DNA concentration will be based on 
results from central laboratory. 
Confirmed viremia clearance: defined as plasma CMV DNA concentration below the lower 
limit of quantification (<LLOQ; i.e., <137 IU/mL) when assessed by COBAS®
AmpliPrep/COBAS® TaqMan® CMV Test at a central specialty laboratory, in 2 consecutive 
post-baseline samples, separated by at least 5 days.
Recurrence of CMV viremia: defined as plasma CMV DNA concentration ≥LLOQ when 
assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive plasma 
samples at least 5 days apart, after achieving confirmed viremia clearance.
Rebound of CMV viremia: defined as increase in viral DNA load for >1 log10 above nadir 
without any prior clearance of viremia. 
6.5.1
Primary Endpoint(s) Analysis
6.5.1.1
Derivation of Endpoint(s)
This section describes the outcome classification for the primary analysis.
The primary efficacy endpoint (a binary response) for the study is confirmed clearance of plasma 
CMV DNA (confirmed CMV viremia clearance) at the end of Study Week 8. 
For clearance of CMV viremia to be declared at the end of Study Week 8, the subject must have 
received exclusively study-assigned treatments through Study Week 8 (i.e., did not receive 
alternative anti-CMV treatment through Study Week 8).
Confirmed CMV viremia clearance at the end of Study Week 8 (Visit10) is defined as plasma 
CMV DNA concentrations <LLOQ (i.e., <137 IU/mL), when assessed by COBAS®
AmpliPrep/COBAS® TaqMan® CMV Test at a central specialty laboratory, in 2 consecutive 
post-baseline samples separated by at least 5 days, regardless of whether study-assigned 
treatment was discontinued before the end of the stipulated 8 weeks of therapy. This is further 
described in Table 2 (Table 12 in the study protocol) under different scenarios. 
In order to be classified as a responder (confirmed clearance of plasma CMV DNA at the end of 
Study Week 8) subjects must meet all of the following criteria based on Study Day relative to the 
first dose of study drug:

Two negative CMV DNA readings in the vicinity of Study Week 8 (between Study
Day 39 [lower limit of Week 6 Visit window] and Study Day 66 [upper limit of Week 9
Visit window] of which one must occur on Study Day 53 or later): an initial negative
CMV DNA reading, named as the primary sample (Sample A), and a confirmatory
negative CMV DNA reading, named as the confirmatory sample (Sample B) at least
5 days after Sample A is read.

No positive CMV DNA reading between the primary and confirmatory samples, i.e.
Sample A and B
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
No alternative anti-CMV DNA treatment prior to the primary or confirmatory sample
This criteria will be assessed by an algorithm that initially chooses a potential confirmatory 
sample (sample B) within the scheduled Week 8 Visit window (if there is more than one sample 
within the Visit 8 window choose the one closet to Day 56; if there are two samples an equal 
number of days from Day 56 choose the later sample) and then selecting the closest sample at 
least 5 days earlier within the Week 6, Week 7 or Week 8 scheduled visit windows as a potential 
primary sample (Sample A). If no sample meets the criteria for Sample A, then the sample 
initially chosen as sample B is reclassified as sample A (a potential primary sample) and the 
closest sample at least 5 days later within the Week 8 or Week 9 scheduled visit windows but on 
or before the start of alternative CMV treatment is chosen as a potential confirmatory sample 
(Sample B). If no sample meets the criteria for Sample B then the subject is classified as a non-
responder.
If there is no sample within the Week 8 visit window and there is a sample within the Visit 7 
window, then a potential primary sample (Sample A) will be chosen within the Week 7 visit 
window and the closest sample at least 5 days later within the Week 9 scheduled visit window 
but on or before the start of alternative CMV treatment  is chosen as a potential confirmatory 
sample (Sample B). If no sample meets the criteria for Sample B then the subject is classified as 
a non-responder.
If there is no sample within the Week 7 or Week 8 visit windows and there is a sample within the 
Visit 6 window, then a potential primary sample (Sample A) will be chosen within the Week 6 
visit window and the closest sample at least 5 days later within the Week 9 scheduled visit 
window  but on or before the start of alternative CMV treatment is chosen as a potential 
confirmatory sample (Sample B). If no sample meets the criteria for Sample B then the subject is 
classified as a non-responder.
Details of the algorithm will be included in the analysis dataset specifications. 
Table 2, as copied from Section 9.8.1 of the protocol, illustrates the algorithm as above. Note 
that Table 2 is not exhaustive. The logic above should be used for derivation of the primary 
efficacy endpoint, not Table 2.
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Table 2
Assessments of Virological Response at Study Week 8
Scenario
CMV DNA Weeks on Study
Week 6a
Week 7
Week 8
Week 9b
Response
Rationale
1
+ / -
-
-
+/-/NA
Yes
2 consecutive “-” at Week 7 
and Week 8
2
+ / -
-
+
+/-/NA
No
Not 2 consecutive “-” at 
Week 7 and Week 8
3
+ / -
+
-
+/-/NA
No
Not 2 consecutive “-” at 
Week 7 and Week 8
4
+ / -
-
NA
-
Yes
2 consecutive “-” as shown by 
available data and both “-” at 
Week 7 and Week 9 for 
missing Week 8
5
-
NA
-
+/-/NA
Yes
2 consecutive “-” as shown by 
available data and both ‘-‘at 
Week 6 and Week 8 for 
missing Week 7
6
-
NA
NA
-
Yes
2 consecutive “-” as shown by 
available data at Week 6 and 
Week 9 and both “-”
CMV: Cytomegalovirus 
NA=not available for evaluation of study drug effect; reason could be not assessable by lab, or starting alternative 
anti-CMV treatment or withdrawal from study etc.
a Week 6 data, if available to evaluate the effect of study drug, only to be used if Week 7 data are unavailable or 
missing
b Week 9 data, if available to evaluate the effect of study drug, only to be used if Week 8 data are unavailable or 
missing
Notes: Scenarios in the table above are provided as examples and may not be all-inclusive of all possibilities.
              "-" = CMV DNA concentration <LLOQ (<137 IU/mL)
"+" = CMV DNA concentration ≥LLOQ (ie, quantifiable)
Response = Confirmed clearance of plasma CMV DNA (CMV viremia clearance) = 2 consecutive post-baseline 
assessments of CMV DNA target <LLOQ, separated by at least 5 days.
Subjects who discontinue treatment prior to Study Week 8 after receiving exclusively study 
assigned treatment will be classified as a responder or non-responder based on CMV DNA data 
according to the algorithm above and not on the data at the end of treatment assessment. This 
follows the virology first hierarchy, that the confirmed viremia clearance at the end of Week 8 
based on CMV DNA data are assessed first.
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6.5.1.2
Main Analytical Approach
The difference in proportion of responders between maribavir and valganciclovir treatment 
groups will be obtained using Cochran-Mantel-Haenszel (CMH) weighted average across all 
strata, with baseline plasma CMV DNA concentration (high, low, very low) and baseline acute 
GVHD (present, absent) as two stratification factors. The 95% confidence intervals (CI) of the 
weighted average of difference across strata will be provided using the normal approximation. If 
the minimum expected  number of subjects in a response category in a treatment group within a 
level of one of the stratification factors is less than 5, then the adjacent groups will be collapsed 
into one stratum level.
The CMH weighted 95% CI is adjusted across the strata and this will form the basis of NI and 
superiority testing. As supportive data, an unadjusted 95% confidence interval based on 
combining the strata will be reported based on the normal approximation to the binomial 
distribution. Homogeneity across strata will be tested using Breslow-Day test. If the test is 
significant at the alpha=0.05 level, stratum-specific differences in proportions will be reported.
If the lower limit of the 95% CI is greater than -7%, it will be concluded that maribavir is as 
efficacious as valganciclovir. If the lower limit of the 95% CI is greater than 0, it will be 
concluded that maribavir is more efficacious than valganciclovir. 
For the NI analysis for primary endpoint defined in Section 3.1.1, the method is specified in 
Section 3.2. For the superiority for the primary endpoint defined in Section 3.1.2, the method is 
specified in Section 3.2. The multiplicity adjustment method is described in Section 3.3.
Reason for being non-responders will be listed and summarized. Non-response will be 
categorized as non-response based on observed CMV DNA data and non-response without 
sufficient observed CMV DNA data. To be classified as non-response based on observed data, 
subjects must have sufficient CMV DNA data to determine response or non-response based on 
observed data: non-response for these subjects will be based on having either the primary sample 
(Sample A) or confirmatory sample (Sample B) ≥LLOQ in the algorithm described in 
Section 6.5.1.1.
Non-response without sufficient observed data will be based on not having either the primary 
sample (Sample A) or confirmatory sample (Sample B) to apply the algorithm described in 
Section 6.5.1.1.
Non-response without sufficient observed data will be further sub-categorized as 
(a) Alternative Anti-CMV treatment taken prior to having sufficient CMV DNA data to
assess the primary endpoint
(b) Missing CMV DNA Data including Randomized but not dosed
(c) Missing CMV DNA data will be subcategorized as due to early study discontinuation
(broken down by reason) and remained on study with CMV DNA data not available.
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Additionally, a snapshot approach will be utilized to summarize the primary efficacy results and 
reason for non-response. The snapshot algorithm is described in detail in Appendix A of the 
CDER (2015) guidance on developing antiretroviral drugs for treatment of Human 
Immunodeficiency Virus-1 Infection (see reference section in this SAP). In the snapshot 
analysis, non-responders will be characterized as non-response due to virologic failure 
including subjects who failed to achieve viremia clearance at Week 8 or at time of alternative 
treatment or early discontinuation for reason other than AE or death, non-response due to drug/
study discontinuation, and non-response due to other reasons. 
6.5.1.3
Sensitivity and Supplementary Analyses of the Primary Efficacy Endpoint
In Section 6.5.1.3 we propose some sensitivity analyses. Some subjects classified as 
non-responders due to missing data will be re-classified as responders or non-responders in some 
sensitivity analyses. 
The following 12 types of sensitivity and supplementary analyses will be performed for the 
primary efficacy endpoint. These analyses will be conducted using the PP Set and the Modified 
Randomized Set unless specified otherwise. 
Type
Analysis Type
1
Analysis addressing sparse strata
2
Analysis using stratification level from randomization
3
Analysis assessing non-responder due to missing data for subjects who 
discontinue study early with confirmed clearance at the time of study 
discontinuation
4
Analysis using subset defined by baseline CMV DNA concentration
5
Analysis taking account of COVID impact
6
Analysis excluding subjects affected by the  COVID 19 pandemic 
7
Analysis restricted to subjects who received 8 weeks of study assigned 
treatment 
8
Analysis allowing for the use of non-study anti-CMV treatment
9
Analysis treating subjects with confirmed viremia clearance at the time of 
early treatment discontinuation as responders
10
Analysis treating subjects with confirmed viremia clearance at the time of 
alternative anti-CMV treatment initiation or early study discontinuation 
before Week 8 as responders
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Type
Analysis Type
11
Analysis treating subjects with confirmed viremia clearance at the time of 
early treatment discontinuation for reasons other than adverse event or death 
as responders, while treating subjects with early treatment discontinuation 
due to adverse events or death as non-responders
The following table summarizes key aspects of the sensitivity analyses. 
Attributes of Sensitivity Analyses
No
Preserve
Responders
[a]
Preserve
Non-
Responders
[b]
Adjustments based on
Subset
Analysis
Model/
Strata 
adjustment
Early
Study
Disc.
Early
Treatment
Disc.
Alternative
Anti-CMV
Use
Covid19
1
Y
Y
N
N
N
N
N
y
2
Y
Y
N
N
N
N
N
Y
3
Y
N
Y
N
N
N
N
N
4
Y
Y
N
N
N
N
Y
N
5
Y
N
Y*
N
N
Y
N
N
6
Y
Y
N
N
N
Y
Y
N
7
Y
Y
N
N
N
N
Y
N
8
Y
N
N
N
Y
N
N
N
9
N
N
N
Y
N
N
N
N
10
Y
N
Y
N
Y
N
N
N
11
N
N
N
Y
N
N
N
N
[a] All responders in the primary analysis are responders in the sensitivity analysis
[b] All non-responders in the primary analysis are non-responders in the sensitivity analysis
*Only if due to Covid 19
1. Sensitivity Analysis 1: Analysis to Address Sparse Strata
(a) Rationale
Methods that are less affected by sparse strata then the CMH test and Breslow Day test will be 
performed after pooling strata in the strata in the same manner as the primary analysis. 
(b) Derivation of Endpoint:
Same as primary analysis 
(c) Analytical Approach
In this analysis, confidence intervals for the difference in the proportion of responders in the 
treatment groups will be based on the stratified Wilson’s score test instead of the CMH test and 
Zelen’s exact test will be conducted for equal odds ratio across strata as an alternative to the 
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Breslow-Day test. This analysis will be based on the same pooling of strata as the primary 
analysis.
The adjusted difference and stratified Newcombe 95% confidence intervals for the difference in 
the proportion of responders in the treatment groups based on the stratified Wilson’s score test 
will be presented. As supportive data, an unadjusted 95% Newcombe confidence interval for the 
difference in proportion of responders in the treatment groups based on combining the strata will 
be presented. A test for homogeneity of odds ratios across strata using Zelen’s test will be 
performed. If Zelen’s test is significant at alpha=0.05 level, stratum-specific difference in 
proportion with Newcombe confidence intervals will also be reported  in addition to the adjusted 
difference and 95% CI in proportion of responders based on the stratified Wilson score test.
2. Sensitivity Analysis 2: Use of CMV VL Stratification Level from Randomization
(a) Rationale
The baseline CMV viral load (VL) from the central laboratory is used to determine CMV viral 
level (high, low, very low) strata in the primary analysis. However, the randomization 
stratification was based on the screening CMV VL mostly from local laboratory. An analysis 
will be performed to reflect the actual randomization. This sensitivity analysis is stipulated in the 
study protocol.
(b) Derivation of Endpoint:
Same as primary analysis 
(c) Analytical Approach
The analysis of the primary efficacy endpoint will be repeated using the stratification level used 
in randomization. For example, the CMV DNA level used in the randomization will be used in 
the analysis rather than the baseline CMV DNA level determined based on the central laboratory 
results. This is to evaluate the impact of treatment effect on primary analysis due to the 
difference in stratum assignment used in randomization  for CMV DNA level and the same 
based on central laboratory results. 
3. Sensitivity Analysis 3: Analysis to assess non-responder due to missing data for subjects
who discontinue study early (during the treatment period) without alternative treatment
and who have confirmed clearance at the time of study discontinuation
(a) Rationale
The primary analysis follows a derivation process for the responder status as specified in 
Section 6.5.1.1 in which some subjects are non-responders due to insufficient CMV DNA data to 
evaluate confirmed viremia clearance at Week 8. In order to assess potential impact of the 
derivation, an analysis will be performed that classifies subjects classified as non-responders 
who discontinue study early (during the treatment phase) with confirmed clearance at the time of 
study discontinuation as responders if they were classified as non-responders due to missing data 
in the primary analysis. 
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(b) Derivation of Endpoint:
Same as primary analysis, except that subjects classified as non-responders due to missing data 
in the primary analysis will be classified as responders in this sensitivity analysis if they meet all 
the following
(i)
Subject discontinues study early (during treatment phase) without taking
other anti-CMV medication prior to the visit of early discontinuation from
the study.
(ii)
At the visit of early study discontinuation, CMV DNA data is <LLOQ,
and the reading at the immediate prior scheduled visit Week is at least
5 days earlier than the reading at the end of treatment visit and is <LLOQ.
(If the reading at the immediate prior scheduled visit week is <LLOQ but
within 5 days of the reading at end of treatment visit then the reading at
two visits prior may be used in its place).
If data is available to definitively determine confirmed viremia clearance at Week 8 based on 
observed CMV DNA data (yes or no ) then it will be used and the criteria for the primary 
analysis outlined in Section 6.5.1.1 will be followed. Subjects who discontinue study early 
(during the treatment phase) and take alternative CMV treatment prior to discontinuation will be 
classified as non-responders. Subjects who discontinue study early (during the treatment phase) 
without taking alternative CMV treatment prior to discontinuation will have response determined 
based on confirmed clearance at the visit of early discontinuation. 
(c) Analytical Approach
Same as primary analysis. 
4. Sensitivity Analysis 4: Using Subset Defined by Baseline CMV DNA Concentration from
Central Laboratory
(a) Rationale
An analysis of primary endpoint on a subset of subjects with baseline CMV DNA concentration 
levels from central lab in a restricted interval of clinical interest.
(b) Derivation of Endpoint:
The analysis of the primary efficacy endpoint will be repeated using the subset of the subjects 
whose baseline CMV DNA concentration based on the central lab assessment were within the 
range of ≥455 IU/mL and ≤91000 IU/mL
The analysis of the primary efficacy endpoint will also be repeated using the subset of the 
subjects whose baseline CMV DNA concentration above LLOQ based on the central lab 
assessment.
(c) Analytical Approach
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5. Sensitivity Analysis 5: Taking Account of COVID Impact
(a) Rationale
Subjects with missing data due to the COVID-19 pandemic are more likely to be classified as a 
non-responder due to missing data. An analysis allowing the use of Visit 5 data to replace 
missing  Visit 7 and of Visit 10 data to replace missing Visit 8 for subjects with missing  data 
due to the COVID 19 pandemic is proposed. 
(b) Derivation of Endpoint:
To assess the impact of COVID-19 pandemic, the primary endpoint definition as outlined in the 
algorithm in Section 6.5.1.1 and illustrated in Table 2 will be followed except for subjects who 
are non-responders due to missing data with some of the missing data due to the COVID-19 
pandemic will be assessed by a modified algorithm. Subjects who had missing CMV DNA level 
data to confirm response at Week 8 due to COVID-19 will be identified based on COVID-19 
related missing assessment as recorded in the protocol deviations and eCRF. The modified 
algorithm will reduce the earliest allowed  Study Day for Sample A from Study Day 39 to Study 
Day 32, and it will increase the latest  allowed  Study Day for Sample B from Study Day 67 to 
Study Day 73.
The specifics of the modified algorithm are described in the analysis dataset specifications.
Table 2 illustrates that subjects will not be classified as non-responders due to missing data even 
though there are some missed visits (2 or less) around Week 8 in the primary analysis of the 
primary endpoint. Similarly, Table 3 illustrates that for patients with missing data due to the  
COVID-19 pandemic, 3 or more consecutive weeks of missed visits around Week 8 may occur 
without having the subject declared as a non-responder due to missing data. For such scenarios, 
available CMV DNA level at Week 5 and/or 10 data will be included in the modified algorithm. 
Table 3 illustrates the modified algorithm as above. Note that Table 3 is not exhaustive. The 
logic above should be used for derivation of the endpoint, not Table 3.
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Table 3
Assessments of Virological Response at Study Week 8 in Subjects with 
missing data between Week 6 and Week 9 due to COVID 19 (Modified 
Algorithm of Table 2)
Scenario
CMV DNA Weeks on Study
Last of 
Week 5 
and 
Week 6
Week 7
Week 8
First of 
Week 9 and 
Week 10
Response
Rationale
1
+ / -
-
-
+/-/NA
Yes
2 consecutive “-” at Week 7 
and Week 8
2
+ / -
-
+
+/-/NA
No
Not 2 consecutive “-” at 
Week 7 and Week 8
3
+ / -
+
-
+/-/NA
No
Not 2 consecutive “-” at 
Week 7 and Week 8
4
+ / -
-
NA
-
Yes
2 consecutive “-” as shown 
by available data and both “-” 
at Week 7 and Week 9/10 for 
missing Week 8
5
-
NA
-
+/-/NA
Yes
2 consecutive “-” as shown 
by available data and both ‘-
‘ at Week 5/6 and  Week 8 
for missing Week 7
6
-
NA
NA
-
Yes
2 consecutive “-” as shown 
by available data at Week 5/6 
and Week 9/10 and both “-”
(c) Analytical Approach
Same as primary analysis. 
6. Sensitivity Analysis 6: Analysis restricted to subjects not impacted by  COVID-19
pandemic
(a) Rationale
An analysis of primary endpoint on a subset of subjects not affected by the COVID-19 pandemic 
is of clinical interest.
(b) Derivation of Endpoint:
The primary efficacy analysis will be performed in the subset of subjects who do not have 
missing CMV DNA data between Visit 6 and Visit 10 due to the COVID 19 pandemic and who 
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have not discontinued the study prior to Week 8 due to the COVID 19 pandemic. This analysis is 
proposed to demonstrate that the results are consistent with the primary results when subjects 
with data impacted by the COVID 19 pandemic are removed. This analysis will be conducted 
following the same methods as described in the primary analysis.
This sensitivity analysis will be conducted only if there are ≥5% of subjects that have missing 
CMV DNA data between Visit 6 and Visit 10 due to the COVID 19 pandemic or who have 
discontinued the study prior to Week 8 due to the COVID 19 pandemic 
(c) Analytical Approach
Same as primary analysis.
7. Sensitivity Analysis 7: Analysis restricted to subjects who received 8 weeks of study
assigned treatment
(a) Rationale
An analysis of primary endpoint on a subset of subjects who received 8 weeks of study assigned 
treatment is of clinical interest.
(b) Derivation of Endpoint:
The primary efficacy analysis will be performed in the subset of subjects who received 8 weeks 
of study assigned treatment. This analysis is proposed to demonstrate that the results are 
consistent with the primary results when subjects receiving less than 8 weeks of study assigned 
treatment are removed. This analysis will be conducted following the same methods as described 
in the primary analysis.
(c) Analytical Approach
Same as primary analysis.
8. Sensitivity Analysis 8: Analysis allowing for the use of non-study anti-CMV treatment
(a) Rationale
An analysis of primary endpoint allowing the use of non-study anti-CMV treatment
(b) Derivation of Endpoint:
Response (defined as 2 consecutive post-baseline assessments of CMV DNA target <LLOQ, 
separated by at least 5 days) at end of Study Week 8 (see Table 2) regardless of the use of 
non-study anti-CMV treatment, will be conducted following the same method as described for 
the primary endpoint of response at Study Week 8.  
(c) Analytical Approach
Same as primary analysis.
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9. Sensitivity Analysis 9: Analysis treating subjects with confirmed viremia clearance at the
time of early treatment discontinuation as responders
(a) Rationale
In order to assess the on-treatment  effect, an analysis will be performed that classifies subjects 
who discontinue treatment early with confirmed clearance at the time of treatment 
discontinuation as responders. Patients who discontinue treatment early and remain in the study 
with sufficient observed CMV DNA data to determine confirmed viremia status at Week 8 will 
have response status determined by whether confirmed viremia clearance is attained at end of 
treatment and the Week 8 CMV DNA data will be ignored in this sensitivity analysis.
(b) Derivation of Endpoint:
Same as primary analysis for subjects who do not discontinue treatment early. Patients who 
discontinue treatment early will be classified as responders if both of the following are met
(i)
Subject discontinues treatment prior to study Week 8  treatment without
taking other anti-CMV medication prior to the visit of early
discontinuation from the study and without a CMV DNA ≥LLOQ within
5 days of early treatment discontinuation.
(ii)
At the visit of early study discontinuation, CMV DNA data is <LLOQ,
and the reading at the immediate prior scheduled visit Week is at least
5 days earlier than the reading at the end of treatment visit and is <LLOQ.
(If the reading at the immediate prior scheduled visit week is <LLOQ but
within 5 days of the reading at end of treatment visit then the reading at
two visits prior may be used in its place). If at the visit of early treatment
discontinuation CMV DNA data is <LLOQ, and there is no prior CMV
reading at either of the two prior scheduled and the subject received at
least 14 days of treatment visits then the first reading at least 5 days after
treatment discontinuation through 10 days after treatment discontinuation
l and on or prior to the initiation of alternative anti-CMV treatment (if
applicable) will be used as the second sample to establish  confirmed
viremia clearance at the time of early treatment discontinuation.
(c) Analytical Approach
Same as primary analysis. Additionally reasons for responders will be presented which include 
details of responders in this analysis who were non-responders in the primary analysis. 
A snapshot approach will be performed to classify responders and non-responders in this 
analysis.
10. Sensitivity Analysis 10: Analysis treating subjects who receive alternative anti-CMV
treatment or discontinue the study prior to Week 8 with confirmed viremia clearance at
the time of alternative anti-CMV treatment initiation or early study discontinuation as
responders
(a) Rationale
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In order to verify that results of the primary analysis are not overly influenced by treating 
patients doing well at the time of initiation of alternative anti-CMV medication or early study 
discontinuation as non-responders, an analysis will be performed that classifies all subjects who 
receive alternative anti-CMV treatment or discontinue the study prior to week 8 with confirmed 
viremia clearance at the time of alternative anti-CMV treatment initiation or early study 
discontinuation as responders. 
(b) Derivation of Endpoint:
Same as primary analysis, except that all subjects who receive alternative anti-CMV treatment or 
discontinue the study prior to week 8 with confirmed viremia clearance at the time of alternative 
anti-CMV treatment initiation or early study discontinuation are responders. In this analysis, for 
subjects who initiate alternative CMV treatment prior to Week 8, only samples taken on or prior 
to the date of the initiation of anti-CMV treatment can be used as primary and secondary 
samples to establish confirmed viremia clearance (See Section 6.5.1.1).  
(c) Analytical Approach
Same as primary analysis.. 
11. Sensitivity Analysis 11: Analysis treating subjects with confirmed viremia clearance at
the time of early treatment discontinuation for reasons other than an adverse event or
death as responders while treating subjects with early treatment discontinuation due to
adverse events or death as non-responders
(a) Rationale
This analysis is performed to assess the on-treatment treatment effect while incorporating 
tolerability in the assessment.
(b) Derivation of Endpoint:
Same as sensitivity analysis 9, except that all subjects who discontinue treatment early due to 
adverse events or death are treated as non-responders, regardless of CMV viremia status at Week 
8 in this sensitivity analysis.
(c) Analytical Approach
Same as primary analysis.
6.5.2 
Secondary Endpoints Analysis
6.5.2.1 
Key Secondary Endpoint Analysis 
The key secondary efficacy endpoint is defined in Section 1.2.2.1.
The key secondary endpoint of this study is a binary response (yes/no) with following criteria:

Achievement of clearance of viremia at the end of Study Week 8 (virologic response) and
no clinical findings of CMV tissue invasive disease at the end of Study Week 8 (CMV
infection symptom control), followed by maintenance of this treatment effect for an
additional 8 weeks off treatment period (i.e., Follow-up Week 16).
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For treatment effect of clearance of CMV viremia and CMV infection symptom control to be 
declared at the end of Study Week 8, regardless of whether either study-assigned treatment was 
discontinued before the end of the stipulated 8 weeks of therapy, and maintenance of such effect 
through Week 16, the subject must have received exclusively a study-assigned treatment (no 
alternative anti-CMV treatment) and maintained symptom control from week 8 through week 16.
CMV infection symptom control includes:

no new clinical findings of CMV tissue invasive disease
The investigator will assess subjects for new occurrence of CMV tissue invasive disease through 
the study and will continue with the assessment of the infection status (i.e., no change, 
improvement, worsening, or resolution) at subsequent visits throughout the study. CMV 
pneumonia, CMV hepatitis, CMV nephritis, CMV GI CMV myocarditis, CMV pancreatitis, 
CMV retinitis, and other CMV symptoms will be assessed by the investigator at each visit. For 
the subject to have CMV infection symptom control at Study Week 8 there can be no clinical 
findings of CMV pneumonia, CMV hepatitis, CMV nephritis, CMV GI disease, CMV 
myocarditis, CMV pancreatitis ,CMV retinitis, and other CMV disease as assessed by the 
investigator at Study Week 8.
Criteria for defining the key secondary efficacy endpoint are:
First being a responder for the primary endpoint at the end of Study Week 8, irrespective of 
study treatment duration, based on CMV viremia clearance and assessment of the tissue invasive 
CMV disease status (i.e., no clinical findings of CMV disease at Week 8)
AND
Maintenance of this treatment effect (both CMV viremia clearance and CMV symptom control) 
through Study Week 16. Maintenance of CMV viremia clearance through Week 16 is determined 
by the absence of 2 consecutive “+” viral measurements (>LLOQ) through Week 16 (see 
Table 4). 
A subject who fails to achieve response for the primary efficacy endpoint will be a 
non-responder for the key secondary efficacy endpoint. It is noted that plasma CMV DNA 
assessment done after the start of alternative anti-CMV treatment are not evaluable for the 
responder assessment toward the study assigned treatment.
Assessment of the key secondary endpoint will be based an algorithm based on Study Day using 
the following concepts.
To determine the virological response maintenance at Week 16, all the following conditions need 
to be satisfied: 
1. Viremia clearance achieved at Week 8
2. Virological response maintenance around Week 12 (See Section 9.2.4 for details)
3. No two consecutive positives between Week 8 and Week 16
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4. Evidence of maintenance around Week 16 (i.e., no confirmed recurrence around Week 16),
meaning one of the following must be true:
a. Week 16 is negative, or
b. If Week 16 is missing, but Week 18 (or unscheduled visit after Week 16) is negative, or
c. If Week 16 is positive, both Week 14 (or unscheduled visit prior to week 16) and Week 18
(or unscheduled visit after Week 16) must be negative
5. No alternative anti-CMV therapy through Week 16 (through Week 18 for scenario 4c)
For the subject to have CMV infection symptom control through Study Week 16 there can be no 
clinical findings of CMV pneumonia, CMV hepatitis, CMV nephritis, CMV GI CMV 
myocarditis, CMV pancreatitis ,CMV retinitis, and other CMV disease clinical findings as 
assessed by the investigator from Week 8 through Study Week 16. 
Table 4, as copied from Section 9.8.2 of the protocol, illustrates the algorithm as above. Note 
that Table 4 is not exhaustive. The logic above should be used for derivation of the key 
secondary endpoint, not Table 4.
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Table 4
Assessments of Responders for Key Secondary Endpoint
Response* at 
Study 
Week 8  
CMV DNA Assessment Week
Key 
secondary 
endpoint 
responder2
Rationale
Row
9
10
11
12
14
16
181
Yes
+/-
+/-
+/-
+/-
+/-
+/-
+/-/NA
No
Any 2 consecutive “+” in 
FU by week 16
1
Yes
+/-
+/-
+/-
+/-
+/-
-
+/-/NA
Yes
Week 16 is “-” and no 2 
consecutive “+” during FU
2
Yes
+/-
+/-
+/-
+/-
+/-
+
+/-/NA
No
Week 16 is “+” and week 18 
is “+” or NA, criteria of 2 
consecutive “+” is met
3
Yes
+/-
+/-
+/-
+/-
+/-
+
-
Yes
Week 16 is “+”, and 2 
consecutive “+” criteria is 
not met based on week 18 
data 
4
Yes
+/-
+/-
+
-
-
NA
-
Yes
Week 16 is missing, 2 
consecutive “+” criteria is 
not met based on week 14 
and 18 data
5
Yes
+/-
+/-
+
-
-
NA
+/NA
No
Week 16 is missing, 2 
consecutive “+” criteria may 
be met based on available 
week 18 data
6
Yes
+/-
/NA
+/-
/NA
+/-
/NA +/-/NA NA NA
+/-/NA
No
Lack of data to show 
maintaining effect through 
week 16
7
No
No
8
*Both virological response and symptomatic CMV infection control
CMV: Cytomegalovirus; FU: Follow-up; NA=not available for evaluation of study drug effect; reason could be
starting alternative anti-CMV treatment, withdrawal from study etc.
1Week 18 data, if available for evaluation of study drug effect, will be utilized to impute Week 16 data when
Week 16 data is unavailable or missing.
2 Must also meet the criterion of CMV infection symptom control to be a responder.
"-" = CMV DNA concentration <LLOQ (<137 IU/mL)
"+" = CMV DNA concentration ≥LLOQ (i.e., quantifiable)
Notes: Scenarios in the table above are provided as examples and may not be all-inclusive of all possibilities.
Only CMV viremia data prior to receiving non-study CMV treatment or rescue treatment will be included in the
assessment.
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6.5.2.2
Main Analytical Approach
The proportion of responders (i.e., subjects who achieve confirmed clearance of viremia at the 
end of Study Week 8 (virologic response) and no clinical findings of CMV tissue invasive 
disease at the end of Study Week 8 (CMV infection symptom control), followed by maintenance 
of this treatment effect for an additional 8 weeks off treatment (i.e., Follow-up Week 16) after 
adjusting for baseline viral load and acute GVHD at baseline will be calculated for each 
treatment group. The difference in proportion of responders between treatment groups will be 
obtained using the same method as described for the primary efficacy endpoint. The NI analysis 
for the key secondary endpoint is specified in Section 3.2.   
Upon meeting the criteria for superiority testing specified in Section 3.1.4 and subject to the 
multiplicity adjustment method described in Section 3.3, the superiority hypothesis (H22) of the 
key secondary efficacy endpoint will be tested in the way of Section 3.2. 
6.5.2.3
Sensitivity and Supplementary Analyses of the Key Secondary Endpoint
The following sensitivity analyses will be conducted using the PP Set and the Modified 
Randomized Set unless otherwise specified:
1. Sensitivity Analysis 1: Analysis to Address Sparse Strata
In this analysis confidence intervals for the difference in the proportion of responders in the 
treatment groups will be based on Wilson’s score test instead of the CMH test and Zelen’s exact 
test will be conducted for equal odds ratio across strata as an alternative to the Breslow-Day test. 
This analysis will be based on the same pooling of strata as the primary analysis.
The adjusted difference and stratified Newcombe 95% confidence intervals for the difference in 
the proportion of responders in the treatment groups based on Wilson’s score test will be 
presented. As supportive data, an unadjusted 95% Newcombe confidence interval for the 
difference in proportion of responders in the treatment groups based on combining the strata will 
be presented. A test for homogeneity of odds ratios across strata using Zelen’s test. If Zelen’s test 
is significant at α=0.05 level, stratum-specific difference in proportion with Newcombe 
confidence intervals will also be reported  in addition to the adjusted difference and 95% CI in 
proportion of responders based on the Wilson score test.
2. Sensitivity Analysis 2: Use of Stratification Level from Randomization
The analysis of the key secondary efficacy endpoint will be repeated using the stratification level 
used in randomization. For example, the CMV DNA level used in the randomization will be used 
in the analysis rather than the CMV DNA level based on the baseline central laboratory results. 
3. Sensitivity Analysis 3: Using Subset Defined by Baseline CMV DNA Concentration
The analysis of the key efficacy endpoint will be repeated using the subset of the subjects whose 
baseline CMV DNA concentration based on the last central lab assessment were within the range 
(≥455 IU/mL and ≤91000 IU/mL). 
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The analysis of the key secondary efficacy endpoint will also be repeated using the subset of the 
subjects whose baseline CMV DNA concentration above LLOQ based on the central lab 
assessment.
4. Sensitivity Analysis 4: Removing the Requirement of Symptom Control
An analysis of the key secondary endpoint will be performed where a less stringent definition of 
response is used. In this analysis subjects are not required to be free of any symptoms of CMV 
infection (i.e., no requirement of symptom control) through Week 16. In this analysis subjects 
will be classified as a responder as long as  CMV viremia clearance confirmed at Week 8 is 
maintained through Week 16.
5. Sensitivity Analysis 5: Analysis Restricted to Patients Not Impacted by COVID-19
The analysis of the key secondary outcome will be performed in the subset of subjects with do 
not have missing CMV DNA data between Visit 6 and Visit 16 due to the COVID 19 pandemic 
and who have not discontinued the study prior to Week 16 due to the COVID 19 pandemic. This 
analysis is proposed to demonstrate that the results are consistent with the primary results when 
subjects with data impacted by the COVID 19 pandemic are removed. 
6. Sensitivity Analysis 6: Analysis Restricted to Patients Who Receive 8 Weeks of Study
Assigned Treatment
The analysis of the key secondary efficacy endpoint will be conducted in the subset of subjects 
who received 8 weeks of study assigned treatment following the same method as described 
above for the key secondary endpoint.
7. Sensitivity Analysis 7: Analysis allowing for the use of non-study anti-CMV treatment
An alternative definition of response at Study Week 16 will include subjects who achieved 
confirmed CMV viremia clearance and CMV infection symptom control at Study Week 8 and 
maintained this effect through Study Week 16, regardless of the use of non-study anti-CMV 
treatment.  The proportion of alternative response will be analyzed following the same method as 
described above for the key secondary endpoint.
Response (defined as 2 consecutive post-baseline assessments of CMV DNA target <LLOQ, 
separated by at least 5 days) at end of Study Week 8 and symptom control through study Week 8 
which is maintained through Study Week 16 regardless of the use of non-study anti-CMV 
treatment, will be conducted following the same method as described for the key secondary 
endpoint.
6.5.3
Other Secondary Endpoints Analysis
The analysis of other secondary efficacy endpoints will be conducted using the Modified 
Randomized Set and PP Set unless otherwise specified. Other secondary efficacy endpoints will 
be summarized by treatment group, and, if indicated, analyzed statistically with a significance 
level of α=0.05 (2-sided), without adjustment for multiple comparisons.
For the following 3 secondary endpoints (a), (b) and (c), the proportion of subjects reaching the 
endpoint and the corresponding 95% CIs will be calculated for each treatment group separately. 
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The difference in each respective proportion between treatment groups and the associated 95% 
CI will be calculated using the same approach as the primary efficacy endpoint, and will be 
assessed using CMH test with acute GVHD and baseline CMV DNA concentration as 
2 stratification factors. 
a) The achievement of the confirmed CMV viremia clearance after 8 weeks of receiving
study-assigned treatment
b) The maintenance of the confirmed CMV viremia clearance after completion of 8 weeks
of receiving study-assigned treatment, through Study Weeks 12, 16, and 20
c) The maintenance of the CMV viremia clearance achieved and symptom control at the end
of Study Week 8 through Study Weeks 12, and 20, regardless of whether either of the
study-assigned treatment was discontinued before the end of the stipulated 8 weeks of
therapy
Details of derivations of virological response maintenance for  (b) and (c) are contained in 
Section 9.2.5 of the Appendix. 
For the following (d), (e) and (f) secondary endpoints, the number and the proportion of subjects 
reaching the endpoints will be calculated.
d) The recurrence of CMV viremia (See Section 6.5 for definition) during the first 8 weeks 
of the study, in the 12-week follow-up period, and at any time during the 20 weeks of the 
study, regardless of whether study-assigned treatment was discontinued before the end of 
the stipulated 8 weeks of therapy
e) The recurrence of confirmed CMV viremia  in the 2 study treatment arms when subjects 
are on treatment and off treatment
f) For the incidence of grade 3 or 4 neutropenia, defined as ANC <1,000/mm3 [1.0 x 109/L] 
or ANC <500/mm3 [0.5 x 109/L] respectively while on treatment, which will be analyzed 
using Safety Set
6.5.3.1
Achievement of confirmed CMV viremia after 8 weeks of receiving study 
assigned treatment
A subject is counted as a responder (a binary response) at Week 8 if meeting the following 
criteria, or non-responder if not meeting any of the following criteria:

The achievement of the confirmed CMV viremia clearance at Week 8

and received 8 weeks of study-assigned treatment
The analysis of response at Study Week 8 after receiving 8 weeks of study-assigned treatment 
will be conducted following the same method as described for the primary endpoint.
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6.5.3.2
The maintenance of CMV viremia clearance after completion of 8 weeks 
of receiving study-assigned treatment, through Study Weeks 12, 16, and 
20
For maintenance effect to be achieved at a time point,  the subjects must have received 
exclusively study-assigned treatments up to that time point.
A subject is counted as a responder (a binary response) at Week 8, 12, 16, 20 if meeting the 
following criteria, or non-responder if not meeting any of the following criteria:

The achievement of the confirmed CMV viremia clearance at Week 8, and
maintained through Week 12, 16, 20

and received 8 weeks of study-assigned treatment
The analysis of response at Study Week 8, 12, 16, and 20 after receiving 8 weeks of 
study-assigned treatment will be conducted following the same method as described for the 
primary endpoint.
6.5.3.3
The maintenance of CMV viremia clearance and symptom control 
achieved at the end of study Week  8 through Study Weeks 12 and 20, 
regardless of whether either study assigned treatment was discontinued 
before the stipulated 8 weeks of therapy
For maintenance effect to be achieved at a time point,  the subjects must have received 
exclusively study-assigned treatments up to that time point and have symptom control.
The response based on the maintenance of the effect of CMV viremia clearance, and CMV 
infection symptom control achieved at the end of Study Week 8 regardless of whether either 
study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy, 
through Weeks 12 and 20 will be determined as below:

Identify subjects who achieved CMV viremia clearance, and CMV infection symptom
control at Study Week 8 regardless of whether either study-assigned treatment was
discontinued before the end of the stipulated 8 weeks of therapy; this is similar to the first
step in identifying responder for the key secondary efficacy endpoint

Subjects who maintain the effect achieved at Study Week 8 through Week 12 (or 20) will
be classified as responder for Week 12 (or 20). If the effect is not maintained, subject will
be classified as a non-responder.
The analysis of achievement of the confirmed CMV viremia clearance and CMV infection 
symptom control at Study Week 8, and maintenance through Week 12, 20 will be conducted 
following the same method as described for the primary endpoint.
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6.5.3.4
The recurrence of CMV viremia during the first 8 weeks of the study, in 
the follow-up period of 12 weeks, and at any time during the 20 weeks of 
the study, regardless of whether either study-assigned treatment was 
discontinued before the stipulated 8 weeks of therapy
The recurrence of CMV viremia is defined as plasma CMV DNA concentration ≥LLOQ when 
assessed by the central laboratory COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 
2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance.
All CMV DNA measurements after achieving confirmed viremia clearance regardless of rescue 
or alternative treatment will be included in the assessment.
The recurrence of CMV viremia during the first 8 weeks of the study, in the follow-up period of 
12 weeks, and at any time during the 20 weeks of the study, regardless of whether either 
study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy 
will be provided. 

Of the number of subjects who achieved viremia clearance anytime on study after
receiving study assigned treatment, the number and percentage who have recurrence in
the following periods will be summarized
o
During the first 8 weeks of study, and in the 12 weeks of follow-up
o
Any time on study
6.5.3.5
The recurrence of confirmed CMV viremia in the 2 study treatment arms 
when subjects are on treatment and off treatment
The recurrence of CMV viremia during study-assigned treatment and in the follow-up period 
after the subject is discontinued from study-assigned treatment will be calculated as follows.

Of the number of subjects who achieved the confirmed viremia clearance any time on
study after receiving study-assigned treatment, the number and percentage of subjects
who have recurrence in the following period will be summarized
o
While on study-assigned treatment - breakthrough
o
While off study-assigned treatment
6.5.3.6
The incidence of grade 3 or 4 neutropenia (defined as ANC<10000/mm3 or 
ANC<500/mm3) while on treatment
For the incidence of grade 3 or 4 neutropenia, defined as ANC <1,000/mm3 [1.0 x 109/L] or 
ANC <500/mm3 [0.5 x 109/L] respectively, the frequency and time to events analysis will be 
analyzed using Safety Set. The number and proportion of subjects with neutropenia (shifts in 
ANC from lower grade to grade 3 or 4, as well as grade 4 post-baseline) while receiving study 
treatment, and the corresponding 95% CI will be calculated for each treatment group.
Time to first occurrence of grade 3 or 4 neutropenia while receiving study treatment will be 
defined as days from date of first dose to the date of first ANC shifts to grade 3 or 
4 post-baseline and will be calculated as [(lab sample date - date of first dose) +1]. The time to 
first neutropenia while receiving study treatment will be summarized using Kaplan Meier 
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method. Subjects who have not experienced the event (grade 3 or 4 neutropenia) will be censored 
at the last date of clinical laboratory assessment at the end of treatment period. 
6.5.4
Analyses of Exploratory Endpoints 
 
6.5.4.1
 
 
 
 
 
 
6.5.4.2
 
 
 
 
 
 
 
 
 
 
6.5.4.3
 
 
 
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6.5.4.4
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.5.4.5
 
 
 
 
 
6.5.4.6
 
 
 
 
 
6.5.4.7
 
 
 
 
 
6.5.4.8
 
 
 
6.5.4.9
  
 
 
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6.5.4.10 
  
 
 
6.5.4.11 
 
 
 
6.5.5 
Subgroup Analyses
The following list of subgroup analyses will be performed for the primary efficacy endpoint and 
the key secondary efficacy endpoint. The proportion of responders and the corresponding 95% 
CI for each endpoint will be summarized by treatment group. The difference in proportion of 
responders between treatment groups and the 95% confidence limits of the difference will be 
calculated using methods similar to the primary efficacy analysis, stratifying for any factors used 
in the primary analysis that remains applicable. Subgroup analysis results will be summarized in 
a forest plot.

CMV DNA viral load (high, low, very low)

Acute GVHD presence/absence at baseline

Age group, adjacent groups may be collapsed to have adequate sample size
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o
≥16 to <18 years of age (adolescents)
o
≥18 to <45 years of age
o
≥45 to <65 years of age
o
≥65 years of age

Enrolling regions (North America, Europe and Asia)

Gender

Use of T-cell depletion agent

CMV serostatus (D+/R+, D-/R+ vs. D-/R-, D+/R-)

History of CMV prophylaxis
6.6
Safety Analysis
The analysis of safety will be based on the “treatment-emergent” principle and for the study 
assigned treatment. 
The safety analysis will be performed using the Safety Set, unless specified otherwise.
The safety analyses will include evaluation and procedures to meet the secondary objective of 
assessing the safety and tolerability of maribavir. Safety evaluation will be made during the 
periods as illustrated in Figure 1, i.e., Screening Phase, Treatment Phase, and Follow-up Phase.  
Two observation periods are defined for safety analyses:

The on-treatment period starts at the time of study treatment initiation through 7 days after
the last dose of study treatment. For subjects who transfer from the study treatment to a
non-study anti-CMV treatment, the on-treatment period starts at the time of the study
treatment initiation through 7 days after the last dose of study treatment, or until the
non-study anti-CMV treatment initiation, whichever is earlier.

The overall-study period starts at the time of the start of the study treatment through the end
of the study.
The safety endpoints for this study are as follows:

Treatment-emergent AEs (TEAEs) and treatment-emergent SAEs (TESAEs), overall study
AEs and overall study SAEs

Clinical laboratory evaluations (including incidence of neutropenia defined as ANC
<500/mm3 [0.5 × 109/L] or ANC <1,000/mm3 [1.0 × 109/L] at any time during the study [on
treatment and overall study period], and time to neutropenia development), and study
treatment dose adjustment due to AEs.
Safety assessments will also include vital sign measurements, physical examination, and ECG. 
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Safety endpoints will be summarized descriptively for the on-treatment period and overall-study 
period. Baseline assessments will be the last assessment before the first dose of study treatment. 
For each safety variable, the last value collected before the first dose of study treatment will be 
used as baseline for all analyses of that safety variable. The last valid assessment obtained after 
baseline during the on-treatment period will be defined as the last value on treatment. The last 
valid assessment obtained after baseline during the overall-study period will be defined as the 
last value on study.
6.6.1 
Adverse Events
Adverse events will be coded using MedDRA Version 23 dated March 2020.  
An AE (classified by preferred term) that started after the first dose of study assigned treatment 
or if started before the date of first dose of study assigned treatment, but increases in severity 
after first dose of study assigned treatment will be considered a TEAE. If more than one AE with 
the same preferred term is reported before the date of the first dose of study assigned treatment, 
then the AE with the highest severity will be used as the benchmark for comparison to the AEs 
occurring after the start of study assigned treatment under the preferred term.  
AEs that occur from the time of informed consent form (ICF) signature to first dose will be 
collected but not evaluated in the safety analyses. They will be listed as pretreatment adverse 
events. 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is 
incomplete, an imputation algorithm will be used to classify the adverse event as pretreatment or 
treatment emergent. The algorithm for imputing date/time of onset will be conservative and will 
classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment. Handling of missing AE start/end dates, missing severity and 
missing relationship are detailed in Section 9.2.2.3.
If more than one AE occurs with the same preferred term for the same subject, then the subject 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by relationship to investigational product.
TEAE summaries will be produced for the on-treatment period and overall-study period, 
respectively using the Safety Set. The primary focus of adverse event reporting will be the 
TEAEs occurring during the on-treatment period. Summaries in terms of severity and 
relationship to study medication will also be provided.
The following summaries will be provided for TEAEs for the on -treatment period

An overall summary of TEAEs, including the number and percentage of subjects with
any AEs, any serious adverse events (SAEs), any severe AEs, AEs causing
discontinuation of study medication, AEs leading to withdrawals from study, fatal AEs
and AEs of special interest (AESI) as well as the total number of events for each category
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
Summary of TEAEs by system organ class (SOC) and preferred term (PT), including the
number and percentage of subjects with a TEAE, as well as the total number of events in
each treatment group

Summary of frequently occurring (in ≥5% in either treatment group) TEAEs by PT in
descending order for maribavir treatment group

Summary of TEAEs related to study treatments by SOC and PT

Summary of frequently occurring TEAEs related to study treatments by PT in descending
order for maribavir treatment group

Summary of TEAEs by maximum severity, SOC, and PT

Summary of TEAEs related to study treatments by maximum severity, SOC, and PT

Summary of treatment emergent SAEs by SOC and PT

Summary of treatment emergent SAEs by maximum severity, SOC and PT

Summary of treatment emergent SAEs considered related to study drugs by SOC and PT

Summary of TEAEs leading to study treatment discontinuation or withdrawal from study
by SOC and PT

Summary of TEAEs related to study treatments leading to study treatment
discontinuation or withdrawal from study by SOC and PT

Summary of TEAEs leading to death by SOC and PT

Summary of TEAEs related to study treatments leading to death by SOC and PT
The following summaries will be provided for TEAEs for the overall period

An overall summary of TEAEs, including the number and percentage of subjects with
any AEs, any serious adverse events (SAEs), any severe AEs, AEs causing
discontinuation of study medication, AEs leading to withdrawals from study, fatal AEs
and AEs of special interest (AESI) as well as the total number of events for each category

Summary of treatment emergent SAEs by SOC and PT

Summary of TEAEs leading to death by SOC and PT

Summary of related treatment emergent SAEs by SOC and PT

Summary of related TEAEs leading to death by SOC and PT
Additionally, exposure adjusted analyses of adverse events based  on rates per 100 patient years 
exposure will include the following.

An overall summary of TEAEs, including the number and percentage of subjects with
any AEs, any serious adverse events (SAEs), any severe AEs, AEs causing
discontinuation of study medication, AEs leading to withdrawals from study, fatal AEs
and AEs of special interest (AESI) as well as the total number of events for each category
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
Summary of treatment emergent SAEs by SOC and PT

Summary of related treatment emergent SAEs by SOC and PT
For the exposure adjusted analysis of adverse events, rates per total length of treatment exposure 
will be displayed in which the total number of patients with at least one event of interest divided 
by the total years of patient year exposure in each treatment group.
All AEs will be presented in a listing. Additional data listings will be presented for SAEs, AEs 
causing discontinuation of study treatment or withdrawal from the study, fatal AEs and AESIs. 
6.6.1.1
Renal Disorder TEAEs
The following summaries of sponsor-defined renal disorder TEAEs will be provided for each 
treatment group using the Safety Set for the on-treatment period:

Summary of renal disorder TEAEs by preferred term and maximum severity

Summary of renal disorder TEAEs related to study treatment by preferred term and
maximum severity

Summary of serious renal disorder TEAEs by preferred term and maximum severity

Summary of serious renal disorder TEAEs related to study treatment by preferred term
and maximum severity
The above summaries of renal disorder TEAEs will be repeated for the following subgroups:

Renal impaired subjects (no, mild, moderate/severe).
6.6.2
Adverse Events of Special Interest
The following events of special interest will be closely monitored and reported throughout the 
study, regardless of relationship to study medication.
Two kinds of AESIs based on different severity grading are listed as follows (see Section 8.1.4 
of study protocol for more details):

Adverse Events of Special Interest (severity grading based on CTCAE Version 4.03)
o
Tissue invasive CMV
o
Relapse or progression of the underlying disease (disease for which transplant
was performed)
o
Taste disturbance (dysgeusia)
o
Nausea, Vomiting, Diarrhea
o
Neutropenia

Adverse Events of Special Interest (grading based on standard severity
categorization to mild, moderate, and severe)
o
Immunosuppressant drug concentration level increased:
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o
Invasive fungal or bacterial infections
o
Graft-versus-host-disease: CRF break it into two categories

Acute Graft-versus-host-disease

Chronic Graft-versus-host-disease
AESI as reported by Investigator and reviewed using the list of MedDRA search terms defined 
by Sponsor medical lead will be analyzed according to the above grouping, primary SOCs and 
PTs for the on-treatment period. 
The following summaries will be provided for AESI including renal events for the on-treatment 
period:

Summary of TEAE of special interest by SOC and PT

Summary of TEAE of special interest related to study treatment by SOC and PT

Summary of TEAE of special interest by PT in descending order of frequency for
maribavir treatment group

Summary of TEAE of special interest related to study treatments by PT in descending
order of frequency for maribavir treatment group

Summary of TEAE of special interest by maximum severity, SOC, and PT

Summary of TEAE of special interest related to study treatments by maximum severity,
SOC, and PT

Summary of serious TEAE of special interest by SOC, and PT

Summary of serious TEAE of special interest related to study treatments by SOC, and PT
Additionally, exposure adjusted analyses of AESI based  on rates per patient years exposure will 
include the following

Summary of TEAE of special interest by SOC and PT

Summary of serious TEAE of special interest by SOC and PT
6.6.2.1
Time to Resolution for Dysgeusia and Similar Terms While on Treatment 
and When Off Treatment
For subjects who had reported AEs as dysgeusia and similar terms after receiving maribavir as 
study assigned treatment, the following durations will be calculated and summarized using 
Kaplan-Meier method and 95% confidence intervals for the estimated 25%, 50%, and 75% times 
will be presented.
Duration of AEs as dysgeusia and similar terms while on maribavir treatment will be calculated 
as event stop date – event start date + 1. The event start date is the start of the first reported event 
from the AEs as dysgeusia and similar terms while on maribavir treatment. 
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For subjects who had only one reported AE as dysgeusia and similar terms, the event stop date is 
the resolution date of the event or censored at the last dose of maribavir treatment, whichever is 
earlier.
For subjects who had more than one reported AE as dysgeusia and similar terms, the event stop 
date is the resolution date of the last reported event or censored at the last dose date of maribivir 
treatment, whichever is earlier.
Time to resolution of AE as dysgeusia and similar terms when off maribavir treatment will be 
calculated for all subjects with ongoing event at time of last dose of maribavir treatment as the 
event stop date – last dose date +1. For subjects who had one reported AE as dysgeusia and 
similar terms ongoing at time of last dose of maribavir treatment, the event stop date is the event 
resolution date in the off-treatment follow-up period or censored at the last study follow-up date, 
whichever is earlier. For subjects who had more than one reported AE as dysgeusia and similar 
terms ongoing at time of last dose of maribavir treatment, the event stop date is the last event 
resolution date in the off-treatment follow-up period or censored at the last study follow-up date.
6.6.2.2
Time to Resolution of Neutropenia While on Treatment and When Off 
Treatment
An analysis of time to resolution of neutropenia based on grouped adverse event terms will be 
performed.
Time to resolution of Grade 3/4 neutropenia and time to resolution of Grade 2/3/4 neutropenia 
and neutropenia of any grade will be analyzed in a similar manner to the endpoint time to 
resolution of dysgeusia and similar terms.
6.6.2.3
Immunosuppressant Drug Concentration Level Increased
The number and percent of subjects with immunosuppressant drug levels increased will be 
presented for each treatment group. The number of patients with an increased drug concentration 
level of at least  one immunosuppressant drug will be summarized as well as the number of 
patients with increased drug concentrations in each of the following: tacrolimus, sirolimus, 
everolimus and cyclosporine.
6.6.3
Subgroup Analysis of TEAE and AESIs
Subgroup analysis of TEAE and AESI will be prepared for the following subgroups.

Race (white, black or African American, Asian, Others)

Gender (male, female)

Age group
o
≥12 to <18 years of age (adolescents)
o
≥18 to <45 years of age
o
≥45 to <65 years of age
o
≥65 years of age

Enrolling regions (North America, Europe and Asia)

Renal impaired subjects (yes. No) and (none, mild, moderate/severe)
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
Hepatic impaired subjects (yes, no)
The following summaries of TEAEs and AESIs will be provided for the on-treatment period
by treatment groups for the subgroups.
o
Summary of TEAE by preferred term in descending order of frequency for maribavir
treatment group for all the above subgroups.
o
Summary of treatment-emergent SAEs by SOC and preferred term for all above
subgroups excluding Race and Hepatic impaired subjects
o
Summary of TEAEs of special interest by AESI class, preferred term in descending
order of frequency for maribavir treatment group for all above subgroup excluding
Race and Hepatic impaired subjects
All AEs will be presented in a listing. Additional data listings will be presented for SAEs, AEs 
causing discontinuation of study treatment or withdrawal from the study, fatal AEs and AESIs.
6.6.4
Clinical Laboratory Data
The clinical laboratory assessments are described in Section 7.2.3.5 of the study protocol at the 
time points specified in Table 1 and Table 2. Clinical laboratory tests will be performed at a 
central laboratory for all specified time points during the study including baseline. Local 
laboratory results can be used for eligibility and their results must be available prior to 
randomization. Analysis of clinical laboratory variables for hematology, chemistry and urinalysis 
will be based on results from central laboratories, unless otherwise specified. Central laboratory 
data will be summarized by descriptive statistics and presented in a data listing. Local laboratory 
results will be provided in a separate data listings. Laboratory data during the follow-up period 
after initiation of anti-CMV treatment will be flagged in data listings and excluded from 
summaries and plots.
Laboratory data summaries for all parameters with a continuous distribution will be presented for 
each treatment throughout study by visit, change from baseline throughout the study by visit, at 
end of treatment, change from baseline to end of treatment, at end of study and change from 
baseline to end of study. Change from baseline by visit, change from baseline to end of 
treatment, change from baseline to the end of study will also be presented in boxplots.
Additional laboratory summaries for selected parameters to assess bone marrow effects and renal 
toxicity will include summaries of values and change from baseline by visit throughout study 
with corresponding box plots. In these analysis data after treatment discontinuation will be 
summarized by weeks since treatment discontinuation. 
To evaluate bone marrow effects:

Hemoglobin

Leukocytes

Lymphocytes

Neutrophils

Platelets

Reticulocytes
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To evaluate renal toxicity:

Creatinine

Urea nitrogen
o
Furthermore, the summary and box plots for creatinine and urea nitrogen
at baseline and last on treatment will be repeated by renal impairment
(none, mild, moderate/severe) at baseline
A summary of clinically significant (yes/no) laboratory (hematology, chemistry, and urinalysis) 
results as determined by the study investigator by treatment group for the on-treatment period 
and the overall study period.
The following hematology and chemistry laboratory results will be graded according to the 
NCI-CTCAE version 4.03 or higher.

Hematology: ANC, Hgb, platelet, WBC, ALC

Chemistry: Serum sodium, potassium, glucose, creatinine, calcium, phosphorus,
magnesium, uric acid, creatinine phosphokinase, total bilirubin, ALT, AST,
gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total cholesterol,
triglycerides
Shift tables showing the shift in NCI CTC toxicity grades from baseline to maximum grade 
post-baseline for the on-treatment period and the overall-study period will be provided reflecting 
the toxicity trend in the course of treatment by treatment group.
Additionally, the number and percentage of subjects with shifts in laboratory results from lower 
grade to maximum grade of either 3 or 4 post-baseline for the on-treatment period and the 
overall-study period will be provided by treatment group. Specifically for ANC, the number and 
percentage of subjects with shifts in laboratory results from lower grade to a maximum grade of 
3 (ANC <1000/mm3 [0.5×109/L]), to a maximum grade of 4 (ANC <500/mm3 [1.0×109/L]) in 
addition to a maximum grade of either 3 or 4 post-baseline for the on-treatment period and the 
overall-study period by treatment group will be provided. (See also Section 6.5.3.6). For 
creatinine a shift analysis from a lower grade to maximum grade of 2, 3 or 4 post baseline will be 
performed.
Furthermore, the time to maximum grade for those subjects who have experienced shifts in 
laboratory results including ANC, Hgb, platelet, WBC, ALC and creatinine from lower grade to 
maximum grade of 3 or 4 post-baseline will be evaluated. The time to the first episode of shift 
from lower grade at baseline to either grade of 3 or 4 post-baseline for the on-treatment period 
and the overall-study period will be summarized using descriptive statistics by treatment group. 
For creatinine an analysis of time from a lower grade to a maximum grade of 2, 3 or 
4 post-baseline will be presented.
6.6.5 
Vital Signs
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, pulse rate, 
temperature and body weight) and their changes from baseline at each post-baseline visit and at 
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the end of study will be presented by treatment group. Baseline will be defined as the last 
assessment before the first dose of study treatment.
Vital sign values will be considered potentially clinically important (PCI) if they meet  the 
observed value criteria or the change from baseline criteria listed in Table 5. The number and 
percentage of subjects with PCI post-baseline values will be tabulated by study period and 
treatment group.. A supportive listing of subjects with post-baseline PCI values will be provided 
including the subject number, site, baseline, and post-baseline PCI values. 
Table 5
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign Parameter
Criteria
Observed Value
Change from Baseline
Systolic blood pressure
(mmHg)
<90
≥140
≥160
Diastolic blood pressure (mmHg)
<60
≥90
≥100
Pulse rate
(beats per minute)
≤50
≥100
≥120
Weight (kg)
-
Increase of 7%
-
Decrease of 7%
Temperature (°C)
<35.0 
>39.0
All vital signs data will be listed for the Safety Set.
6.6.6 
Electrocardiogram (ECG)
A 12-lead ECG will be performed at Visit 2/Day 0, Visit 10/Week 8 (end of treatment visit), 
Visit 18/Week 20 (end of study visit), and at any additional time during the study, if clinically 
indicated. ECG data will include heart rate, RR duration, PR duration, QT duration, QRS 
duration. The corrected QT interval (QTc) will be calculated using the Fridericia’s formula. The 
investigator will be responsible for providing the interpretation for all ECGs in terms of clinical 
significance to the subject. Summary of investigator’s interpretation of the ECG results will be 
provided. 
In addition, ECG variable values will be considered potentially clinically significant (PCS) if 
they meet or exceed the upper limit values listed in Table 6. The number and percentage of 
subjects with post-baseline PCS values will be tabulated by treatment group for the on-treatment 
period and the overall study period. The percentages will be calculated relative to the number of 
subjects with available non-PCS baseline and at least 1 post-baseline assessment. The numerator 
is the total number of subjects with at least 1 PCS post-baseline ECG value. A listing of all 
subjects with post-baseline PCS values will be provided including the subject number, site, 
baseline, and post-baseline PCS values.
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Table 6
Criteria for Potentially Clinically Significant ECG Values
ECG Parameter
Criteria
Observed Value
Heart Rate
(bpm)
≤50
≥100
QRS Interval (msec)
≥200
QRS Duration (msec)
≥120
QTcF (msec)
≥450 and <480
≥480 and <500
≥500
QTcF (msec) change from 
baseline
≥30 and <60
≥60
PR interval (msec)
>200
bpm: beat per minute; msec: millisecond
6.6.7
Other Safety Data
Physical examinations will be performed at timepoints specified in the Schedule of Events in the 
study protocol (Table 1 and Table 2) according to standard practices at the investigational site. 
Abnormalities identified at the screening visit (Visit 1) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit 1) 
will be captured as AEs on the AE CRF page, as deemed clinically relevant by the investigator. 
Physical examinations performed will be provided in a data listing. 
6.6.8
Extent of Exposure
Exposure to study treatment will be summarized in terms of exposure duration and number of 
doses for the Safety Set. Study treatment administration will be recorded on the drug 
administration eCRF and eDiary. The dose adjustment and dose interruption for study drugs will 
be collected on the eCRF. Available data collected on eCRF and eDiary will be used in assessing 
the treatment exposure. It is noted that eDiary malfunction due to issues such as device or 
internet connection has been reported during the study resulting in some data loss. 

Exposure duration will be calculated as the number of days from the date of first dose of
study drug to the date of the last dose of study treatment plus 1.

Actual exposure days to study drug will be calculated as the number of days on which at
least 1 dose of study drug was taken. Given the known eDiary issue, the actual exposure
days will be calculated in the following two ways to assess the impact of the eDiary
issue:
1. Determine the number of days on which at least 1 dose of study drug was taken based
on available eDiary data
2. Determine the number of days on which at least 1 dose of study drug was taken based
on available eDiary data; for subjects with no eDiary record, the exposure duration on
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which at least 1 dose of study drug was taken will be based on exposure duration 
minus the number of days with dose withheld as recorded on the eCRF

Total number of doses taken will be calculated as the cumulative number of doses taken
as recorded on the eDiary.
The measures of exposure (exposure duration, actual exposure days) will be summarized using 
descriptive statistics (n, mean, standard deviation, minimum, median, and maximum) and will be 
reported by treatment group.
The number and percent of subjects with dose change, type of change, and reason for change as 
recorded on the eCRF will be provided. Study treatment dose adjustment, specifically 
valganciclovir dose adjustment, and interruptions for neutropenia or renal function impairment or 
other AE, and maribavir dose interruptions for any AE, will be summarized. The assessment of 
missing eDiary entry in comparison to dose withheld as recorded in eCRF will be provided in a 
data listing by subject.
All drug exposure and compliance information, study drug administrations including dose 
change, type of change, and reason of change as recorded on eCRF and dose administration as 
recorded in eDiary will be presented chronologically by subject in data listings.   
6.6.9
Measurement of Treatment Compliance
The treatment compliance is defined as the number of actual exposure days divided by the 
exposure duration days multiplied by 100. 
The dosing compliance is defined as the total number of doses taken divided by the expected 
number of doses multiplied by 100. The expected number of doses is calculated as the 4 tablets 
(morning and evening) multiplied by the actual exposure days.  
Treatment compliance and dosing compliance will be summarized using descriptive statistics (n, 
mean, standard deviation, minimum, median, and maximum) by treatment group for the Safety 
Set. Treatment compliance will also be performed excluding subjects who missed at least 50% of 
doses during at least one weekly visit. The proportion of patients with at least 80% treatment 
compliance ,who took study treatment at least 80% of planned study treatment days (adjusting 
for dose interruptions according to the protocol) prior study treatment discontinuation (either at 
Week 8 or early treatment discontinuation) will be summarized by treatment group.
Dose adjustment and interruptions of Valganciclovir is allowed based on ANC and Creatinine 
Clearance as outlined in Table 7 of the study protocol as well as for adverse events. Only 
one dose of maribavir is used in the study. In order to maintain the blinding sham dose 
adjustments are performed in the maribavir group. Dose interruptions due to adverse events is 
allowed for both valganciclovir and maribavir.
The following summaries for dose adjustment and dose interruption will be provided:

Dose adjustment:
o
The number and percentage of subjects with dose change at least once, and
number of times
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o
The number and percentage of subjects with dose adjustment (increased,
decreased, frequency change) at least once, and number of times
o
The number of subjects with dose change, the number of subjects who have dose
adjustment due to intolerance at least once, and number of times

Dose interruption:
o
The number and percentage of subjects with at least one interruption, total
number of interruption, and reason of interruption.
6.7
Pharmacokinetic and Pharmacodynamic Analyses
6.7.1
Pharmacokinetic Analysis
All summaries and analyses of the PK data will be based on the PK Set and adolescent PK Set as 
applicable. Analyses of the PK data may be performed using the supportive PK set if there is 
more than 10% difference in the number of subjects between the PK Set and Supportive PK Set.
For logistic reasons, PK data collected in Chinese subjects may be available at a later time than 
other countries. A separate data package (tables, figures, and listings) may be generated for 
Chinese PK data once available. 
6.7.1.1
Drug Concentration
In adult subjects of at least 18 years old, who received maribavir treatment, sparse blood samples 
at pre-dose (Cmin) and 2 to 4 hour post-dose administration at Week 1, Week 4, and Week 8 will 
be collected. For subjects ≥16 to <18 years of age, an intensive PK sampling (pre-dose, 1, 2, 3, 
4,6, 8, and 12 hours post-dose) will be performed at Week 1 and sparse PK sampling similar to 
adults (≥18 years) will be performed at Week 4 (pre-dose only) and Week 8 (pre-dose and 2 to 
4 hour post-dose). Unscheduled sparse PK samples will also be collected upon the diagnosis of 
GI GVHD during treatment phase. PK samples will be analyzed for the determination of plasma 
maribavir concentrations. Any pre-dose or post-dose PK samples that were collected post dosing 
or prior to dosing, respectively, will be included in the PK concentration dataset and PK 
concentration listings, but will be excluded from estimating PK parameters and PK concentration 
summaries.
It is noted that eDiary has malfunctioned during the study resulting in some loss of dosing date 
and time data. Some of the plasma maribavir concentrations are impacted because of the lack of 
actual time relative to dosing. It is noted that remediation by having the dosing date and time 
recorded at the site when drawing the PK samples has been implemented when the issue was 
confirmed. To evaluate the impact due to the eDiary malfunction, two sets of plasma maribavir 
concentrations will be constructed. The primary plasma maribavir concentration dataset will 
include all plasma maribavir concentrations, where impacted plasma maribavir concentrations 
will have the actual time imputed with nominal time according to the sparse sampling or 
intensive sampling schedule (primary concentration dataset) due to missing dosing date and time 
after eDiary malfunction. The impacted maribavir concentrations will be evaluated individually 
to confirm the appropriateness of this method, where a previous dosing pattern and/or the central 
tendency of actual time data distribution may be examined. A secondary plasma maribavir 
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concentrations dataset will include the subset of plasma maribavir concentrations where actual 
time are confirmed with the available dosing data (secondary concentration dataset).  
6.7.1.2
Handling Below Lower Limit of Quantitation Values
The following procedures will be used for plasma concentrations below the lower limit of 
quantification (LLOQ):

Samples that are below LLOQ are treated as zero in the calculation of summary statistics
(e.g. mean, SD, etc.) for the plasma concentrations at individual time points. In boxplots
for which median, Q1 and Q3 are presented, samples that are below LLOQ are treated as
1/2 LLOQ.

Mean concentrations are reported as zero if all values are below LLOQ, and no
descriptive statistics are reported. If the calculated mean (±SD) concentration is less than
the LLOQ, the value will be reported as calculated. The mean values derived using these
conventions will be used to create the mean plasma concentration versus time plots.

For calculation of area under the plasma concentration curve (AUC), below LLOQ values
are set equal to zero in the dataset loaded into WinNonlin for pharmacokinetic analysis.
WinNonlin uses the zero values that occur before the first time point with a concentration
greater than LLOQ, but WinNonlin excludes the zero values from the AUC calculation
for all later time points.

Missing concentration data will not be imputed.
6.7.1.3
Analysis of Pharmacokinetic Endpoints
Maribavir concentrations will be listed by subject, visit, planned sampling time, and actual 
sampling time for all subjects including adolescent subjects. Planned pre-dose PK sample which 
were collected at post-dose time will be included in the listing with flag and excluded from 
summary statistics. Additionally, a by-subject listing of maribavir concentrations in subjects with 
confirmed GVHD will be generated. A by-subject listing of week 8 viremia response and 
recurrence during the treatment phase will be generated for subjects with pre-dose maribavir 
concentration below LLOQ at one or more PK visits. Maribavir concentrations will be 
summarized by visit and nominal time using descriptive statistics (number of observations [n], 
mean, SD, coefficient of variation (%CV), geometric mean, %CV of the geometric mean, 
median, maximum, minimum) using the PK Set (primary concentration dataset). Nominal time 
of 0 hour will be assigned for pre-morning dose samples, and for the 2 to 4 hours post morning 
dose sample, a nominal time based on the central tendency of actual time data distribution will 
be used. This summary will be repeated using the adolescent PK Set. If there are less than (≤) 
3 observations in the adolescent PK set, only n, minimum, and maximum will be presented. This 
summary will also be repeated using the secondary concentration dataset as well as the 
Supportive PK Set as a sensitivity analysis to assess the impact of both eDiary malfunction and 
protocol deviations. 
A scatter plot of all reportable maribavir concentration vs. actual sampling time will be generated 
using the primary concentration dataset and the secondary concentration dataset by using the PK 
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Set. This will be repeated using the adolescent PK Set. If there are less than 3 observations in the 
adolescent PK set, only n, minimum, and maximum will be presented.  
Cmin will be listed and summarized by visit using the PK Set. Planned pre-dose PK samples 
which were collected at post-dose time will not be used in Cmin estimations.
Average Cmin will be calculated for each subject using pre-dose maribavir concentration values at 
Week 1, Week 4, and Week 8 and a listing will be provided. This will be repeated separately 
using the adolescent PK Set if it has ≥3 subjects. For each adolescent subject, AUC(0-tau), Cmax, 
Tmax, CL/F, and Vz/F at week 1 will be listed. Summary (number of observations, mean, SD, 
coefficient of variation, median, maximum, minimum, geometric mean, and coefficient of 
variation of geometric mean) will be provided. If there are less than (<) 3 observations, only n, 
minimum, and maximum will be presented for the PK parameters. Box plot of average Cmin by 
confirmed CMV viremia clearance response at Week 8 for all subjects will be provided.
6.7.1.4
Population PK and PK/PD Analysis
In a separate analysis and report, maribavir concentrations will be analyzed by population 
pharmacokinetic modeling (PopPK) using nonlinear mixed effect model approach with 
NONMEM v7 or above. Impact of subject demographics (e.g. age, gender, race and body
weight) and other risk factors (e.g. hepatic impairment, renal impairment, concurrent 
medications, subject population) on model parameters will be evaluated. Post hoc maribavir PK 
parameters such as AUC, Cmax, and Cmin will be generated and summarized by identified 
covariates and subject demographics and characteristics of interest. This analysis may be 
conducted by combining maribavir PK data from other Phase 1, Phase 2 and Phase 3 studies. 
 
 
 
If needed, an interim population PK analysis of maribavir PK data obtained from the study 
subjects will be performed. Interim population PK analysis will be performed by an independent 
unblinded team or CRO who will have no involvement in the conduct of the study. Results from 
this analysis will not be shared with any members of the study team until after database lock. 
Rules governing this process are detailed in the sponsor’s (or designee’s) standard operating 
procedures.
6.8
6.8.1
 
 
 
 
 
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6.8.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.9
6.10
Interim Analyses
No formal interim analysis for efficacy will be performed. 
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
An independent data monitoring committee (DMC) is established to act in an expert, advisory 
capacity for periodic assessment of the data to monitor participant safety and to ensure the 
validity and scientific merit of the trial.
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7.
REFERENCES
Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable 
RR, Miller V, Griffiths PD, 2016. Clinical Infectious Diseases, 64, 87–91
 
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8.
CHANGES TO PROTOCOL PLANNED ANALYSES
This statistical analysis plan is developed based on the analyses specified in the DATA 
MANAGEMENT AND STATISTICAL METHODS section of protocol amendment 8.
 A 
sensitivity analysis of the primary efficacy endpoint using multivariate regression in the protocol 
was removed from the SAP.  
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9.
APPENDIX
9.1
Study Schedule 
The study schedule tables refer to the SHP620-302 protocol:
Table 1: Schedule of Assessment 1: Screening Phase and Study Treatment Phase
Table 2: Schedule of Assessment 2: Follow-up Phase
9.2
Data Handling Conventions 
9.2.1
Repeated or Unscheduled Assessments of Safety Parameters
It is possible that repeat or unscheduled assessments are made for some safety variables (e.g., 
clinical laboratories, vital signs, and ECGs, etc.).
If a subject has repeated assessments before the start of study assigned treatment, then the results 
from the most recent assessment prior to the start of study assigned treatment will be used as 
baseline. If end of study assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics.
However, all post-baseline assessments will be used for PCS value determination and all 
assessments will be presented in the data listings.
9.2.2
Handling of Missing, Unused, and Spurious Data
9.2.2.1
Missing Date of Investigational Product
When the date of the last dose of study assigned treatment is missing for a subject in the safety 
set, all efforts should be made to obtain the date from the investigator. If it is still missing after 
all efforts, then the last visit date when study assigned treatment was returned will be used in the 
calculation of treatment duration.
9.2.2.2
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)
For prior or concomitant medications, or procedure, incomplete (i.e., partially missing) start date 
and/or stop date will be imputed. When the start date and the stop date are both incomplete for a 
subject, impute the start date first.
9.2.2.2.1
Incomplete Start Date
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
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Missing Day and Month

If the year of the incomplete start date is the same as the year of the date of the first dose
of investigational product, then the day and month of the date of the first dose of
investigational product will be assigned to the missing fields

If the year of the incomplete start date is before the year of the date of the first dose of
investigational product, then December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the date of the first dose of
investigational product, then 01 January will be assigned to the missing fields.
Missing Month Only

The day will be treated as missing and both month and day will be replaced according to
the above procedure.
Missing Day Only

If the month and year of the incomplete start date are the same as the month and year of
the date of the first dose of investigational product, then the day of the date of the first
dose of investigational product will be assigned to the missing day

If either the year is before the year of the date of the first dose of investigational product or
if both years are the same, but the month is before the month of the date of the first dose of
investigational product, then the last day of the month will be assigned to the missing day

If either the year is after the year of the date of the first dose of investigational product or
if both years are the same, but the month is after the month of the date of the first dose of
investigational product, then the first day of the month will be assigned to the missing day.
9.2.2.2.2
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of investigational product is missing, then replace it with the last treatment visit date. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date.
Missing Day and Month

If the year of the incomplete stop date is the same as the year as of the date of the last dose
of investigational product, then the day and month of the date of the last dose of
investigational product will be assigned to the missing fields

If the year of the incomplete stop date is before the year of the date of the last dose of
investigational product, then 31 December will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the date of the last dose of
investigational product, then 01 January will be assigned to the missing fields.
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Missing Month Only

The day will be treated as missing and both month and day will be replaced according to
the above procedure.
Missing Day Only

If the month and year of the incomplete stop date are the same as the month and year of
the date of the last dose of investigational product, then the day of the date of the last dose
of investigational product will be assigned to the missing day

If either the year is before the year of the date of the last dose of investigational product or
if both years are the same, but the month is before the month of the date of the last dose of
investigational product, then the last day of the month will be assigned to the missing day

If either the year is after the year of the last dose of investigational product or if both years
are the same, but the month is after the month of the date of the last dose of investigational
product, then the first day of the month will be assigned to the missing day.
9.2.2.3
Missing Date Information for Adverse Events 
For AEs with partial start dates, non-missing date parts will be used to determine if the AE is 
treatment-emergent or not. If a determination cannot be made using the non-missing date parts as 
to when the AE occurred relative to study drug administration, e.g. AE start year and month are 
the same as the year and month of the first dose of investigational product, then the AE will be 
classified as treatment-emergent.
To facilitate categorization of AEs as treatment emergent, imputation of dates can be used. For 
AEs, the default is to only impute incomplete (i.e., partially missing) start dates. Incomplete stop 
dates may also be imputed when calculation of the duration of an AE is required per the protocol. 
If imputation of an incomplete stop date is required, and both the start date and the stop date are 
incomplete for a subject, impute the start date first.
AE with incomplete start date will be imputed following the same rule as described above for 
incomplete start date for the concomitant medications. 
AE with incomplete stop date will be imputed following the same rule as described above for 
incomplete stop date for the concomitant medications. 
9.2.2.4
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while both the actual and the imputed values will be used in data listings.
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9.2.2.5 
Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned. The imputed 
values for relationship to double-blind investigational product will be used for incidence 
summaries, while both the actual and the imputed values will be presented in data listings. 
9.2.2.6 
Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable. The appropriately 
determined coded value will be used in the statistical analysis. However, the actual values as 
reported in the database will be presented in data listings. Some illustrative examples are 
provided below. Table A1 is not comprehensive. 
Table A1 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables 
Clinical Laboratory Test 
Possible Results (in SI units) 
Coded Value for Analysis 
Chemistry:  ALT 
<5 
0 
Chemistry:  AST 
<5 
0 
Chemistry:  Total Bilirubin 
<1.6 
0 
Urinalysis:  Glucose 
≥55 
Positive 
≤0 
Negative 
Urinalysis:  pH 
≥9.0 
9.0 
 
9.2.3 
Definition of Visit Windows 
For the purpose of providing analyses by study visit, visit windows will be assigned based on the 
study day (i.e., the number of days from the first dose of study drug).  Thus the grouping of data 
by study visit is accomplished based on the calendar date of the assessment at which the data are 
obtained rather than the nominal study visit for which the assessment was conducted. Visit 
windows for various variables are defined in the tables in this section based on schedules 
assessments.  
Note: Study Day visit windows for data analysis purposes are not the same as protocol specified 
visit windows for the purpose of scheduling clinical assessments of subjects; in general the data 
analysis visit window corresponding to a specific study visit is larger than the clinical assessment 
visit window. References in this document to “visit window”. 
Baseline or treatment onset is defined as the last measurement on or prior to the first dose date of 
study-assigned treatment during the study. For the purpose of visit  windowing study day is 
determined as the date of the assessment minus the date of the first dose for treated patients and 
the date of the assessment minus randomization date for randomized patients who were not 
dosed with study drug. 
For the purpose of analysis of visit summaries, the week on study (Study Week 0 through Study 
Week 20) for all data on treatment phase and follow-up phase will be determined based on the 
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analysis visits. Visit windows are described in the window below. If two or more measurements 
end up in one week with some taken on or before the start of alternative anti-CMKV treatment, 
the last  measurement taken on or prior to the start date of alternative anti-CMV treatment within 
the window will be used for the summary by week. If all measurements within a window occur 
after the initiation of alternative anti-CMV treatment the last visit within the window will be 
chosen for the analysis visit. Flags for measurements taken after the start of alternative anti-
CMV treatment will be created and readings after the start of alternative anti-CMV treatment 
will not be used in analyses when appropriate. Assessments done on or before the first study 
treatment administration are considered baseline. 
The following table describes the windowing for assessments that are scheduled to be collected 
at baseline, weekly for Week 1 through Week 12, Week 14, Week 16, Week 18 and Week 20 
(CMV DNA test, 
Note that  this visit windowing is not used to obtain 
the primary and confirmatory samples for the primary efficacy outcome (Section 6.5.1.1).
Analysis Visit
FROM 
TO
Week 0
-x
0
Week 1
1
9
Week 2
10
16
Week 3
17
23
Week 4
24
30
Week 5
31
38
Week 6
39
45
Week 7
46
52
Week 8
53
59
Week 9
60
66
Week 10
67
73
Week 11
74
80
Week 12
81
90
Week 14
91
104
Week 16
105
118
Week 18
119
132
Week 20
133
  146
Three observation periods are defined for safety analyses:
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
The on-treatment period starts at the time of study treatment initiation through 7 days after
the last dose of study treatment. For subjects who transfer from the study treatment to a
non-study anti-CMV treatment, the on-treatment period starts at the time of the study
treatment initiation through 7 days after the last dose of study treatment, or until the
non-study anti-CMV treatment initiation, whichever is earlier.

The follow-up period starts one day after the end of the on-treatment period through the end
of the study.

The overall-study period starts at the time of the start of the study treatment through the end
of the study.
Safety endpoints will be summarized descriptively for the on-treatment period and overall-study 
period. Baseline assessments will be the last assessment before the first dose of study treatment. 
For each safety variable, the last value collected before the first dose of study treatment will be 
used as baseline for all analyses of that safety variable. The last valid assessment obtained after 
baseline during the on-treatment period will be defined as the last value on treatment. The last 
valid assessment obtained after baseline during the overall-study period will be defined as the 
last value on study.
The  following table describes the windowing during the treatment phase  for hematology, and 
chemistry that are scheduled to be collected at baseline, weekly for Day 4, Week 1 through 
Week 8, Week 10, Week 12, Week 16 and Week 20.
Analysis Visit
FROM 
TO
Week 0
-x
0
Day 4
1
5
Week 1
6
9
Week 2
10
16
Week 3
17
23
Week 4
24
30
Week 5
31
38
Week 6
39
45
Week 7
46
52
Week 8
53
63
Week 10
64
77
Week 12
78
90
Week 16
91
104
Week 20
133
146
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9.2.4 
Derivation of Maintenance for Secondary Endpoints
Patients must be free of CMV symptoms throughout a period in order classify as response 
maintenance.
For secondary outcomes (b) and (c) of Section 6.5.3, to determine the virological response 
maintenance at Week 12, all the following conditions need to be satisfied: 
1. Viremia clearance achieved at Week 8
2. No two consecutive positives before Week 12
3. Evidence of maintenance around Week 12, meaning one of the following must be true:
a. Week 12 is negative, or
b. If Week 12 is missing, but Week 14 (or unscheduled visit after Week 12) is negative, or
c. If Week 12 is positive, both Week 11 (or unscheduled visit prior to week 12) and Week 14
(or unscheduled visit after Week 12) must be negative
4. No alternative anti-CMV therapy through Week 12
Additionally, to determine the virological response maintenance at Week 16, all the following 
conditions need to be satisfied: 
1. Viremia clearance achieved at Week 8
2. Virological response maintenance at Week 12; this clarifies the amount of missingness
permitted
3. No two consecutive positives before Week 16
4. Evidence of maintenance around Week 16, meaning one of the following must be true:
a. Week 16 is negative, or
b. If Week 16 is missing, but Week 18 (or unscheduled visit after Week 16) is negative, or
c. If Week 16 is positive, both Week 14 (or unscheduled visit prior to week 16) and Week 18
(or unscheduled visit after Week 16) must be negative
5. No alternative anti-CMV therapy through Week 16
Moreover, to determine the virological response maintenance at Week 20, all the following 
conditions need to be satisfied: 
1. Viremia clearance achieved at Week 8
2. Virological response maintenance at Week 16; this clarifies the amount of missingness
permitted
3. No two consecutive positives before Week 20
4. Week 20 is negative
5. No alternative anti-CMV therapy through Week 20
9.2.5
Baseline for Efficacy and Safety Endpoints
Baseline or treatment onset is defined as the last measurement on or prior to the first dose date of 
study-assigned treatment during the study (Visit 2/Day 0).
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9.3
Analysis Software 
Statistical analyses will be performed using Version 9.2 (or newer) of SAS® on a suitably 
qualified environment.
Pharmacokinetic analysis will use WinNonlin Phoenix version 6.3 or higher (Pharsight 
Corporation, Mountain View, California, USA).  
Statistical analyses will be performed using Version 9.2 (or newer) of SAS® on a suitably 
qualified environment.
Pharmacokinetic analysis will use WinNonlin Phoenix version 8.0 or higher (Pharsight 
Corporation, Mountain View, California, USA). 
9.4
Changes from the Previous Version of the SAP
SAP Section 
Impacted Text 
(shown in bold)
Change 
Rationale for Change
Section 3.2
The NI analysis testing will 
be performed on the per 
protocol set (PP Set), 
superiority analysis will be 
performed on the Modified 
Randomized Set. 
The primary analysis for both NI 
and superiority testing will be 
performed in the Modified 
Randomized Set. Both NI and 
superiority analyses will also be 
performed in the per protocol (PP 
Set) as supportive
Address regulatory 
feedback
Section 6.5.1.2 
A descriptive analysis and listing of 
reasons for non-response for the 
primary outcome was added.
Address regulatory 
feedback
Section 6.5.1
Sensitivity analysis 9 for the 
primary endpoint added: analysis 
treating subjects with confirmed 
viremia clearance at the time of 
early treatment discontinuation as 
responders
Address regulatory 
feedback
Section 6.5.1
Sensitivity analysis 10 for the 
primary endpoint added: analysis 
treating subjects who receive 
alternative anti-CMV treatment or 
discontinue the study prior to week 
8 with confirmed viremia clearance 
at the time of alternative anti-CMV 
treatment initiation or early study 
discontinuation as responders.
Address regulatory 
feedback
Section 6.5.1
Sensitivity analysis 12 for the 
primary endpoint added; analysis 
treating subjects with confirmed 
viremia clearance at the time of 
early treatment discontinuation for 
reasons other than adverse event or 
death as responders, while treating 
subjects with early treatment 
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feedback
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SAP Section  
Impacted Text  
(shown in bold) 
Change  
Rationale for Change 
discontinuation due to adverse 
events or death as non-responders  
Section 6.5.3.6 
Analysis of time to neutropenia of 
any grade removed. 
Because many patients 
have neutropenia at 
study entry it was 
decided that the 
analysis of time to 
Grade 3 neutropenia 
and the analysis of 
time Grade 3 or 4 
neutropenia is 
sufficient. 
Section 6.6.1 
Exposure adjusted AE analysis 
added 
The information will 
be valuable in 
assessing the safety of 
study treatment 
Section 6.6.2 
Exposure adjusted AESI analysis 
added 
The information will 
be valuable in 
assessing the safety of 
study treatment 
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