Clinical trial NCT05137717
Conditions: Cytomegalovirus (CMV)
Sponsor: Takeda
Start date: 2022-01-18; Completion date: 2023-06-27
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aim of the study is to check if maribavir can treat Japanese people with Cytomegalovirus (CMV) infection, and to check side effect from the study treatment and how much maribavir participants can take without getting side effects from it.

Japanese recipients of a hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) will take Maribavir tablets two times a day for 8 weeks in this study.

During the study, participants will visit their study clinic 18 times as a maximum.

Detailed description:

Arms: arm 1: Maribavir 400 milligrams (mg), tablets, orally twice a day (BID) for up to 8 weeks.
Interventions: intervention 1: Maribavir
Intervention descriptions: intervention 1: Maribavir tablets

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
NCT Number: NCT05137717 
Title: A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, Safety, and 
Pharmacokinetics of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection 
in Japanese Recipients of a Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ 
Transplant (SOT) 
Study Number: TAK-620-3001 
Document Version and Date: Amendment 1/ 28-Oct-2021 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


Protocol:
TAK-620-3001
Title:
A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, 
Safety, and Pharmacokinetics of Maribavir for the Treatment of 
Cytomegalovirus (CMV) Infection in Japanese Recipients of a 
Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ Transplant 
(SOT)
Short Title:
Open-label, Single-Arm Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of Maribavir in the Treatment of CMV Infection in 
HSCT or SOT Recipients
Study Phase:
Phase 3
Acronym:
N/A
Drug:
Maribavir
IND Number:
Non-IND
EUDRACT
Number:
Non-EUDRACT
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
Principal / 
Coordinating 
Investigator:
Multicenter study
Protocol History:
Amendment 1 (Version 2.0): 28 Oct 2021
Original Protocol (Version 1.0): 26 Jul 2021
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TAK-620
Clinical Study Protocol: TAK-620-3001 Amendment 1
28 Oct 2021
Protocol Amendments
Summary of Change(s) Since the Last Version of the Approved Protocol
Original Protocol:
26 Jul 2021
Amendment Date:
28 Oct 2021
Global/Region/Country/Site 
Specific:
Japan
Description of Each Change and Rationale
Section(s) Affected by Change
“To assess treatment-emergent breakthrough CMV infections and 
resistance mutations.” was removed from secondary objectives and “To 
evaluate the recurrence of CMV viremia during study treatment and in the 
follow-up period after the subject is discontinued from study treatment.” 
was added. Accordingly, “The genotypic characterization of breakthrough 
infections while on maribavir treatment and CMV resistance mutations 
recurrences after maribavir treatment.” was removed from the secondary 
endpoints and “Recurrence of CMV viremia during study treatment and in 
the follow-up period after the subject is discontinued from study 
treatment” was added.
Section 1.1 Synopsis, Section 3.1.2, 
Section 3.2
HIV testing has been modified to be available at a local laboratory as well 
as central laboratory.
Section 1.1 Synopsis, Table 1
footnote k, Section 5.2, 
Section 8.1.1.1, Appendix 2
Specified the dose of maribavir per dose.
Table 4
Table 6 “Common Excluded Treatments and Associated Washout Period” 
was modified including footnotes.
Section 6.6.4
Modified the description of prohibited concomitant medications.
Section 6.6.4
Modified the description of prohibited treatment to match the revised 
footnote in Table 6.
Section 8.1.1
Added “CMV history” to be specified as an item to be collected at 
Screening Visit.
Section 8.1.1.1
Modified the description of screen failure as follows:
A screen failure is a subject who has given informed consent and failed to 
meet the inclusion except No.4 and/or met at least 1 of the exclusion 
criteria and has not been administered the study treatment. However, 
subjects who were excluded based on the exclusion criteria of low platelet 
count, hemoglobin, and low neutrophil counts or liver or renal parameters 
can be retested once within the 14-day screening period at the 
investigator’s discretion when other inclusion criteria are fulfilled. 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 trial.
Section 8.1.1.1
Modified the description of CMV genotyping as follows:

CMV DNA test: Cytomegalovirus quantification in the plasma
samples taken at each visit of study treatment phase will be
conducted at central specialty laboratory. Cytomegalovirus
genotyping by the central specialty laboratory to assess for mutations
in the UL97, UL27, and UL54 genes will be conducted at Visit
2/Study Week 0/Day 0 (Baseline). After Visit 2, CMV genotyping
will be assessed in every sample that meets the criteria specified in
the resistance analysis plan (see Section 8.2.2.2).
Section 8.1.2
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Clinical Study Protocol: TAK-620-3001 Amendment 1
28 Oct 2021
Protocol Amendments
Summary of Change(s) Since the Last Version of the Approved Protocol
Original Protocol:
26 Jul 2021
Amendment Date:
28 Oct 2021
Global/Region/Country/Site 
Specific:
Japan
Description of Each Change and Rationale
Section(s) Affected by Change
Modified the wording of “recurrence or the CMV viremia recurrence” to 
“confirmed recurrence or the confirmed CMV viremia recurrence” for 
clarity.
Section 1.1 Synopsis, 
Section 8.2.2.1
Modified the description of CMV genotyping and phenotyping included in 
the efficacy endpoints to match the protocol of Study SHP620-302.
Section 1.1 Synopsis, 
Section 8.2.2.2
Modified the definition of rebound as follows:
Rebound is defined as increase in viral DNA load for >1 log10 above nadir 
without prior clearance of viremia.
Section 1.1 Synopsis, 
Section 8.2.2.2
Replaced “exploratory” to “secondary” and modified as follows:
Of note, the similarity between SHP620-302 study and Japan study will be 
based on both the primary endpoint and secondary endpoints.
Section 1.1 Synopsis, Section 9.3
Modified the description of efficacy analyses.
Section 1.1 Synopsis, Section 9.5
Added “Baseline safety analyses is defined as the last value for the 
assessment prior to taking the first dose of study treatment.”
Section 1.1 Synopsis, Section 9.6
Added the list of CMV mutations known to confer resistance to 
valganciclovir, and other commercially available anti-CMV agents as 
Appendix 6.
Appendix 6
Minor editorial revisions (including changes for consistency and clarity) are not described in this 
table.
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EMERGENCY CONTACT INFORMATION
When a serious adverse event (SAE) occurs through the adverse event (AE) collection period it 
should be reported according to the following procedure: 
An SAE should be reported by the investigator to the sponsor/the Emergency Reception Center 
for Safety Information (ERCSI) (see Protocol Annex) within 24 hours of the first awareness of 
the event, along with any relevant information. The investigator should submit the detailed SAE 
form to the sponsor/the ERCSI appropriate personnel (see Protocol Annex) within 10 calendar 
days. The information should be completed as fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious

Subject identification number

Investigator’s name

Name of the study drug

Causality assessment
The investigator should submit the original copy of the SAE form to the sponsor.
Any SAE spontaneously reported to the investigator following the AE collection period should
be reported to the sponsor if considered related to the study participation.
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to the sponsor within 24 hours. If requested, defective product(s) will be returned to 
the sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to the sponsor licensed or investigational products, received in writing, electronically, or orally, 
which indicates an impact to a product’s strength, identity, safety, purity, or quality, or which 
suggests that the product did not meet the criteria defined in the regulatory applications, licenses, 
or marketing authorizations for the product. Examples of investigational product quality 
complaints include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use
missing

Label illegible

Incomplete, inaccurate, or
misleading labeling

Lot number or serial number
missing
Packaging

Damaged packaging (eg, 
secondary, primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within
package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Product Quality Complaint Data 
Collection Form” via the email address:
Telephone number (provided for reference if needed):
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE........................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.....................3
EMERGENCY CONTACT INFORMATION .....................................................................6
PRODUCT QUALITY COMPLAINTS................................................................................7
TABLE OF CONTENTS ........................................................................................................8
LIST OF IN-TEXT TABLES ...............................................................................................12
LIST OF IN-TEXT FIGURES .............................................................................................12
LIST OF APPENDICES .......................................................................................................12
1. PROTOCOL SUMMARY ................................................................................................13
1.1 Synopsis........................................................................................................................13
1.2 Schema .........................................................................................................................23
1.3 Schedule of Activities..................................................................................................24
2. INTRODUCTION..............................................................................................................30
2.1 Indication and Current Treatment Options.............................................................30
2.2 Product Background and Clinical Information .......................................................31
2.2.1 Pharmacokinetics, Metabolism, and Drug-Drug Interactions.........................32
2.2.2 Efficacy..................................................................................................................34
2.2.3 Safety .....................................................................................................................37
2.3 Study Rationale ...........................................................................................................39
2.4 Benefit/Risk Assessment.............................................................................................40
2.5 Compliance Statement................................................................................................40
3. OBJECTIVES AND ENDPOINTS ..................................................................................41
3.1 Study Objectives..........................................................................................................41
3.1.1 Primary Objective ................................................................................................41
3.1.2 Secondary Objectives ...........................................................................................41
3.2 Study Endpoints ..........................................................................................................42
4. STUDY DESIGN................................................................................................................44
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4.1 Overall Design .............................................................................................................44
4.2 Scientific Rationale for Study Design........................................................................46
4.3 Justification for Dose ..................................................................................................47
4.4 Duration of Subject Participation and Study Completion Definition....................48
4.5 Sites and Regions.........................................................................................................48
5. STUDY POPULATION ....................................................................................................49
5.1 Inclusion Criteria ........................................................................................................49
5.2 Exclusion Criteria .......................................................................................................50
5.3 Restrictions ..................................................................................................................51
5.4 Reproductive Potential ...............................................................................................51
5.4.1 Female Contraception..........................................................................................51
5.4.2 Male Contraception..............................................................................................53
6. STUDY INTERVENTION................................................................................................54
6.1 Investigational Product...............................................................................................54
6.1.1 Identity of Investigational Product .....................................................................54
6.1.2 Blinding the Treatment Assignment...................................................................54
6.2 Administration of Investigational Product...............................................................54
6.2.1 Interactive Response Technology for Investigational Product Management.54
6.2.2 Allocation of Subjects to Treatment ...................................................................54
6.2.3 Dosing ....................................................................................................................54
6.2.4 Unblinding the Treatment Assignment ..............................................................55
6.2.5 Dose Modification.................................................................................................55
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product..............55
6.3.1 Labeling.................................................................................................................55
6.3.2 Packaging ..............................................................................................................55
6.3.3 Storage...................................................................................................................55
6.4 Drug Accountability....................................................................................................56
6.5 Subject Compliance ....................................................................................................57
6.6 Prior and Concomitant Therapy ...............................................................................57
6.6.1 Prior Treatment....................................................................................................58
6.6.2 Concomitant Treatment.......................................................................................59
6.6.3 Permitted Treatment............................................................................................59
6.6.4 Prohibited Treatment...........................................................................................61
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL .......................................................................62
7.1 Discontinuation of Study Treatment.........................................................................62
7.2 Reasons for Discontinuation ......................................................................................62
7.3 Withdrawal from the Study .......................................................................................63
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit............................63
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8. STUDY ASSESSMENTS AND PROCEDURES............................................................64
8.1 Study Periods...............................................................................................................64
8.1.1 Screening Period...................................................................................................64
8.1.1.1 Screening Visit (Visit 1/Study Week -2/Day -14 to Day 0) .........................64
8.1.2 Study Treatment Period.......................................................................................66
8.1.3 Follow-up Period ..................................................................................................68
8.1.4 Additional Care of Subjects after the Study......................................................69
8.2 Study Assessments.......................................................................................................69
8.2.1 Demographic and Other Baseline Characteristics ............................................69
8.2.1.1 Height and Weight.........................................................................................69
8.2.1.2 Medical and Medication History..................................................................70
8.2.2 Efficacy..................................................................................................................71
8.2.2.1 CMV DNA Quantitation (CMV infection) ..................................................71
8.2.2.2 CMV Genotyping and Phenotyping.............................................................71
8.2.2.3 CMV Infection Symptomatic Assessment ...................................................72
8.2.2.4 Graft Outcomes..............................................................................................73
8.2.2.5 Graft-versus-host-disease (GVHD) Assessments ........................................73
8.2.2.6 Comorbidity Status........................................................................................74
8.2.3 Safety .....................................................................................................................74
8.2.3.1 Physical Examination ....................................................................................74
8.2.3.2 Adverse Events...............................................................................................75
8.2.3.3 Vital Signs.......................................................................................................75
8.2.3.4 Clinical Laboratory Tests..............................................................................75
8.2.3.5 Pregnancy Test...............................................................................................76
8.2.3.6 Electrocardiogram.........................................................................................76
8.2.4 Other......................................................................................................................76
8.2.4.1 Clinical Pharmacology...................................................................................76
8.2.4.2 Pharmacodynamics........................................................................................77
8.2.4.3 Genetics...........................................................................................................77
8.2.4.4 Health-related Quality of Life.......................................................................77
8.2.4.5 Healthcare Resource Utilization...................................................................77
8.2.5 Volume of Blood to Be Drawn from Each Subject............................................77
9. STATISTICAL CONSIDERATIONS .............................................................................78
9.1 Statistical Analysis Process.........................................................................................78
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee...78
9.3 Sample Size and Power Considerations....................................................................78
9.4 Statistical Analysis Sets...............................................................................................79
9.5 Efficacy Analyses.........................................................................................................80
9.5.1 Primary Efficacy Endpoint..................................................................................80
9.5.2 Secondary Efficacy Endpoints.............................................................................82
9.5.3 Pharmacokinetic Analyses...................................................................................83
9.6 Safety Analyses............................................................................................................83
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10. REFERENCES.................................................................................................................85
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LIST OF IN-TEXT TABLES
Table 1. Schedule of Activities 1: Screening Phase and Study Treatment Phase ............24
Table 2. Schedule of Activities 2: Follow-up Phase ............................................................28
Table 3. Objectives and Endpoints.......................................................................................42
Table 4. Study Treatment Dosing-Standard Regimen .......................................................55
Table 5. Prior Medications, Therapies, and Procedures....................................................58
Table 6. Common Excluded Treatments and Associated Washout Period......................61
Table 7. Assessments of Virological Responders at Study Week 8 ...................................81
LIST OF IN-TEXT FIGURES
Figure 1. Study Schematic Diagram.....................................................................................23
LIST OF APPENDICES
Appendix 13 Protocol History.............................................................................................131
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1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-620-3001
Drug: Maribavir
Title of the study: A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, Safety, and 
Pharmacokinetics of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection in Japanese Recipients of 
a Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ Transplant (SOT)
Short title: Open-label, Single-Arm Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Maribavir 
in the Treatment of CMV Infection in HSCT or SOT Recipients
Study phase: Phase 3
Number of subjects:
The study is planned to enroll approximately 44 asymptomatic subjects, and few patients with resistant or 
refractory CMV infection in Japan.
Investigators: 
Multicenter study.
Sites and Region: 
The study will be conducted in approximately 15 study sites in Japan.
Study period (planned): 2021 to 2023
Clinical phase:
3
Objectives:
Primary Objectives:

To evaluate the efficacy of maribavir in CMV viremia clearance at the end of Study Week 8 (8 weeks
after start of administration) in Japanese HSCT or SOT recipients with CMV infection.

To assess the safety and tolerability of maribavir in Japanese transplant recipients with CMV infection.
Secondary Objectives:

To assess the maintenance of CMV viremia clearance and infection symptom control achieved at Study
Week 8 (8 weeks after start of administration) , through Study Week 12 (4 weeks of post-treatment),
Study Week 16 (8 weeks of post-treatment), and Study Week 20 (12 weeks of post-treatment).

To evaluate the time to first confirmed CMV viremia clearance.

To evaluate the recurrence of confirmed CMV viremia requiring treatment during the 12-week
follow-up period in subjects who achieved confirmed viremia clearance at Study Week 8.

To assess the time course of changes in plasma CMV viremia load from Baseline.

To evaluate the recurrence of CMV viremia during study treatment and in the follow-up period after the
subject is discontinued from study treatment.

To assess the profile of mutations in the CMV genes conferring resistance to maribavir.

To assess the CMV viremia clearance at cut-off value of 137 IU/mL at the end of Study Week 8.

To characterize the pharmacokinetics (PK) of maribavir.
 
 
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Rationale:
Immunosuppressive therapies required for successful transplantation lead to an increased vulnerability to severe 
infections, including CMV. The number of patients with HSCT and SOT cases in Japan in 2018 were 5,673 and 
2,427, respectively. In Japan, for HSCT recipients, 1 antiviral (letermovir) is approved for prophylaxis, while 
there are 3 approved antivirals (ganciclovir, valganciclovir, and foscarnet) for the treatment of CMV disease, 
which are also used as preemptive therapy agents in clinical practice. For SOT recipients, valganciclovir is
approved for prophylaxis, while ganciclovir and valganciclovir are approved for CMV disease and are also used 
as preemptive therapy agents. The use of these anti-CMV agents is limited by their toxicities such as 
myelosuppression (ganciclovir and valganciclovir) and renal dysfunction (foscarnet). Clinical studies of 
maribavir to date demonstrate that it is not associated with myelosuppression or renal impairment and may allow 
longer treatment durations at a prescribed dose for patients during prolonged periods of immunosuppression 
following transplantation. The efficacy and safety of maribavir has been evaluated outside of Japan for the 
treatment of CMV infections and disease in resistant/refractory adult transplant recipients in a Phase 3 trial
(completed). In addition, there is an ongoing Phase 3 study in subjects with asymptomatic CMV infection in 
HSCT recipients.
This study is designed to assess the efficacy, safety, and PK of maribavir, administered at 400 mg twice daily
(BID)in Japanese HSCT or SOT recipients with CMV infection, including subjects with symptomatic CMV 
infection who are resistant or refractory to ganciclovir, valganciclovir, or foscarnet.
Investigational product, dose, and mode of administration:
Investigational product:

Maribavir will be provided as a 200 mg tablet (oral tablet) and administered at a dose of 400 mg BID.

No placebo or any active comparator/reference products will be used in the study.
Methodology:
Study TAK-620-3001 is a Phase 3, multicenter, open-label study to evaluate the efficacy, safety and tolerability, 
and PK of maribavir in Japanese HSCT or SOT recipients with CMV infection, including subjects with 
symptomatic CMV infection who are resistant or refractory to ganciclovir, valganciclovir, or foscarnet. The study 
will assess the efficacy of maribavir by measuring the plasma CMV deoxyribonucleic acid (DNA) clearance at 
Study Week 8. To be eligible for the study, subjects must have a documented CMV infection with a screening 
value of >455 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by a 
central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV 
DNA results. Results should be available prior to the first study treatment administration to confirm subject 
eligibility for the study. Both samples should be taken within 14 days prior to first dose of study treatment with 
the second sample obtained within 5 days prior to first dose of study treatment at Visit 2/Day 0. The study will 
have 3 phases: (1) 2-week screening phase; (2) 8-week 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.
“Asymptomatic subjects” are those who do not have CMV tissue-invasive disease or CMV syndrome (SOT 
subjects only) at Baseline, as determined by the investigator according to the criteria specified by Ljungman et 
al., 2017.
“Symptomatic subjects” are those who have CMV tissue-invasive disease or CMV syndrome (SOT subjects 
only) at Baseline, as determined by the investigator according to the criteria specified by Ljungman et al., 2017. 
“Refractory” will be defined as: documentation of failure to achieve >1 log10 (common logarithm to base 10) 
decrease in CMV DNA level in plasma after a 14 day or longer treatment period with intravenous (IV)
ganciclovir/oral valganciclovir, or IV foscarnet. This definition applies to the current CMV infection and the most 
recently administered anti-CMV agent.
“Resistant” will be defined as: documentation of 1 or more CMV genetic mutations associated with resistance to 
ganciclovir, valganciclovir, or foscarnet. 
The documentation of the resistance during screening will be based on the central specialty laboratory genotyping 
assay results. Plasma samples obtained at Baseline for CMV DNA genotyping will be used for the final 
determination of mutations in the UL97, UL27, and UL54 genes known to confer resistance to anti-CMV agent; 
this assessment will be based on the results from the central specialty laboratory and utilized for analysis.
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Screening Phase
Subjects will be screened during an approximate 2-week screening phase which will occur from Day -14 to Day 0 
in which subjects will undergo evaluation to establish eligibility. If applicable, subjects who meet eligibility 
requirements will undergo washout of any prohibited medications, the length of which will be specified in the 
eligibility criteria. Ganciclovir, valganciclovir, and foscarnet must be discontinued prior to the first dose of study 
treatment. Subjects receiving letermovir must discontinue 3 days prior to first dose of study treatment. 
Study Treatment Phase
During the treatment phase (Day 1/Study Week 1 to Day 56/Study Week 8), maribavir will be administered twice 
daily.
Assessments to be performed at weekly study visits during treatment include: CMV DNA quantification testing, 
evaluation of symptoms suggestive of CMV disease, underlying disease assessments, graft outcomes and GVHD 
assessments, resolution or improvement of CMV tissue-invasive disease (symptomatic subjects only), clinical 
laboratory testing (hematology and chemistry), and concomitant medications and adverse event (AE) review. 
Pharmacokinetic sample collection, physical examination, vital sign assessment, electrocardiograms (ECGs), 
immunosuppressive drug level monitoring, and urinalysis will be conducted at selected visits throughout the 
treatment phase. 
Monitoring of concomitant immunosuppressant concentration levels (eg, tacrolimus, cyclosporine, and 
everolimus) will be conducted at designated study time points. Cytomegalovirus DNA genotyping will be 
performed on samples at Baseline and in cases of rebound or lack of response to therapy.
Historical laboratory results for tests may be used for eligibility assessment (human immunodeficiency virus 
[HIV] or hepatitis test results) provided that these 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 study treatment administration and all clinical laboratory results required for eligibility 
verification must be available prior to treatment administration, including 2 separate CMV DNA assessments. 
Initiation of study treatment (ie, first dose) will only occur after completion of all required Visit 2/Day 0 
procedures and confirmation of eligibility. This will be done under the supervision of investigator site personnel.
Depending on the time of the first dose of study treatment at Visit 2/Day 0, a second dose should be administered 
at Visit 2/Day 0 provided that doses can be separated by a minimum of 8 hours; otherwise, only 1 dose should be 
administered at 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.
For subjects that, in the investigator’s judgment, have a lack of response or are unable to tolerate treatment and
require discontinuation of study treatment, alternative anti-CMV treatment may be administered as deemed
necessary. Subjects who discontinue study treatment prior to Study Week 8 will complete the end of treatment
procedures described for Study Week 8. These subjects will follow a modified Schedule of activities (SoA) 
through the remaining weekly visits of the study treatment phase and regular SoA through the 12-week follow-up 
phase.
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 
the protocol for a complete list of the evaluations.
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Study Design Flow Chart
CMV DNA Quantitation
Blood samples will be assessed at a central specialty laboratory for the quantification of CMV DNA in plasma
using the qPCR. Central specialty laboratory plasma CMV DNA results will be reported to the investigator site as 
available. Additional CMV DNA testing at central specialty laboratory may be performed and collected at more 
frequent intervals, or additional assay methods may be used 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) to be determined depending on the selected 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 to be determined depending on the selected central specialty laboratory in 2 consecutive 
plasma samples at least 5 days apart, after attaining viremia clearance.
CMV Genotyping and Phenotyping
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 the subjects, it is not possible to wait for this central specialty 
laboratory assessment prior to a subject’s study treatment administration to confirm lack of resistance to any 
previously used agents. For asymptomatic subjects, 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.
During the study, CMV genotyping will be conducted at the central specialty laboratory when the CMV DNA 
viral load is above a predefined cut off level: in cases of failure to clear CMV viremia during treatment; cases of 
recurrence of viremia on and off treatment; and cases of viremia rebound if >1 log10 above nadir while on 
treatment (Rebound is defined as increase in viral DNA load for >1 log10 above nadir 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.
Additionally, virus susceptibility testing (phenotyping) could be performed on selected de-novo CMV 
mutations/variants of maribavir-treated subjects by recombinant phenotyping to define the association of these 
mutations with anti-CMV drug resistance. Details of the analysis would be specified in a resistance analysis plan.
CMV Infection Symptomatic Assessment
Cytomegalovirus tissue-invasive disease will be defined as described by Ljungman et al., 2017. The gold 
standard for diagnosing CMV tissue-invasive disease is the identification of CMV inclusions in the infected cells 
of the tissues OR identification of CMV in biopsy tissue samples. However, in some cases both diagnostic 
methods are required when tissue samples have a high chance of being contaminated by body fluids that shed 
virus (bronchoalveolar lavage [BAL], urine or stool). In some subjects, when it is not possible to obtain a tissue 
biopsy, a culture of CMV from body fluids or CMV DNA quantitation (for selected cases) may be used to 
confirm diagnosis, with a lower level of confidence in diagnosis. CMV syndrome (in SOT subjects only) will also 
be defined as described by Ljungman et al., 2017, and requires at least 2 of 6 signs and symptoms to be present.
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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All subjects will be monitored for the occurrence of CMV tissue-invasive disease and CMV syndrome throughout
the study. For symptomatic subjects who present with CMV tissue-invasive disease and CMV syndrome at 
Baseline, the investigator will document the initial diagnosis of CMV tissue-invasive disease and CMV syndrome 
at Visit 2/Day 0 (ie, absence or presence at Baseline) and all serial assessments of infection status (ie, no change, 
improvement, worsening, or resolution) at all subsequent visits in the study. 
The recurrence of symptomatic CMV infection will be defined as the presence of signs or symptoms of the CMV
tissue-invasive disease or CMV syndrome (same or new symptomatology) confirmed as per Ljungman et al., 
2017 after the period of resolution of symptomatic CMV infection in subjects symptomatic at Baseline.
In subjects asymptomatic at Baseline, the occurrence of new CMV tissue-invasive disease or CMV syndrome 
after start of study treatment will be assessed by the investigator at all scheduled study visits.
PK Assessment
Pharmacokinetic samples will be obtained for all subjects. Measurements of plasma samples for PK analysis will 
be conducted while the study is ongoing.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
Subjects must:
1.
Be able to provide written, personally signed, and dated informed consent (and assent where
applicable) to participate in the study before completing any study-related procedures. When subject
is below age of 20, voluntary agreement shall be obtained from a parent/both parents or legally
authorized representative (LAR) using the written consent form.
2.
Be Japanese with Japanese nationality, ≥16 years of age at the time of consent.
3.
Be a recipient of HSCT or SOT that is functioning at the time of Screening.
4.
Have a documented CMV infection with a screening value of >455 IU/mL in plasma in
2 consecutive assessments, separated by at least 1 day, as determined by a central specialty
laboratory qPCR or comparable quantitative CMV DNA results. Both samples should be taken
within 14 days prior to first dose of study treatment with the second sample obtained within 5 days
prior to first dose of study treatment at Visit 2/Day 0.
5.
Have the current CMV infection after HSCT or SOT, either primary or reactivation, which, in the
investigator’s opinion, requires treatment and have any of the following.
a.
Asymptomatic subjects: The subjects do not have CMV tissue-invasive disease or CMV
syndrome (SOT subjects only) at Baseline, as determined by the investigator according to the
criteria specified by Ljungman et al., 2017.
b.
Resistant or refractory subjects: The subjects must have a current CMV infection that is
refractory to the most recently administered of the anti-CMV treatment agent(s). Refractory is
defined as documented failure to achieve >1 log10 (common logarithm to base 10) decrease in
CMV DNA level in plasma after a 14 day or longer treatment period with IV ganciclovir/oral
valganciclovir, or IV foscarnet.
6.
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 ≥1,000/mm3 (1.0 × 109/L)
b.
Platelet count ≥25,000/mm3 (25 × 109/L)
c.
Hemoglobin ≥8 g/dL
d.
Estimated creatinine clearance ≥30 mL/minute (estimated glomerular filtration rate by
Modification of Diet in Renal Disease)
7.
Have a negative serum human chorionic gonadotropin (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
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protocol, during the study treatment administration period and for 90 days after the last dose of 
study treatment.
8.
Be able to swallow tablets.
9.
Have life expectancy of ≥8 weeks.
10. Weigh ≥40 kg.
11. 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 central nervous system (CNS) CMV tissue-invasive disease or CMV retinitis as assessed by
the investigator at the time of Screening and prior to administration at Visit 2/Day 0.
2.
Be receiving valganciclovir, ganciclovir, foscarnet, or letermovir when study treatment is initiated,
or anticipated to require 1 of these agents during the 8-week treatment period.
NOTE: Subjects receiving letermovir must discontinue 3 days prior to first dose of study treatment.
Ganciclovir, valganciclovir, and foscarnet must be discontinued prior to the first dose of study
treatment.
3.
Have known hypersensitivity to the active substance or to an excipient of the study treatments.
4.
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.
5.
Require mechanical ventilation or vasopressors for hemodynamic support at the time of Baseline.
6.
Pregnant or nursing female.
7.
Have previously completed, discontinued, or have been withdrawn from this study.
8.
Have received any investigational agent (including CMV-specific T-cells) with known anti-CMV
activity within 30 days before initiation of the study treatment at any time.
9.
Have received any unapproved agent or device within 30 days before initiation of the study
treatment.
10. 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 maribavir, or
compromise the safety or well-being of the subject.
11. Have previously received maribavir.
12. 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 × ULN
at Screening (except for documented Gilbert’s syndrome), as analyzed by local or central laboratory.
13. Have known (previously documented) positive results for HIV. Subjects must have a confirmed
negative HIV test result within 3 months of study entry or, if unavailable, be tested by a local or
central laboratory during the screening period.
14. 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 or SOT was performed), as determined by the investigator, are not to be enrolled.
15. Be undergoing treatment for acute or chronic hepatitis C.
Duration of subject participation in the study:

Planned duration of Screening Phase: 2 weeks.

Planned duration of Study Treatment Phase: 8 weeks.

Planned duration of Follow-up Phase: 12 weeks.
The study will be completed in approximately 17 months.
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Statistical Analysis:
Subject Populations:

Enrolled Set: consists of all subjects who have signed an informed consent and have begun some
study procedures.

Full Analysis Set: consists of all subjects who have taken at least 1 dose of study treatment; the
Full Analysis Set will be used for efficacy analyses.

Per-Protocol Set: consists of all subjects in Full Analysis Set who do not have major predefined
protocol deviations that may affect the primary efficacy assessment.

Safety Set: consists of all subjects who have taken at least 1 dose of study treatment. The Safety
Set will be used for safety analyses.

Pharmacokinetic Set: consists of all subjects in the Safety Set who had plasma samples drawn and
tested for maribavir concentrations.
Primary Endpoints:
The primary endpoints of this study are: 

Efficacy endpoint: Confirmed clearance of plasma CMV DNA (CMV viremia clearance) at the
end of Study Week 8.

Safety and tolerability assessments: treatment-emergent serious adverse events (SAEs),
treatment-emergent adverse events (TEAEs) (including instances of CMV disease), maribavir
dose interruptions for AEs, maribavir dose discontinuations for AEs, number of subjects with
clinically significant vital signs, number of subjects with abnormal physical examination findings,
number of subjects with abnormal clinical laboratory evaluations, number of subjects with
clinically significant ECG parameters, and concentration of immunosuppressant drug. New onset
of acute or chronic GVHD, graft rejection, or graft loss will be reported and may be assessed as
AE/SAE.
Secondary Endpoints:
Secondary Efficacy Endpoints:

The maintenance of the confirmed CMV viremia clearance and infection symptom control
achieved at Study Week 8 through Study Week 12 (4 weeks of post-treatment period), Study
Week 16 (8 weeks of post-treatment/follow-up phase), and Study Week 20 (12 weeks of
post-treatment).

The time to first confirmed viremia clearance at any time during the study.

The recurrence of confirmed CMV viremia during the 12-week follow-up period in subjects with
confirmed viremia clearance at Study Week 8 requiring additional anti-CMV treatment.

The time course of changes in plasma CMV viremia load from Baseline by study week.

Recurrence of CMV viremia during study treatment and in the follow-up period after the subject
is discontinued from study treatment.

Assessment of the profile of mutations in the CMV genes conferring resistance to maribavir.

Confirmed plasma CMV DNA at the end of Study Week 8 to be less than 137 IU/mL.
Secondary Pharmacokinetic Endpoint:

Maribavir Cmin (predose maribavir concentration)
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Statistical Methodology:
All analyses will be descriptive.
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 to be declared at the end of Study Week 8 during the 
treatment period, the subject must have received study treatment exclusively. Confirmed CMV viremia clearance 
at the end of Study Week 8 is defined as plasma CMV DNA concentrations <LLOQ with the assay at a central 
specialty laboratory, in 2 consecutive postbaseline samples, separated by at least 5 days at Study Week 8. Subjects 
who take alternative anti-CMV treatment before Study Week 8 or have missing data at Study Week 8 due to early 
discontinuation or any other reasons will be counted as nonresponders. 
Assessments of Virological Responders at Study Week 8
Scenario
CMV DNA Weeks on Study
Rationale
Week 6
Week 7
Week 8
Week 9a
Response
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; DNA=deoxyribonucleic acid; LLOQ=lower limit of quantification; NA=not available 
for evaluation of study drug effect; reason could be either not assessable by lab, by starting alternative anti-
CMV treatment, 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 
“+” = 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.
The proportion of subjects achieving the confirmed CMV viremia clearance at Study Week 8 and the corresponding
95% confidence intervals (CIs) will be calculated.
Other secondary efficacy endpoints and exploratory endpoints will be summarized descriptively. The 
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denominator for the percentages will be based on the number of subjects. Time-to-event endpoints will be 
summarized using Kaplan-Meier estimation. Ninety-five percent CIs for the estimated 25%, 50%, and 75% times 
will be presented.
Primary Safety and Tolerability Endpoints: 
Safety and tolerability of maribavir for the treatment of CMV infection after HSCT or SOT will be assessed by 
evaluation of SAEs, TEAEs (including instances of CMV disease), AEs leading to interruptions of study 
treatment, AEs leading to discontinuation of study treatment, AEs leading to withdrawals from the study, number 
of subjects with clinically significant vital signs, number of subjects with abnormal clinical laboratory 
evaluations, number of subjects with clinically significant ECG parameters, and number of subjects with 
abnormal physical examination findings. New onset of acute or chronic GVHD, graft rejection, or graft loss will 
be reported and may be assessed as AE/SAE. Immunosuppression drug levels will be summarized over time.
Two observation periods are defined for the purpose of safety analyses: 1) On-treatment period: from the time of
maribavir initiation through 7 days after the last dose of study treatment, and 2) Overall-study period: start of
maribavir administration through the end of the study. 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 the study treatment.
Treatment-emergent AEs 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 the study treatment but increasing in severity after the first dose of 
study treatment.
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical investigation subject who 
has signed informed consent to participate in a study but prior to administration of any study drug; it does not 
have a causal relationship with study drug. The PTEs will not be evaluated in the safety analysis; they will be 
listed as pretreatment AEs.
The number of events, incidence, and percentage of TEAEs will be displayed by preferred terms (PTs) using the 
Medical Dictionary for Regulatory Activities (MedDRA®) for the on-treatment period and overall-study period. 
Summaries in terms of severity and relationship to the study treatment will also be provided. Treatment-emergent 
SAEs will be summarized separately in a similar fashion. Summaries of AEs leading to interruptions of study 
treatment, discontinuation of study treatment, withdrawals, AEs leading to death, and SAEs will be provided.
Adverse events will be analyzed according to primary system organ classes (SOCs) and PTs. Summary tables 
with SOCs and PTs will be generated presenting the number and percentage of subjects by AE, severity, 
seriousness, and relationship to the study treatment for the on-treatment period and overall-study period. 
Usage of concomitant medications will be summarized descriptively for the on-treatment period and 
overall-study period. Additionally, administration of hematopoietic growth factors, blood, and blood products 
will be summarized.
Baseline safety analyses is defined as the last value for the assessment prior to taking the first dose of study 
treatment. Change from Baseline in vital signs and clinical laboratory tests during on-treatment period and 
overall-study period will be summarized with descriptive statistics at each assessment visit. Potentially clinically 
important findings will also be summarized.
Maribavir dose interruptions for any AE will be summarized. Abnormal physical examination findings will be
listed. A summary of electrocardiogram findings will be provided.
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PK Analysis:
The pharmacokinetic endpoint for this study is maribavir Cmin.
Individual maribavir plasma concentrations data will be presented in a listing. Maribavir Cmin (predose maribavir 
concentration) will be summarized by Visit using descriptive statistics.
In a separate analysis and report, all maribavir concentrations obtained in this study will be combined with PK 
data from the Phase 1, Phase 2 and Phase 3 studies in adults conducted outside Japan, and analyzed by population 
PK analysis approach using a nonlinear mixed effect model approach using NONMEM Version 7 or above.
Sample Size Justification: 
Post-transplant (SOT/HSCT) CMV infection is a rare condition and the number of patients expected to participate 
in this clinical trial in Japan is anticipated to be limited. For the start of domestic development of TAK-620, 
Takeda conducted a feasibility assessment for the planned clinical study. Specifically, a survey on the number of 
patients in university or large hospitals in Japan where HSCT or SOT are performed was carried out. The number 
of patients with asymptomatic CMV infection was estimated to be about 44 for HSCT and about 9 for SOT, for a 
total of about 53 patients. Assuming a dropout rate of 15%, approximately 44 patients with asymptomatic CMV 
infection are expected to be enrolled. On the other hand, the number of patients with resistant or refractory CMV 
infection is very small, and only a few patients (approximately 3) can be expected to be enrolled at the maximum.
From the standpoint of feasibility, approximately 44 asymptomatic patients and few resistant or refractory 
patients are expected to be enrolled in this study. 
The target number of patients with asymptomatic CMV infection should be determined from the viewpoint of 
evaluating the similarities in outcome between the prospective study and the overseas Phase III study (Study 
SHP620-302) as well as the feasibility of the new study.
For the proportion of patients who achieved CMV clearance at Week 8 in the TAK-620 group in Study 
SHP620-302, since the results have not been available, we can assume 68%, which was used as the estimation for 
sample size justification in Study SHP620-302. Regarding the proportion of patients who achieved CMV 
clearance at Week 8 in this study, since it is the same target population and primary endpoint as Study 
SHP620-302, it is appropriate to assume 68% as Study SHP620-302.
In addition, we considered it appropriate to use -15% as a reference value for the difference in the point estimate 
between studies based on the noninferiority margin used in 2 noninferiority studies comparing valganciclovir and 
ganciclovir for CMV treatment (The study reported by Chawla et al., 2012 and VICTOR study [Asberg et al., 
2007]).
With a sample size of 44 in asymptomatic patients, if the true response rates for this study is the same as that of 
the Study SHP620-302, the probability of observing a response rate similar to that of the Study SHP620-302 is 
high, that is, over 95% the point estimate from this study will be above the point estimate of Study SHP620-302
minus 15%.
Of note, the similarity between SHP620-302 study and Japan study will be based on both the primary endpoint 
and secondary endpoints.
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1.2 Schema
Figure 1. Study Schematic Diagram
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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1.3 Schedule of Activities
Table 1. Schedule of Activities 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phase
Study Treatment Phasea
Study Visit 
1
2
2Ab
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Week
-2 to 0
0
1b
1
2
3
4
5
6
7
8
Study Day (permitted window)c
-14 to 0
0d
4 
(±1)
7 
(+2)
14 
(±2)
21 
(±2)
28
(±2)
35 
(±3)
42 
(±3)
49 
(±3)
56
(±3)
Informed consente
X
Inclusion/exclusion criteria
X
X
Physical examinationf
X
X
X
Height
X
Weight
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Medical history
X
Xg
Prior medications, therapies, and 
procedures
X
X
12-lead ECGh
X
X
Hematology/Chemistryi
X
X
X
X
X
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
Pregnancy testj
X
X
X
X
HIV statusk
X
HBV, HCV test
Xl
CMV DNA testm
X
X
X
X
X
X
X
X
X
X
CMV infection symptomatic 
assessmentn
X
X
X
X
X
X
X
X
X
X
X
Immunosuppressant drug 
concentration levelso
X
X
X
X
PK plasma samplesp
X
X
X
Interactive Response Technologyq
X
X
X
X
X
X
X
X
X
Study treatment dispensedr
X
X
X
X
X
X
X
X
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Table 1. Schedule of Activities 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phase
Study Treatment Phasea
Study Visit 
1
2
2Ab
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Week
-2 to 0
0
1b
1
2
3
4
5
6
7
8
Study Day (permitted window)c
-14 to 0
0d
4 
(±1)
7 
(+2)
14 
(±2)
21 
(±2)
28
(±2)
35 
(±3)
42 
(±3)
49 
(±3)
56
(±3)
Underlying disease assessments
X
X
X
X
X
X
X
X
X
X
Graft outcomest
X
X
X
X
X
X
X
X
X
X
GVHD assessment (for HSCT 
subjects only)
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 proceduresu
X
X
X
X
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
X
X
X
X
X
X
AE=adverse event; CMV=cytomegalovirus; CRF=case report form; DNA=deoxyribonucleic acid; ECG=electrocardiogram; GI=gastrointestinal; 
GVHD=graft-versus-host-disease; HBV=hepatitis B virus; HCV=hepatitis C virus; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; 
HSCT=hematopoietic stem cell transplant; IRT=interactive response technology; PK=pharmacokinetic; qPCR=quantitative polymerase chain reaction; SAE=serious adverse 
event, SoA=schedule of activities. 
a
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 SoA through the remaining weekly visits scheduled for the study treatment phase and the regular SoA 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 study treatment phase: dispense or use 
of study treatment, and PK plasma sample collection. After completing the 8-week duration specified for the study treatment phase, subjects will enter the 12-week follow-up 
phase.
b
Immunosuppressant drug concentration testing and Visit 2A are solely for subjects receiving immunosuppressive therapy with tacrolimus, cyclosporine, or everolimus. 
Visit 2A will occur at Day 4±1 day for subjects receiving immunosuppressive agent at Baseline; or 4±1 day after initiating 1 of these immunosuppressive treatments for 
subjects who start during the study. 
c Permissible assessment windows: Visit 2A, ±1 day, Visit 3 (Study Week 1) +2 days, Visit 4 (Study Week 2) to Visit 6 (Study Week 4), ±2 days; Visit 7 (Study Week 5) to 
Visit 10 (Study Week 8), ±3 days.
d
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 initiation of the 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, and confirmation of eligibility. This will be done under the supervision of investigator’s site 
personnel.
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Table 1. Schedule of Activities 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phase
Study Treatment Phasea
Study Visit 
1
2
2Ab
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Week
-2 to 0
0
1b
1
2
3
4
5
6
7
8
Study Day (permitted window)c
-14 to 0
0d
4 
(±1)
7 
(+2)
14 
(±2)
21 
(±2)
28
(±2)
35 
(±3)
42 
(±3)
49 
(±3)
56
(±3)
e
Informed consent must be obtained before any study-specific procedures are performed, and the first informed consent can be obtained more than 14 days prior to Day 0. If 
over 14 days have passed since the first informed consent date, it must be obtained again before starting study treatment. 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, and 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 with a screening value of >455 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as 
determined by a central specialty laboratory qPCR or comparable quantitative CMV DNA results. Results should be available before the subject is administered study 
treatment to verify subject eligibility for the study. Both samples should be taken within 14 days prior to first dose of study treatment administration with the second sample 
obtained within 5 days prior to first dose of study treatment administration. 
f
Symptom-oriented physical examinations other than protocol-specified examinations will be performed when clinically indicated. 
g
Updated medical history at Visit 2/Day 0.
h
Electrocardiograms other than protocol-specified ECGs will be performed when clinically indicated.  
i
Central clinical laboratory tests will be performed for all specified time points during the study with the exception of Visit 2A (for subjects receiving tacrolimus, 
cyclosporine, or everolimus); a local laboratory 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 initiation of the study treatment. Local laboratory hCG test 
results can be used for the assessment of pregnancy at Visit 2/Day 0/Study Week 0, prior to study treatment administration. Sample for hematology/chemistry/pregnancy will 
be taken for analyses by the central laboratory before study treatment administration at Baseline.
j
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.  
k
Human immunodeficiency virus status confirmed within 3 months prior to eligibility assessment 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 or central 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 study treatment 
administration.
l
Hepatitis B virus 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 the study treatment administration.
m
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. The 
screening results from the central specialty laboratory will be utilized for eligibility assessment. 
n
Subjects with CMV tissue-invasive disease or CMV syndrome (SOT subjects only) present at Visit 2/Day 0 (Baseline) will have serial assessments at all subsequent visits for 
infection status (no change, improvement, worsening, or resolution of disease/syndrome and associated symptoms) until resolution. All subjects will be assessed at each visit 
for new tissue-invasive disease or CMV syndrome, and any new tissue-invasive disease or CMV syndrome will have serial assessments at all subsequent visits for infection 
status (no change, improvement, worsening, or resolution of disease/syndrome and associated symptoms) until resolution.
o
If the subject is receiving immunosuppressant drugs (tacrolimus, cyclosporine, or everolimus) at Visit 2 (Day 0), then a blood sample to measure immunosuppressant drug
concentration will be obtained at Visit 2 (Day 0) prior to study treatment administration. 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
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Table 1. Schedule of Activities 1: Screening Phase and Study Treatment Phase
Phase
Screening 
Phase
Study Treatment Phasea
Study Visit 
1
2
2Ab
3
4
5
6
7
8
9
10 (End of 
Treatment)
Study Week
-2 to 0
0
1b
1
2
3
4
5
6
7
8
Study Day (permitted window)c
-14 to 0
0d
4 
(±1)
7 
(+2)
14 
(±2)
21 
(±2)
28
(±2)
35 
(±3)
42 
(±3)
49 
(±3)
56
(±3)
immunosuppressant, and at the next scheduled study visit. Tests will be performed at a local laboratory or central laboratory. The results of the measurement of 
immunosuppressant concentration must be recorded on the eCRF.
p
Pharmacokinetic samples will be taken before the morning dose of the study treatment at all 3 PK visits. A PK plasma sample will also be taken 2 to 4 hours after the 
morning dose of study treatment at Visit 3/Study Week 1 and Visit 10/Study Week 8. There will be no postdose PK plasma sample collected for Visit 6/Study Week 4. 
Additional PK plasma samples will be collected from the subjects with biopsy-proven GI GVHD with diarrhea (>300 mL/day), biopsy-proven GI GVHD with nausea and 
vomiting, 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). 
q
The IRT system will be used for dispensing study treatment.
r
All administered/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. 
s
Underlying disease that led to HSCT or SOT, including relapse/progression, will be assessed at all visits throughout the study treatment phase.
t
Graft outcomes (acute rejection or graft loss) will be assessed for both SOT and HSCT subjects.
u
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 Activities 2: Follow-up Phase
Phase
Follow-up Phasea
Visit
11
12
13
14
15
16
17
18 (End 
of Study)
Study Week (Follow-up Week)b
9(1) 
10(2)
11(3)
12(4)
14(6)
16(8)
18(10)
20(12)
Study Day (Follow-up Day), (permitted window)
63(7), 
(±2)
70(14), 
(±2)
77(21), 
(±2)
84(28), 
(±2)
98(42), 
(±3)
112(56), 
(±3)
126(70), 
(±3)
140(84), 
(±3)
Physical examination (including weight)
X
Vital signs
X
12-Lead ECGc
X
Hematology/Chemistryd
X
X
X
X
Urinalysisd
X
Immunosuppressant drug concentration levele
X
Underlying disease assessmentf
X
X
X
X
X
X
X
X
CMV DNA testg
X
X
X
X
X
X
X
X
CMV infection symptomatic assessmenth
X
X
X
X
X
X
X
X
Graft outcomesi
X
X
X
X
X
X
X
X
GVHD assessment (for HSCT subjects only)
X
X
X
X
X
X
X
X
Comorbidity status evaluation
X
X
X
AE monitoringj
X
X
X
X
X
X
X
X
SAE monitoringj
X
X
X
X
X
X
X
X
Concomitant medications, therapies, and proceduresk
X
X
X
X
X
X
X
X
AE=adverse event; CMV=cytomegalovirus; DNA=deoxyribonucleic acid; ECG=electrocardiogram; GVHD=graft-versus-host disease; HSCT=hematopoietic stem cell 
transplant; SAE=serious adverse event; SOT=solid organ transplant. 
a
Subjects who withdraw from the study during the follow-up phase will perform the Visit 18/Study Week 20 (Follow-up Week 12) end of study procedures.
b
Permissible assessment windows: Study Weeks 9 to 12 (Follow-up Weeks 1 to 4) ±2 days; Study Weeks 14 to 20 (Follow-up Weeks 6 to 12) ±3 days.
c
Electrocardiograms other than protocol-specified ECGs will be performed when clinically indicated.
d
Clinical laboratory testing performed at a central laboratory for all specified time points during the follow-up phase.
e
If the subject is receiving immunosuppressant drugs (tacrolimus, cyclosporine, or everolimus) on Study Day 0, then a blood sample to measure immunosuppressant drug 
concentration will be obtained at the Follow-up Week 1 post-treatment follow-up visit (ie, 1 week [±2 days] after discontinuation of study treatment). 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 at the Follow-up Week 1 post-treatment follow-up visit (ie, 1 week [±2 days] after discontinuation of study treatment). Tests will be performed 
at a local laboratory or central laboratory. The results of the measurement of immunosuppressant concentration must be recorded on the eCRF.
f
Underlying disease that led to HSCT or SOT, including relapse/progression, will be assessed at all visits throughout the follow-up phase.
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Table 2. Schedule of Activities 2: Follow-up Phase
Phase
Follow-up Phasea
Visit
11
12
13
14
15
16
17
18 (End 
of Study)
Study Week (Follow-up Week)b
9(1) 
10(2)
11(3)
12(4)
14(6)
16(8)
18(10)
20(12)
Study Day (Follow-up Day), (permitted window)
63(7), 
(±2)
70(14), 
(±2)
77(21), 
(±2)
84(28), 
(±2)
98(42), 
(±3)
112(56), 
(±3)
126(70), 
(±3)
140(84), 
(±3)
g
Blood sample taken at all study visits (processed to obtain plasma), for all CMV DNA tests (quantitation, genotyping) during the follow-up phase will be tested in the central 
specialty laboratory. 
h
Subjects with CMV tissue-invasive disease or CMV syndrome (SOT subjects only) present at Visit 2/Day 0 (Baseline) will have serial assessments at all subsequent visits for
infection status (no change, improvement, worsening, or resolution of disease/syndrome and associated symptoms) until resolution. All subjects will be assessed at each visit 
for new tissue-invasive disease or CMV syndrome, and any new tissue-invasive disease or CMV syndrome will have serial assessments at all subsequent visits for infection 
status (no change, improvement, worsening, or resolution of disease/syndrome and associated symptoms) until resolution.
i
Graft outcomes (acute rejection or graft loss) will be assessed for in both SOT and HSCT subjects.
j
Serious adverse events and nonserious AEs deemed related to the study treatment will be monitored and recorded through Visit 18/Study Week 20/Follow-up Week 12 (end 
of study). Nonserious AEs will be recorded through 30 days after the last dose of study treatment.
k
All medications, therapies, and procedures used to treat AEs will be recorded through Visit 18/Study Week 20/Follow-up Week 12 (end of study). 
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2. INTRODUCTION
2.1 Indication and Current Treatment Options 
Cytomegalovirus (CMV) is a beta herpes virus that commonly infects humans; serologic 
evidence of prior infection can be found in 40% to 100% of various adult populations
(de la Hoz et al., 2002). However, serious disease occurs almost exclusively in individuals with 
compromised immune systems. Cytomegalovirus remains a significant problem for patients 
undergoing various types of transplants that are associated with the use of potent 
immunosuppressive chemotherapy, including hematopoietic stem cell transplants (HSCT) and 
solid organ transplants (SOT) (de la Hoz et al., 2002; Razonable and Emery, 2004). 
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) predominately in patients with HSCT, and associations 
between CMV and graft rejection or other allograft pathology in patients with SOT, and reduced 
patient survival (Rubin, 1989; Hodson et al., 2005; Ljungman et al., 2006). 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.
Cytomegalovirus prevention strategies (prophylaxis or preemptive therapy) for various high-risk 
transplant subjects exist, however, CMV infection or disease can still occur within the early 
(initial approximate 3 months) or later post-transplantation time periods (Boeckh et al., 2003; 
Legendre and Pascual, 2008). Cytomegalovirus viremia is considered 1 of the most important 
predictors of development of CMV disease (Emery et al., 2000; Humar et al., 1999). In kidney 
transplant recipients, the highest incidence of symptomatic CMV infection (syndrome) or disease 
occurs in CMV-seronegative recipients who receive a kidney from a CMV-seropositive donor 
(Paya et al., 1989; Kanj et al., 1996; Singh et al., 2004; Winston et al., 1995).
Although the 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 (not approved in Japan) are generally effective, their use is limited by their respective 
toxicities; bone marrow suppression caused by ganciclovir/valganciclovir and renal impairment 
caused by foscarnet or cidofovir (not approved in Japan) (Boeckh et al., 2003; 
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Ljungman et al., 2001; Reusser et al., 2002; Salzberger et al., 1997). These toxicities are of 
particular concern in transplant patients, in whom the bone marrow has been ablated or 
significantly suppressed (patients with HSCT), who receive ongoing immunosuppressants to 
prevent organ rejection (patients with SOT) or GVHD (in patients with HSCT), or who may 
require the use of other therapies that are potentially toxic to the kidneys or other organs (patients 
with SOT and HSCT).
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 approximate 
3 months) or later post-transplantation time periods (Boeckh et al., 2003; 
Legendre and Pascual, 2008).
In contrast, preemptive strategies are widely preferred as a prevention method by transplant 
centers and include close surveillance of target viral deoxyribonucleic acid (DNA) concentration 
(CMV viremia), which varies depending on host’s risk for CMV disease, current 
immunosuppression, and treatment center practice. Cytomegalovirus viremia is considered 1 of 
the most important predictors of development of CMV disease (Emery et al., 2000; 
Humar et al., 1999). 
In Japan, for HSCT recipients, 1 antiviral (letermovir) is approved for prophylaxis while there 
are 3 approved antivirals (ganciclovir, valganciclovir, and foscarnet) for the treatment of CMV
disease, which are also used as preemptive therapy agents in clinical practice. For SOT recipients
valganciclovir is approved for prophylaxis, while ganciclovir and valganciclovir are approved for 
CMV disease. The use of these anti-CMV agents is limited by their toxicities. Also, development 
of antiviral resistance to these anti-CMV agents is an ongoing clinical problem leading to graft 
loss and even mortality for some transplant patients.
Maribavir is currently under development for the treatment of CMV infection or disease, 
including those resistant or refractory to ganciclovir, valganciclovir, or foscarnet, 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 patients with HSCT.
2.2 Product 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 has a favorable nonclinical and clinical safety 
profile. It is a potent member of a 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 
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ganciclovir 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 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 antiviral (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 and clinically against strains of CMV that are resistant to 
ganciclovir or foscarnet.
2.2.1 Pharmacokinetics, Metabolism, and Drug-Drug Interactions
Results from the Phase 1 studies demonstrated that following oral administration, maribavir was 
rapidly and well absorbed with mean peak plasma concentrations generally achieved between 
1 and 3 hours postdose. After administration of single and multiple doses (both twice daily [BID] 
and 3 times daily regimens) over 28 days, total maribavir plasma concentrations increased with 
increasing dose proportionally up to 1,600 mg (single dose) and 2,400 mg (multiple doses), 
respectively. At dose levels ≥900 mg BID, there was no apparent increase in maximum 
concentration (Cmax) levels. Maribavir demonstrates time-independent pharmacokinetics (PK). 
Pharmacokinetic data obtained in Phase 2 studies were similar to the data observed in healthy 
volunteers. 
Administration of maribavir in conjunction with food resulted in a 28% decrease in Cmax and
prolonged time to maximum concentration from 1.5 hours to 2.0 hours without a significant
effect on area under the concentration-time curve (AUC) when compared with administration 
under fasting conditions. Bioavailability of a 100 mg tablet was unaffected by crushing the tablet 
or changes in gastric pH. Maribavir was bound to plasma proteins, namely human serum 
albumin, lipoproteins, and alpha-1-acid-glycoprotein. The fraction of unbound maribavir was 
estimated at approximately 1.5% in healthy subjects. Following 400 mg BID doses, the 
elimination half-life of maribavir was estimated to be 3.87 hours in healthy subjects and 
4.32 hours in transplant patients based on noncompartmental analysis. Maribavir is metabolized 
primarily in the liver through CYP3A4 pathway with the formation of the primary metabolite, 
VP 44469. Renal clearance is a minor route of elimination of maribavir.
A mass balance study in healthy male and female subjects following administration of a single 
400 mg oral dose of [14C] maribavir resulted in fecal recovery of radiolabel that averaged about 
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14% and recovery of radiolabel in the urine that averaged about 61%. In plasma, the
predominant drug-related species was unchanged maribavir, representing approximately 88% of 
total radioactivity and VP 44469 represented approximately 12% during the first 24 hours.
In vitro studies indicated that CYP3A4 (a hepatic metabolizing enzyme) is the primary enzyme 
involved in the formation of VP 44469 from maribavir; CYP1A2 may also be involved in 
VP 44469 formation. In vitro studies also demonstrated that maribavir is not an inhibitor of 
CYP3A4, CYP2A6, CYP2B6, CYP2C8, CYP2D6, or CYP2E1. It is potentially a weak inhibitor 
of CYP1A2, 2C9, and 2C19. VP 44469 is not an inhibitor of CYP enzymes.
Maribavir is a substrate as well as an inhibitor of P-glycoprotein (P-gp: a transporter protein). 
Clinical studies conducted to evaluate the potential of drug-drug interactions demonstrated the 
following:
•
Concomitant administration of maribavir (400 mg BID) with tacrolimus, a substrate of
CYP3A4 and P-gp, resulted in increased tacrolimus Cmax, AUC, and plasma
concentration at the end of a dosing interval (Ctrough) by 38%, 51%, and 57%,
respectively.
•
Maribavir did not have a clinically significant effect on the activity of CYP1A2, CYP3A,
CYP2C9, CYP2C19 or CYP2D6.
•
Concurrent administration of rifampin, a strong inducer of CYP3A4 and P-gp, and
maribavir significantly reduced plasma concentrations of maribavir, resulting in a 60%
reduction in AUC and 82% reduction in Ctrough, reduced half-life, and significantly
increased clearance, most likely due to induction of hepatic and intestinal CYP3A4, and
potential induction of P-gp.
•
Concomitant administration of antacid had no effect on maribavir exposure.
•
Concomitant administration of ketoconazole increased maribavir AUC and Cmax by 53%
and 10%, respectively.
No clinically relevant impact on maribavir PK related to age (18 to 79 years), sex, race 
(Caucasian, Black, Asian or others), ethnicity (Hispanic/Latino, or non-Hispanic/Latino), or 
weight (36 to 141 kg) were identified based on population PK analysis. Transplant types (eg, 
HSCT versus. SOT) or between SOT types (liver, lung, kidney, or heart) or presence of 
gastrointestinal (GI) GVHD do not impact PK of maribavir.
The effect of renal impairment on maribavir PK was evaluated in a single dose (400 mg) study 
with 12 subjects with normal renal function (creatinine clearance >80 mL/minute), 10 subjects 
with mild/moderate renal impairment (creatinine clearance 30 to 80 mL/minute), and 9 subjects 
with severe renal impairment (creatinine clearance <30 mL/minute). Mean PK parameter
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estimates based on total or unbound plasma drug concentrations for subjects with normal renal 
function, mild/moderate renal impairment, and severe renal impairment were similar. Based on 
the results from this study, renal impairment does not affect the PK of maribavir; dose 
adjustment for subjects with mild to severe renal impairment is not needed. There is no 
experience with the use of maribavir in subjects receiving peritoneal dialysis or hemodialysis. 
Due to the high plasma protein binding of maribavir, dialysis is unlikely to reduce plasma 
concentrations of maribavir significantly.
The effect of hepatic impairment on the PK of maribavir was evaluated in a single dose study 
(200 mg) with 10 subjects with normal hepatic function and 10 subjects with moderate hepatic 
impairment based on a Child-Pugh Class B classification. Moderate hepatic impairment results 
in a modest increase in total plasma maribavir Cmax and AUC values (and modestly reduced 
clearance values) when compared with subjects with normal hepatic function. However, Cmax
and AUC values based on unbound plasma concentrations of maribavir were comparable among 
these groups.
The population PK analysis conducted based on relevant Phase 1, 2 and 3 studies showed that 
the steady-state area under the concentration-time curve from time 0 extrapolated to infinite time 
(AUC0-∞), Cmax, and Ctrough were 27%, 5%, and 70% higher, respectively, in transplant patients
than in healthy subjects likely due to the decreased liver/kidney function in transplant patients 
and their multiple concomitant medications which could impact the disposition of maribavir. The 
apparent differences in exposure between healthy subjects and transplant patients are not 
considered clinically significant. 
2.2.2 Efficacy
Once the safety and tolerability of maribavir was established across a wide range of doses (up to 
2,400 mg/day for 28 days) in 15 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 log10 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 SHP620 (Maribavir)
Investigator’s Brochure Edition 20.0 04Feb21.
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 those that are resistant or refractory to 
currently available anti-CMV therapies. As a result, 2 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 1,200 mg BID. Both studies demonstrated favorable 
anti-CMV activity of maribavir and showed that maribavir was well-tolerated.
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. 
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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 
(≥10,000 copies/mL) was similar between the overall maribavir and valganciclovir groups (34% 
versus 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. 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). 
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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 were planned based on the results from these Phase 2 studies for CMV 
treatment.
The primary objective for the recently completed Study SHP620-303 was to compare the 
efficacy of maribavir to investigator assigned treatment (IAT) in CMV viremia clearance at the 
end of Study Week 8 in transplant recipients who were resistant or refractory to prior 
anti-CMV treatment. Maribavir was superior to IAT in achieving confirmed CMV viremia 
clearance in transplant recipients. The proportion of maribavir-treated subjects who achieved 
confirmed CMV viremia clearance at Week 8 was more than 2-fold higher than subjects who 
received standard-of-care treatment with IAT in the randomized set (maribavir: 55.7%; IAT: 
23.9%).
The key secondary objective of this study was to compare the efficacy of the 2 study treatment 
arms on CMV viremia clearance and CMV tissue-invasive disease and CMV syndrome 
improvement or resolution at the end of Study Week 8, and maintenance of this treatment effect 
through Study Week 16. Forty-four (18.7%) maribavir-treated subjects and 12 (10.3%) subjects 
in the IAT group were responders not only for virologic response, but also for CMV 
infection symptom control at the end of Week 8 and maintained the treatment effect through 
Week 16 (adjusted difference in proportions [95% confidence interval (CI)]: 9.5 [2.02, 16.88], 
p=0.013).
Study SHP620-303 concluded that maribavir was an efficacious treatment for subjects with 
post-transplant CMV infection and disease. The effect of maribavir on viral clearance was 
superior to conventional therapy, demonstrating superiority to IAT in achieving CMV viremia 
clearance at Week 8 in post-transplant recipients with refractory CMV infection, including 
resistant CMV (SHP620-303 [Maribavir] Clinical Study Report).
2.2.3 Safety
Maribavir has been administered across a broad range of oral doses from 50 mg to 2,400 mg/day. 
Clinical safety experience has been obtained from 16 Phase 1 studies in adult healthy volunteers, 
special populations (subjects with renal and hepatic impairment, and stable renal transplant 
recipients), and human immunodeficiency virus (HIV)-infected subjects.
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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 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 SHP620-203), 
subjects received maribavir at 1 of 3 dose strengths: 400, 800, or 1,200 mg BID, and both studies 
demonstrated that maribavir was well-tolerated. 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.
Data from Study SHP620-303 showed that maribavir treatment was not associated with 
treatment-limiting toxicities, in contrast to the currently available anti-CMV therapies. The 
incidence of neutropenia was lower for maribavir-treated subjects than for 
ganciclovir/valganciclovir-treated subjects. Maribavir had a lower incidence of overall 
hematologic TEAEs compared with ganciclovir/valganciclovir (28.2% versus 42.9%). Maribavir 
did not appear to cause nephrotoxicity. The incidence of selected TEAEs associated with renal 
disorders was half the rate for maribavir-treated subjects (15.8%) compared with 
foscarnet-treated subjects (31.9%). The AE profile was consistent across subgroups of subjects 
based on age, sex, race, region, transplant type, resistance (resistant or not resistant), presence or 
absence of symptomatic infection, and presence of renal impairment at Baseline (SHP620-303
[Maribavir] Clinical Study Report).
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 patients with HSCT and 
SOT. 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.
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Refer to the latest version of the maribavir IB (SHP620 [Maribavir] Investigator’s Brochure
Edition 20.0 04Feb21) and clinical study report of SHP620-303 study (SHP620-303 [Maribavir] 
Clinical Study Report) for the most detailed and most current information regarding the drug 
metabolism, PK, efficacy, and safety (including the adverse drug reactions) of maribavir.
2.3 Study Rationale
Immunosuppressive therapies required for successful transplantation lead to an increased 
vulnerability to severe infections, including CMV. The number of patients with HSCT and 
SOT cases in Japan in 2018 were 5,673 and 2,427, respectively (The Japanese Data 
Center for Hematopoietic Cell Transplantation [Internet]. Japan. Annual change in the number 
of reports by transplant type. 2019 [cited 2021 Apr 16]. Available from: 
http://www.jdchct.or.jp/data/report/2019/2-1.pdf.; Japanese society for clinical renal 
transplantation, 2019; The Japanese liver transplantation society, 2019;
The Japanese society for heart transplantation, 2019;
The Japanese pancreas and islet transplantation association working group for pancreas 
transplantation, 2019; The Japanese society of lung and heart-lung transplantation, 2019).
In Japan, for HSCT recipients, 1 antiviral (letermovir) is approved for prophylaxis, while there 
are 3 approved antivirals (ganciclovir, valganciclovir, and foscarnet) for the treatment of CMV 
disease, which are also used as preemptive therapy agents in clinical practice. For SOT 
recipients, valganciclovir is approved for prophylaxis, while ganciclovir and valganciclovir are 
approved for CMV disease and are also used as preemptive therapy agents. The use of these anti-
CMV agents is limited by their toxicities such as myelosuppression (ganciclovir and 
valganciclovir) and renal dysfunction (foscarnet). Clinical studies of maribavir to date 
demonstrate that it is not associated with myelosuppression or renal impairment and may allow 
longer treatment durations at a prescribed dose for patients during prolonged periods of 
immunosuppression following transplantation. 
The efficacy and safety of maribavir has been evaluated outside of Japan for the treatment of 
CMV infections and disease in resistant/refractory adult transplant recipients in a Phase 3 trial
(completed). In addition, there is an ongoing Phase 3 study in subjects with asymptomatic CMV 
infection in HSCT recipients. Study SHP620-303 was recently completed. 
This study is designed to assess the efficacy, safety, and PK of maribavir, administered at 
400 mg BID in Japanese HSCT or SOT recipients with CMV infection, including subjects with 
symptomatic CMV infection who are resistant or refractory to ganciclovir, valganciclovir, or 
foscarnet.
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2.4 Benefit/Risk Assessment
Maribavir is a potent and selective, orally bioavailable benzimidazole riboside antiviral drug 
with a novel mechanism of action against human cytomegalovirus being developed for the 
treatment of CMV infection or disease, including those resistant or refractory to ganciclovir, 
valganciclovir, or foscarnet, in transplant patients.
In 2 Phase 2 treatment studies (SHP620-202 and SHP620-203), maribavir at doses ≥400 mg BID 
was effective in treating CMV infection resistant or refractory to ganciclovir/valganciclovir or 
foscarnet and treatment effect was comparable to valganciclovir in the study of patients with 
asymptomatic CMV infection.
To date, maribavir has been safe and well-tolerated in 1,806 subjects in placebo-controlled 
studies, open-label studies, and in studies that compared maribavir with other CMV therapies 
(ganciclovir and valganciclovir) for prophylaxis and for CMV treatment in transplant 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 and SHP620-303 
treatment study, coupled with acceptable safety and tolerability, establish the positive 
benefit-risk profile and warrant continuation of maribavir development (SHP620 [Maribavir] 
Investigator’s Brochure Edition 20.0 04Feb21).
Refer to the latest version of the IB for the overall benefit/risk assessment and the most accurate 
and current information regarding drug metabolism, PK, efficacy, and safety (including the 
adverse drug reactions) of maribavir.
2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
Title 21 of the US Code of Federal Regulations (US CFR), the European Union Directives 
(2001/20/EC; 2005/28/EC), and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigators are described fully in Appendix 1.
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
•
To evaluate the efficacy of maribavir in CMV viremia clearance at the end of Study
Week 8 (8 weeks after start of administration) in Japanese HSCT or SOT recipients with
CMV infection.
•
To assess the safety and tolerability of maribavir in Japanese transplant recipients with
CMV infection.
3.1.2 Secondary Objectives
•
To assess the maintenance of CMV viremia clearance and infection symptom control
achieved at Study Week 8 (8 weeks after start of administration), through Study Week 12
(4 weeks of post-treatment), Study Week 16 (8 weeks of post-treatment), and Study
Week 20 (12 weeks of post-treatment).
•
To evaluate the time to first confirmed CMV viremia clearance.
•
To evaluate the recurrence of confirmed CMV viremia requiring treatment during the
12-week follow-up period in subjects who achieved confirmed viremia clearance at Study
Week 8.
•
To assess the time course of changes in plasma CMV viremia load from Baseline.
•
To evaluate the recurrence of CMV viremia during study treatment and in the follow-up
period after the subject is discontinued from study treatment.
•
To assess the profile of mutations in the CMV genes conferring resistance to maribavir.
•
To assess the CMV viremia clearance at cut-off value of 137 IU/mL at the end of Study
Week 8.
•
To characterize the PK of maribavir.
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3.2 Study Endpoints
Table 3. Objectives and Endpoints
Objectives
Endpoints
Primary
•
To evaluate the efficacy of
maribavir in CMV viremia
clearance at the end of Study
Week 8 (8 weeks after start
of administration) in
Japanese HSCT or SOT
recipients with CMV
infection.
•
Confirmed clearance of plasma CMV DNA (CMV viremia
clearance) at the end of Study Week 8.
•
To assess the safety and
tolerability of maribavir in
Japanese transplant
recipients with CMV
infection.
•
Safety and tolerability assessments: treatment-emergent SAEs,
TEAEs (including instances of CMV disease), maribavir dose
interruptions for AEs, maribavir dose discontinuations for AEs,
number of subjects with clinically significant vital signs, number of
subjects with abnormal physical examination findings, number of
subjects with abnormal clinical laboratory evaluations, number of
subjects with clinically significant ECG parameters, and
concentration of immunosuppressant drug. New onset of acute or
chronic GVHD, graft rejection, or graft loss will be reported and
may be assessed as AE/SAE.
Secondary
Efficacy Endpoints
•
To assess the maintenance of
CMV viremia clearance and
infection symptom control
achieved at Study Week 8
(8 weeks after start of
administration), through
Study Week 12 (4 weeks of
post-treatment), Study
Week 16 (8 weeks of
post-treatment), and Study
Week 20 (12 weeks of
post-treatment).
•
The maintenance of the confirmed CMV viremia clearance and
infection symptom control achieved at Study Week 8 through Study
Week 12 (4 weeks of post-treatment period), Study Week 16
(8 weeks of post-treatment/follow-up phase), and Study Week 20
(12 weeks of post-treatment).
•
To evaluate the time to first
confirmed CMV viremia
clearance.
•
The time to first confirmed viremia clearance at any time during the
study.
•
To evaluate the recurrence of
confirmed CMV viremia
requiring treatment during
the 12-week follow-up
period in subjects who
achieved confirmed viremia
clearance at Study Week 8.
•
The recurrence of confirmed CMV viremia during the 12-week
follow-up period in subjects with confirmed viremia clearance at
Study Week 8 requiring additional anti-CMV treatment.
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Table 3. Objectives and Endpoints
Objectives
Endpoints
•
To assess the time course of
changes in plasma CMV
viremia load from Baseline.
•
The time course of changes in plasma CMV viremia load from
Baseline by study week.
•
To evaluate the recurrence of
CMV viremia during study
treatment and in the follow-
up period after the subject is
discontinued from study
treatment.
•
Recurrence of CMV viremia during study treatment and in the
follow-up period after the subject is discontinued from study
treatment
•
To assess the profile of
mutations in the CMV genes
conferring resistance to
maribavir.
•
Assessment of the profile of mutations in the CMV genes
conferring resistance to maribavir.
•
To assess the CMV viremia
clearance at cut-off value of
137 IU/mL at the end of
Study Week 8.
•
Confirmed plasma CMV DNA at the end of Study Week 8 to be
less than 137 IU/mL.
Pharmacokinetic Endpoint
•
To characterize the PK of
maribavir.
•
Maribavir Cmin (predose maribavir concentration)
AE(s)=adverse event(s), CMV=cytomegalovirus, Cmin=minimum concentration, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, GVHD=graft-versus-host disease, HSCT=hematopoietic stem cell transplant, 
PK=pharmacokinetic, SAE=serious adverse event, SOT=solid organ transplant, TEAE=treatment-emergent 
adverse event. 
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4. STUDY DESIGN
4.1 Overall Design
This is a Phase 3, multicenter, open-label study to evaluate the efficacy, safety and tolerability, 
and PK of maribavir in Japanese HSCT or SOT recipients with CMV infection, including 
subjects with symptomatic CMV infection who are resistant or refractory to ganciclovir, 
valganciclovir, or foscarnet. The study will assess the efficacy of maribavir by measuring the 
plasma CMV DNA clearance at Study Week 8. To be eligible for the study, subjects must have a 
documented CMV infection with a screening value of >455 IU/mL in plasma in 2 consecutive 
assessments, separated by at least 1 day, as determined by a central specialty laboratory 
quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. 
Results should be available prior to the first study treatment administration to confirm subject 
eligibility for the study. Both samples should be taken within 14 days prior to first dose of study 
treatment with the second sample obtained within 5 days prior to first dose of study treatment at
Visit 2/Day 0. 
As shown in Figure 1, the study will have 3 phases: (1) 2-week screening phase; (2) 8-week 
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: 
As presented in the Schedule of activities (SoA) (Table 1), subjects will be screened from 
Day -14 to Day 0 to establish eligibility for study participation. If applicable, subjects who meet 
eligibility requirements will undergo washout of any prohibited medications, the length of which 
is specified in Table 6.
Study Treatment Phase:
Once all screening assessments following informed consent (and assent where applicable) are 
completed and eligibility is confirmed, the subject will receive maribavir 400 mg BID for 
8 weeks starting at Visit 2/Day 0.
Assessments to be performed at weekly study visits during treatment include: CMV DNA 
quantification testing, evaluation of symptoms suggestive of CMV disease, underlying disease 
assessments, graft outcomes and GVHD assessments, resolution or improvement of CMV 
tissue-invasive disease (symptomatic subjects only), clinical laboratory testing (hematology and 
chemistry), and concomitant medications and AE review. Pharmacokinetic sample collection, 
physical examination, vital sign assessment, ECGs, immunosuppressive drug level monitoring, 
and urinalysis will be conducted at selected visits throughout the treatment phase. 
Monitoring of concomitant immunosuppressant concentration levels (eg, tacrolimus,
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cyclosporine, and everolimus) will be conducted at designated study time points. 
Cytomegalovirus DNA genotyping will be performed on samples at Baseline and in cases 
of rebound, or lack of response to therapy.
Historical laboratory results for tests specified in the SoA (Table 1) may be used for eligibility 
assessment (HIV or hepatitis test results) provided that these 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 study treatment administration and all clinical laboratory 
results required for eligibility verification must be available prior to treatment administration, 
including 2 separate CMV DNA assessments. Initiation of study treatment (ie, first dose) will 
only occur after completion of all required Visit 2/Day 0 procedures and confirmation of 
eligibility. This will be done under the supervision of investigator site personnel. If the baseline 
sample analyzed by central specialty laboratory reports mutation, then the subject will continue 
receiving treatment but will be excluded from the Per-Protocol Set for analysis. 
All subjects will perform study-specific evaluations weekly during the 8-week study treatment 
phase (Table 1).
Depending on the time of the first dose of study treatment at Visit 2/Day 0, a second dose should 
be administered at Visit 2/Day 0 provided that doses can be separated by a minimum of 8 hours; 
otherwise, only 1 dose should be administered at 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.
For subjects that, in the investigator’s judgment, have a lack of response or are unable to tolerate 
treatment and require discontinuation of study treatment, alternative anti-CMV treatment may be 
administered as deemed necessary. Subjects who discontinue study treatment prior to Study 
Week 8 will complete the end of treatment procedures described for Study Week 8 in the SoA. 
These subjects will follow a modified SoA through the remaining weekly visits of the study 
treatment phase and regular SoA through the 12-week follow-up phase.
All subjects who complete the study treatment phase through Visit 10/Study Week 8 will enter 
the 12-week follow-up phase.
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 
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the 12-Week Follow-up Phase. Refer to SoA 2 (Table 2). See Section 7 for details regarding 
discontinuation and withdrawal. 
If a subject is unable to travel to the site for the follow-up visits, AEs and SAEs 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.
4.2 Scientific Rationale for Study Design
This study will assess the efficacy and safety of maribavir for the treatment of CMV infection in 
HSCT or SOT recipients. In Japan, for HSCT recipients, 1 antiviral (letermovir) is approved for 
prophylaxis, while there are 3 approved antivirals (ganciclovir, valganciclovir, and foscarnet) for 
the treatment of CMV disease, which are also used as preemptive therapy agents in clinical 
practice. For SOT recipients, valganciclovir is approved for prophylaxis, while ganciclovir and 
valganciclovir are approved for CMV disease. However, the use of these anti-CMV agents is 
limited by their toxicities; treatment with maribavir may address the unmet medical need for this 
population. In HSCT recipients, when CMV replication is detected above the predefined 
threshold during the monitoring of CMV infection, the pre-emptive treatment is generally given 
for a minimum of 2 weeks with further extension until CMV becomes undetectable. There is a 
difference in practice regarding the minimum duration of therapy. Valganciclovir (previously 
ganciclovir) is often used for preemptive therapy, although foscarnet can be used as well 
(Busca et al., 2007; Reusser et al., 2002). However, foscarnet is associated with nephrotoxicity, 
and requires IV hydration and frequent electrolyte monitoring (Reusser et al., 2002). Ganciclovir 
or valganciclovir use is associated with bone marrow toxicities that specifically in the HSCT 
recipients are a considerable clinical issue.
In the SHP620-202 study (HSCT and SOT recipients with resistant or refractory CMV 
infections), the majority of maribavir subjects achieved confirmed undetectable plasma CMV 
DNA levels by Week 6 of study drug treatment, while CMV recurrence occurred at rates not 
unexpected for a population with such an overwhelmingly severe illness and concurrent lack of 
host immune responsiveness. A fixed duration, 8-week treatment regimen, in this Phase 3 study 
will account for a longer duration of treatment need in patients of certain transplant types (ie, 
lung transplant) consistent with clinical practice as well as the prolonged period of 
immunosuppression/vulnerability in this patient population; furthermore, in the context of a 
clinical trial, the 8-week treatment duration will allow standardization of the duration of 
treatment for measuring the primary efficacy endpoint. 
The clearance of CMV viremia (plasma CMV DNA clearance) is considered a surrogate marker 
that correlates with direct clinical benefit for the treatment of CMV infection or disease. While 
no registration trials for the treatment of established CMV infection in transplant patients have 
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been conducted, the VICTOR study (Asberg et al., 2007) of IV ganciclovir versus oral 
valganciclovir for the treatment of CMV disease in SOT recipients demonstrated that clearance 
of CMV viremia was highly correlated with resolution of CMV disease. This correlation was 
further evidenced with the subsequent analysis of VICTOR study plasma samples using the 
COBAS® AmpliPrep/COBAS® TaqMan® CMV Test, a test calibrated to the World Health 
Organization International Standard for Human CMV for Nucleic Acid Amplification 
Techniques. These findings, together with the maribavir Phase 2 study results, support a primary 
efficacy endpoint weighted on the CMV viremia clearance to demonstrate the efficacy of 
maribavir for the treatment of CMV infections. Clinicians consider CMV viremia clearance 
when evaluating the success of therapy hence the CMV plasma/blood monitoring protocols are 
employed in patients with high-risk of CMV infection or reactivation of latent CMV infection, 
and information of the viral load guides the decision for preemptive treatment in the absence of 
the symptomatic disease.
Primary endpoint based on CMV viremia clearance will be assessed at the end of Study Week 8 
as on treatment clearance is the most relevant assessment to determine antiviral treatment effect. 
Assessment of treatment effect off therapy will be measured as key secondary and secondary 
endpoints. Although important from the clinical standpoint, recurrence of CMV DNA after 
treatment is more influenced by other factors such as host immune status, other comorbidities, 
and immunosuppressive treatments for prevention of transplant rejection than by the 
effectiveness of the anti-CMV drug treatment.
4.3 Justification for Dose
Results from the 2 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 
1,200 mg BID maribavir dose groups in the clearance of CMV viremia within up to 6 weeks 
after starting the study drug treatment. In both Phase 2 studies, the most common TEAEs 
included dysgeusia, events of nausea, vomiting, and diarrhea, and elevated immunosuppressant
drug concentration levels. These comparable efficacy and slightly 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 PK, 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. The expression of
CYP3A4, which is the primary enzyme for maribavir metabolism in the liver, occurs during the 
first weeks of life (Lu and Rosenbaum, 2014). The expression of CYP1A2, which is also 
involved with maribavir metabolism, the last enzyme to develop, is present by 13 months of life. 
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By 1 to 2 years of age, all the isoenzyme activities are similar to those of adults. Therefore, the 
bioavailability, clearance and systemic exposure of maribavir in adolescent subjects is not 
expected to be substantially different from adults at the same oral dose.
In a Phase 1 single dose PK study, subjects of Japanese descent showed 10% higher Cmax and 
25% higher AUC compared to their age, sex and body mass index matched non-Hispanic, 
Caucasian subjects following oral administration of 400 mg maribavir. The population PK 
analysis suggested that race (Caucasian, Black, Asian, or others) did not have any clinically 
significant impact on the PK of maribavir. Compared to the exposure in Caucasian SOT or 
HSCT patients, AUC and Cmax were 4% lower and 4% higher, respectively, in Asian patients. 
Therefore, the exposure in Japanese patients is not expected to be clinically significantly 
different from that in Caucasian patients (TAK-620-1020 [Maribavir] Clinical Study Report).
4.4 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 22 weeks 
(screening phase: 2 weeks; study treatment phase: 8 weeks; follow-up phase: 12 weeks). 
Follow-up visits will occur weekly for the first 4 weeks (Follow-up Weeks 9 to 12), followed by 
visits every 2 weeks for the last 8 weeks (Follow-up Weeks 12 to 20) of this 12-week follow-up 
phase. The study will be completed in approximately 17 months.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessments. This includes the follow-up visit or contact, 
whichever is later (refer to Section 8.1.3 for the defined follow-up period for this protocol).
4.5 Sites and Regions
The study will be conducted in approximately 15 study sites in Japan.
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5. STUDY POPULATION
The study is planned to enroll 44 asymptomatic subjects, and few patients with resistant or 
refractory CMV infection in Japan.
Each subject must participate in the informed consent process and provide written informed 
consent (and assent where applicable) before any procedures specified in the protocol are 
performed.
5.1 Inclusion Criteria
The subject will be considered eligible for the study if the subject meets all of the criteria below.
Subjects must:
1.
Be able to provide written, personally signed, and dated informed consent (and assent
where applicable) to participate in the study before completing any study-related
procedures. When subject is below age of 20, voluntary agreement shall be obtained from
a parent/both parents or legally authorized representative (LAR) using the written consent
form.
2.
Be Japanese with Japanese nationality, ≥16 years of age at the time of consent.
3.
Be a recipient of HSCT or SOT that is functioning at the time of Screening.
4.
Have a documented CMV infection with a screening value of >455 IU/mL in plasma in
2 consecutive assessments, separated by at least 1 day, as determined by a central
specialty laboratory qPCR or comparable quantitative CMV DNA results. Both samples
should be taken within 14 days prior to first dose of study treatment with the second
sample obtained within 5 days prior to first dose of study treatment at Visit 2/Day 0.
5.
Have the current CMV infection after HSCT or SOT, either primary or reactivation,
which, in the investigator’s opinion, requires treatment and have any of the following.
a.
Asymptomatic subjects: The subjects do not have CMV tissue-invasive disease or
CMV syndrome (SOT subjects only) at Baseline, as determined by the investigator
according to the criteria specified by Ljungman et al., 2017.
b.
Resistant or refractory subjects: The subjects must have a current CMV infection
that is refractory to the most recently administered of the anti-CMV treatment
agent(s). Refractory is defined as documented failure to achieve >1 log10 (common
logarithm to base 10) decrease in CMV DNA level in plasma after a 14 day or longer
treatment period with IV ganciclovir/oral valganciclovir, or IV foscarnet.
6.
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):
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a.
Absolute neutrophil count ≥1,000/mm3 (1.0 × 109/L)
b. Platelet count ≥25,000/mm3 (25 × 109/L)
c.
Hemoglobin ≥8 g/dL
d. Estimated creatinine clearance ≥30 mL/minute (estimated glomerular filtration
rate by Modification of Diet in Renal Disease)
7.
Have a negative serum human chorionic gonadotropin (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 after the last dose of study treatment.
8.
Be able to swallow tablets.
9.
Have life expectancy of ≥8 weeks.
10. Weigh ≥40 kg.
11. Be willing and have an understanding and ability to fully comply with study procedures
and restrictions defined in the protocol.
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met.
Subjects must not:
1.
Have central nervous system (CNS) CMV tissue-invasive disease or CMV retinitis as
assessed by the investigator at the time of Screening and prior to administration at
Visit 2/Day 0.
2.
Be receiving valganciclovir, ganciclovir, foscarnet, or letermovir when study treatment is
initiated, or anticipated to require 1 of these agents during the 8-week treatment period.
NOTE: Subjects receiving letermovir must discontinue 3 days prior to first dose of study
treatment. Ganciclovir, valganciclovir, and foscarnet must be discontinued prior to the
first dose of study treatment.
3.
Have known hypersensitivity to the active substance or to an excipient of the study
treatments.
4.
Have severe vomiting, diarrhea, or other severe GI illness within 24 hours prior to the
first dose of study treatment that would preclude administration of oral medication.
5.
Require mechanical ventilation or vasopressors for hemodynamic support at the time of
Baseline.
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6.
Pregnant or nursing female.
7.
Have previously completed, discontinued, or have been withdrawn from this study.
8.
Have received any investigational agent (including CMV-specific T-cells) with known
anti-CMV activity within 30 days before initiation of the study treatment at any time.
9.
Have received any unapproved agent or device within 30 days before initiation of the
study treatment.
10. 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 maribavir, or compromise the safety or well-being of the subject.
11. Have previously received maribavir.
12. 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 × ULN at Screening (except for documented Gilbert’s syndrome), as
analyzed by local or central laboratory.
13. Have known (previously documented) positive results for HIV. Subjects must have a
confirmed negative HIV test result within 3 months of study entry or, if unavailable, be
tested by a local or central laboratory during the screening period.
14. 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 or SOT was performed), as determined by the investigator,
are not to be enrolled.
15. Be undergoing treatment for acute or chronic hepatitis C.
5.3 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 6.6.4), and activities of 
daily life as determined by the investigator.
5.4 Reproductive Potential
5.4.1 Female Contraception
There is no clinical experience with maribavir in pregnant subjects.
All female subjects of childbearing potential will be tested and should have negative serum 
human chorionic gonadotropin pregnancy test results prior to administration of study treatment. 
They must agree to abstain from sexual activity that could result in pregnancy or agree to use an 
acceptable method of contraception. Females of childbearing potential who are not currently 
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sexually active must agree to use an acceptable contraception, as defined below, if they become 
sexually active during the study period and for 90 days after the last dose of the 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. Sexually active females of 
childbearing potential should be using an acceptable method 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 
childbearing potential and are presented below: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation (oral) 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 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 (all types) or intrauterine hormone-releasing systems 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.
•
Vasectomized male partner is a highly effective birth control method provided that
partner is the sole sexual partner of the female study 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 treatment. 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 subjects 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.
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 post 
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sterilization do not need a pregnancy test performed prior to administration of study treatment 
and do not have to agree to the use of acceptable methods of contraception.
5.4.2 Male Contraception
Per 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. 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.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The investigational product is maribavir, which will be provided in a 200 mg tablet (oral tablet)
form. Additional information is provided in the current maribavir IB.
No placebo or any active comparator/reference products will be used in the study.
6.1.2 Blinding the Treatment Assignment
Not applicable.
6.2 Administration of Investigational Product
6.2.1 Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) will be employed in this study to assign subject 
numbers, manage the tracking and confirmation of shipment, supply, inventory, ordering, 
expiration, site assignments, and return of study treatment. The IRT provider will provide a user 
manual and training to each site, with detailed instructions on use of the IRT.
6.2.2 Allocation of Subjects to Treatment 
This is an open-label study. All subjects will be assigned the same study treatment. 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site, the subject number is assigned to subjects by the IRT system according to the sequence of 
presentation for study participation. 
6.2.3 Dosing
Initiation of the study treatment (ie, first dose) will occur at Visit 2/Day 0 only after completion 
of all required procedures and confirmation of eligibility. The first dose should be administered 
under the supervision of the investigator’s site personnel. 
Depending on the time of the first dose of the study treatment at Visit 2/Day 0, a second dose 
should be administered at Visit 2/Day 0 provided that doses can be separated by a minimum of 
8 hours; otherwise, only 1 dose should be administered at Visit 2/Day 0. The study treatment will 
then be administered (preferably) q12h. When q12h dosing is not feasible, the doses should be 
separated by a minimum of 8 hours.
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Maribavir 200 mg tablets will be provided for daily dosing. Subjects will take the maribavir
400 mg BID dose for 8 weeks of the study treatment phase. There are no dose modifications for 
maribavir.
Table 4. Study Treatment Dosing-Standard Regimen
Regimen
AM
PM
Maribavir (400 mg, BID)
400 mg (2 tablets of 200 mg)
400 mg (2 tablets of 200 mg)
BID=twice daily.
6.2.4 Unblinding the Treatment Assignment
Not applicable.
6.2.5 Dose Modification
Not applicable.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1 Labeling
Labels containing study information and study treatment kit number are applied to the study 
treatment container. 
All study treatment product will be labeled with a minimum of the following: protocol number,
study treatment kit number, dosage form, storage conditions,the statements “For clinical trial use 
only” and other information that may be required by the local laws.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2 Packaging
The study treatment, maribavir, is packaged in 40-count white 60cc square high-density 
polyethylene bottles with child-resistant cap and foil induction seal.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3 Storage
The head of clinical trial site has overall responsibility for ensuring that study treatment is stored 
in a secure, limited-access location. Maribavir tablets will be stored at controlled room 
temperature (15°C to 30°C or 59°F to 86°F). Limited responsibility may be delegated to the 
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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 study 
treatment bottle/carton labels as they are distributed.
Study treatment must be stored in accordance with labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the study treatment 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 study treatment 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 
study treatment that could affect the integrity of the product(s), eg, fumigation of a storage room.
6.4 Drug Accountability
Investigators will be provided with sufficient amounts of the study treatment to carry out this 
protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the study treatment, documenting shipment content and condition. Accurate records of 
all study treatment dispensed, used, returned, and/or destroyed must be maintained as detailed 
further in this section. An IRT will be used to assign subject numbers and the study treatment.
The investigator has the overall responsibility for administering/dispensing the study treatment. 
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 study treatment only to subjects included in this 
study following the procedures set out in the study protocol. Each subject will be given only the 
study treatment carrying his/her treatment assignment. All administered/dispensed medication
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will be documented in the subject’s source, electronic case report form (eCRF) and/or other 
study treatment record and may include additional information as required per applicable
regulations. The investigator is responsible for ensuring the retrieval of all study supplies from 
subjects. The disposition of the dispensed study treatment and study treatment lost by the subject 
or site staff will be documented in the accountability log. The destruction of the unused study 
treatment at the site is not allowed by the sponsor.
No study treatment 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.
With the written agreement of the sponsor, at the end of the study all unused study treatment, 
subject-returned study treatment, and empty/used study treatment packaging will be returned to a 
sponsor specified designation. Should local, state or national laws prohibit the return of unused 
study treatment, subject-returned study treatment, and empty/used study treatment packaging to 
the sponsor designated locations, it may be destroyed at the site or a local facility once the 
sponsor has reviewed and approved the site’s standard operating procedure. In this case, 
Certificates of Destructions identifying what was destroyed, when and how, must be obtained 
with copies provided to the sponsor. Destruction of study treatment 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 study 
treatment delivered with those used and returned. All study treatment must be accounted for and 
all discrepancies investigated and documented to the sponsor’s satisfaction.
6.5 Subject Compliance
Subjects must be instructed to bring their unused study treatment, empty/used study treatment
packaging at every visit. Drug accountability must be assessed at the container/packaging level 
for unused study treatment or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form. The number of 
tablets prescribed and the number of tablets returned will be documented on the CRFs.
6.6 Prior and Concomitant Therapy
All non-study treatment including but not limited to herbal treatments and vitamins received 
within 30 days prior to the Screening visit (Visit 1) and through the final study contact (including 
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protocol-defined follow-up period) must be recorded in the subject’s source document and 
eCRF.
6.6.1 Prior Treatment
Prior treatment information must be recorded in the subject’s source document and eCRF page 
and will include the following presented in Table 5.
Table 5. Prior Medications, Therapies, and Procedures
Time Period
(Prior to Visit 2/Study
Week 0/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 at Visit 2/Day 0
Induction therapy for 
transplant*
Including but not limited to:

Pre-transplant irradiation

Chemotherapy agents

Lymphocyte depleting and
nondepleting therapies, including
monoclonal, polyclonal, and
anti-thymocyte globulin
preparations.
Anti-CMV prophylaxis and 
treatment*
Including, but not limited to:

Ganciclovir

Valganciclovir

Foscarnet

CMV immune globulin
(CMV-IGIV***, Cytogam®***)

Leflunomide***

IVIG

Artesunate***

CMV-specific T-cell transfer***
(considered investigational)

Letermovir
All medications within 3 months 
prior to the first dose of study 
treatment at Visit 2/Study 
Week 0/Day 0
Transplant maintenance, 
rejection treatment, and 
other adjuvant/related 
therapy
Including, but not limited to:

Systemic steroids

Tacrolimus, cyclosporine,
everolimus, sirolimus***,
mycophenolate

GVHD prophylaxis and treatment

Antirejection medications
including T-cell depleting 
therapies***

Photopheresis
Hematopoietic growth 
factors
-
Blood or blood product 
transfusions
-
Other anti-infective agents

Prophylaxis and/or treatment of
viral, bacterial and fungal
infections
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Table 5. Prior Medications, Therapies, and Procedures
Time Period
(Prior to Visit 2/Study
Week 0/Day 0)
Category
Prior Medications, Therapies, and 
Procedures
Within 30 days or 5 half-lives 
(whichever is longer)
All other

All other prescription medications

All other OTC medications 

All herbal supplements**
Any therapeutic or diagnostic 
intervention performed within 30 
days prior to the first dose of study 
treatment at Visit 2/Study 
Week 0/Day 0
Including, but not limited to:

Biopsies (along with the results
obtained)

Dialysis

X-rays, CT scans, MRI, ultrasound
imaging (along with significant
findings).
CMV=cytomegalovirus, CMV-IGIV=Cytomegalovirus Immune Globulin Intravenous, CT=computed 
tomography, GVHD=graft-versus-host disease, IVIG=intravenous immunoglobulin, MRI=Magnetic resonance 
imaging, OTC=over-the-counter.
* Subjects for whom transplant was performed >3 months from the time of Screening, limited (no dose data)
information for induction therapy will be collected. Similarly, for anti-CMV treatment data older than >3 month
prior to Screening will be recorded in more limited manner (dose prescribed, major interruptions, overall
treatment duration).
** If half-life is unknown, report use within 30 days prior to study.
*** Leflunomide is not approved for anti-CMV prophylaxis and treatment in Japan. Sirolimus and T-cell
depleting therapies are not approved for transplant maintenance and rejection treatment in Japan. Other
medications are not approved in Japan.
6.6.2 Concomitant Treatment 
Concomitant treatment refers to all treatment (including medication) taken between the dates of 
the first dose of the study treatment and the end of the follow-up period, inclusive. A 
concomitant procedure is any therapeutic and diagnostic intervention (eg, surgery/biopsy) or 
diagnostic assessment (bacterial cultures, imaging such as X-ray, computed tomography scans) 
performed between the dates of the first dose of the study treatment and the end of the follow-up 
period, inclusive. Concomitant treatment information must be recorded in the subject’s source 
document.
6.6.3 Permitted Treatment
All concomitant treatment information must be recorded on the subject’s source document and 
appropriate eCRF page.
Additional treatment strategies may complement the use of the study treatments, eg, reducing or 
modifying the immunosuppressant drug (tacrolimus, cyclosporine, or everolimus) use, or use of 
hemopoietic growth factors as needed for neutropenia.
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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 treatment administration period, particularly through 
Visit 10/Study Week 8. Note that the sample for the assessment of immunosuppressant agent 
concentration is included in the SoA 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 herpes virus 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, valaciclovir, 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, valaciclovir, 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 CYP3A4 (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 1,200 mg BID in Phase 2 studies. 
The following concomitant medications should be taken with caution: 
Maribavir has the potential to inhibit CYP2C19 and P-gp and therefore, may increase the 
concentration of drugs that are substrates of CYP2C19 and 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) when administered with tacrolimus, resulted in 
increased tacrolimus Cmax, AUC, and Ctrough by 38%, 51%, and 57%, respectively. Therefore, 
monitoring tacrolimus blood concentration and tacrolimus-associated AEs, 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 CYP2C19 or P-gp and have narrow therapeutic 
window, careful monitoring is recommended both after initiation of maribavir (when substrate 
levels may increase) and after discontinuation of maribavir (when substrate levels may decrease).
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6.6.4 Prohibited Treatment
The washout periods of common prior treatments that are excluded medications in this study are 
presented in Table 6.
Table 6. Common Excluded Treatments and Associated Washout Period
Treatment
Minimum Number of Days Before First Dose
Prior to the
first dose of 
study 
treatment
3 days
14 days
30 days
Artesunate*
X
-
-
Ganciclovir, valganciclovir, and 
foscarnet 
X
-
-
-
Letermovir
-
X
-
-
Leflunomide*
-
-
X
-
Any investigational anti-CMV 
agent
-
-
X
Any unapproved agent or device
-
-
X
CMV vaccine*
Any time before or during the study.
CMV=Cytomegalovirus
* Leflunomide is not approved for anti-CMV prophylaxis and treatment in Japan. Artesunate and CMV vaccine
are not approved in Japan.
Treatments not listed above are considered allowable. 
Besides the medications indicated in Table 6, concomitant use of any of the following 
medications is prohibited in all subjects during the study. 
•
Strong CYP3A inducers: avasimibe, carbamazepine, phenytoin, rifampin, rifabutin,
St. John’s wort (Hypericum perforatum), phenobarbital, primidone, mitotane,
enzalutamide, apalutamide, bosentan, efavirenz.
•
Herbal medications known to have potential toxicities or drug interactions, eg, Ginkgo
biloba or Piper methysticum (kava).
Potent inducers of CYP3A4 and CYP3A4/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. 
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
If the subject discontinues the study treatment but does not withdraw consent, regardless of the 
reason, the evaluations listed for Visit 10/Study Week 8 will be performed as completely as 
possible. Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for discontinuation, date of discontinuation of the 
study treatment, and the total amount of the study treatment administered must be recorded in the 
source documents.
These subjects will follow a modified SoA through the remaining weekly visits scheduled for the 
study treatment phase and the regular SoA 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: dispense or use of any study treatment, and PK 
plasma sample collection. After completing the 8-week duration specified for the study treatment 
phase, subjects will enter the 12-week follow-up phase. 
Subjects who discontinue will not be replaced. 
7.2 Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document and the CRF. If a subject is discontinued for more than 1 reason, each 
reason should be documented in the source and the most clinically relevant reason should be 
indicated. 
Reasons for discontinuation include, but are not limited to:
•
AE
•
CMV CNS infection*
•
Protocol deviation
•
Withdrawal of consent (by subject or by parent or both parents/LAR for pediatric subject)
•
Pregnancy
•
Lost to follow-up
•
Lack of efficacy
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•
Sponsor decision
•
Death
•
Other (the investigator must specify on the CRF)
*Maribavir does not cross the blood-brain barrier. 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.
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.
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the 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/Study 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/Study 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.
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is 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 the subject return to the site for final safety evaluations and return any unused study 
treatment.
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8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Periods
Refer to Table 1 for SoA for the screening and study treatment phase and Table 2 for the SoA for 
the follow-up phase. Study assessments are detailed in Section 8.2.
8.1.1 Screening Period 
Prior to initiation of any study procedures, the informed consent (and assent where applicable) to 
participate in the study must be obtained from a subject or the subject’s parent or legal guardian 
if the subject is <20 years of age.
Subjects will be screened during an approximate 2-week screening phase which will occur from 
Day -14 to Day 0 in which subjects will undergo evaluation to establish eligibility. To be eligible 
for the study, subjects must have a documented CMV infection with a screening value of 
>455 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined
by a central specialty laboratory qPCR or comparable quantitative CMV DNA results. Both
samples should be taken within 14 days prior to first dose of study treatment with the second
sample obtained within 5 days prior to first dose of study treatment at Visit 2/Day 0. If
applicable, subjects who meet eligibility requirements will undergo washout of any prohibited
medications, the length of which will be specified in the eligibility criteria. Ganciclovir,
valganciclovir, and foscarnet must be discontinued prior to the first dose of study treatment.
Subjects receiving letermovir must discontinue 3 days prior to first dose of study treatment.
8.1.1.1 Screening Visit (Visit 1/Study Week -2/Day -14 to Day 0)
As specified in Table 1, the screening procedures will include: 
•
Informed consent
•
Inclusion/Exclusion criteria (see Section 5.1 and Section 5.2)
•
Height and body weight
•
Vital signs (see Section 8.2.3.3)
•
Medical history, including transplant history (eg, underlying disease that led to HSCT or
SOT, including relapse/progression) and CMV history
•
Prior medication, therapies, and procedures, including any prior anti-CMV medication
used to treat the current CMV infection (see Section 6.6)
•
Hematology/Chemistry (see Section 8.2.3.4)
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•
Serum pregnancy test for all females of childbearing potential (see Section 8.2.3.5).
Additional urine pregnancy tests may be done per institutional requirements. Urine
pregnancy test results are not sufficient for eligibility determination.
•
HIV status: Historical results for HIV tests performed within 3 months prior to the
eligibility assessment (screening) will be acceptable. If no HIV test result within
3 months is available, the subject must have testing done locally or centrally during the
screening period and have the results available prior to administration of study treatment.
Negative results must be confirmed prior to study treatment administration.
•
CMV DNA test (quantitation): Documentation of CMV infection with CMV DNA in
2 consecutive samples separated by at least 1 day as determined by a central specialty
laboratory qPCR or comparable quantitative CMV DNA results. The DNA results with
the first sample should be available within 14 days prior to administration of study
treatment at Visit 2/Study Week 0/Day 0. The second sample must be taken within 5 days
prior to administration of study treatment. The laboratory used for DNA quantification
should be central specialty laboratory.
•
Symptomatic CMV infection status (no change, improvement, worsening, or resolution
of disease/syndrome and associated symptoms) assessment
•
Interactive response technology (see Section 6.2.1)
•
Graft outcomes (acute rejection or graft loss in both SOT and HSCT subjects) and GVHD
(for HSCT subjects only) assessments
At Screening, either central or local laboratory results for hematology/chemistry/pregnancy 
testing can be used for qualification; for CMV DNA quantification, only central laboratory 
results can be used.
A screen failure is a subject who has given informed consent and failed to meet the inclusion
except No.4 and/or met at least 1 of the exclusion criteria and has not been administered the 
study treatment. However, subjects who were excluded based on the exclusion criteria of low 
platelet count, hemoglobin, and low neutrophil counts or liver or renal parameters can be retested
once within the 14-day screening period at the investigator’s discretion when other inclusion 
criteria are fulfilled. 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 
trial.
The Screening and Visit 2/Study Week 0/Day 0 visits can occur on the same day, if laboratory 
results are available for the determination of eligibility.  
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8.1.2 Study Treatment Period 
Visit 2/Study Week 0/Day 0 (Baseline) to Visit 10/Study Week 8/Day 56 (End of Treatment)
Permissible assessment windows during the 8-week study treatment phase are: Visit 2A, ±1 day;
Visit 3 (Study Week 1) +2 days; Visit 4 (Study Week 2) to Visit 6 (Study Week 4), ±2 days; and 
Visit 7 (Study Week 5) to Visit 10 (Study Week 8), ±3 days.
As specified in Table 1 the following assessments will be performed during the study treatment 
phase:
•
Administration of study treatment at Visit 2/Study Week 0/Day 0 (Baseline)
•
Physical examination at Visit 2/Study Week 0, Visit 6/Study Week 4, and Visit 10/Study
Week 8 (see Section 8.2.3.1)
•
Weight at Visit 2/Study Week 0, Visit 4/Study Week 2, Visit 6/Study Week 4,
Visit 8/Study Week 6, and Visit 10/Study Week 8 (see Section 8.2.3.1)
•
Vital signs at Visit 2/Study Week 0, Visit 4/Study Week 2, Visit 6/Study Week 4,
Visit 8/Study Week 6, and Visit 10/Study Week 8 (see Section 8.2.3.3)
•
Review of medical history and prior medication at Visit 2/Study Week 0
•
12-lead ECG at Visit 2/Study Week 0 and Visit 10/Study Week 8 (see Section 8.2.3.6)
•
Hematology/Chemistry tests will be done at all the visits from Visit 2/Study Week 0 to
Visit 10/Study Week 8. For subjects receiving tacrolimus, cyclosporine, or everolimus; a
local laboratory will assess potassium and magnesium at Visit 2A (see Section 8.2.3.4).
•
Urinalysis will be done at Visit 2/Study Week 0, Visit 4/Study Week 2, Visit 6/Study
Week 4, Visit 8/Study Week 6, and Visit 10/Study Week 8 (see Section 8.2.3.4).
•
Pregnancy test at Visit 2/Study Week 0, Visit 6/Study Week 4, and Visit 10/Study
Week 8 (see Section 8.2.3.5)
•
Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) test at Visit 2/Study Week 0
•
Underlying disease that led to HSCT or SOT, including relapse/progression, will be
assessed at all visits throughout the study treatment phase, except Visit 2A.
•
CMV DNA test: Cytomegalovirus quantification in the plasma samples taken at each
visit of study treatment phase will be conducted at central specialty laboratory.
Cytomegalovirus genotyping by the central specialty laboratory to assess for mutations in
the UL97, UL27, and UL54 genes will be conducted at Visit 2/Study Week 0/Day 0
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(Baseline). After Visit 2, CMV genotyping will be conducted in every sample that meets 
the criteria specified in the resistance analysis plan (see Section 8.2.2.2).
•
Symptomatic CMV infection status (no change, improvement, worsening, or resolution
of disease/syndrome and associated symptoms) will be assessed at all visits until
resolution for subjects with CMV tissue-invasive disease or CMV syndrome (SOT
subjects only) present at Visit 2/Study Week 0/Day 0 (Baseline).
•
Development of new tissue-invasive disease or CMV syndrome will be assessed at all
visits. Any new tissue-invasive disease or CMV syndrome status (no change,
improvement, worsening, or resolution of disease/syndrome and associated symptoms)
will be assessed at all visits until resolution.
•
Immunosuppressant drug concentration levels for subjects receiving immunosuppressant
will be measured at Visit 2/Study Week 0/Day 0 (Baseline), Visit 2A/Day 4,
Visit 3/Study Week 1/Day 7, and Visit 10/Study Week 8/Day 56 (see Section 8.2.3.4). If
maribavir is discontinued early during the treatment phase, immunosuppressant drug
concentration should also be measured 1 week after the discontinuation.
•
Pharmacokinetic sample collection will be as follows: at Visit 3/Study Week 1/Day 7
(predose and between 2 to 4 hour postdose); at Visit 6/Study Week 4/Day 28 (only
predose); and at Visit 10/Study Week 8/Day 56 (predose and between 2 to 4 hour
postdose) (see Section 8.2.4.1).
•
IRT at all visits through the study treatment phase, except Visit 2A/Study Week 1 and
Visit 10/Study Week 8
•
Study treatment is dispensed at every visit, except Visit 2A/Study Week 1 and
Visit 10/Study Week 8 (Week 0 through Week 7).
•
Graft outcomes (acute rejection or graft loss in both SOT and HSCT subjects) and GVHD
(for HSCT subjects only) assessments will be done at all visits through the study
treatment phase, except Visit 2A/Study Week 1.
•
Hepatic function grading will be assessed according to the Child-Pugh classification (see
Appendix 5 and Section 8.2.1.2) at Visit 2/Study Week 0.
•
Comorbidity status evaluation at Visit 2/Study Week 0, Visit 6/Week 4, and
Visit 10/Week 8
•
Concomitant medications, therapies, and procedures will be assessed through the study
treatment phase.
•
AE/SAE monitoring will be assessed throughout the study treatment phase.
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For subjects who permanently discontinue study treatment early but do not withdraw consent, 
refer to Section 7.1 regarding modified schedule of assessments.
8.1.3 Follow-up Period
Visit 11/Study Week 9/Follow-up Week 1 to Visit 18/Study 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 to 12 (Follow-up 
Weeks 1 to 4) ±2 days; Study Weeks 14 to 20 (Follow-up Weeks 6 to 12) ±3 days.
As specified in Table 2 study evaluation include:
•
Physical examination (including weight) at Visit 18/Study Week 20
•
Vital signs at Visit 18/Study Week 20
•
12-lead ECG at Visit 18/Study Week 20
•
Hematology/Chemistry tests will be done at Visit 12/Study Week 10, Visit 14/Study
Week 12, Visit 16/Study Week 16, and Visit 18/Study Week 20.
•
Urinalysis at Visit 18/Study Week 20
•
Immunosuppressant drug concentration levels at Visit 11/Study Week 9, if treatment
continued until Study Week 8 (drug concentration level to be measured 1 week after the
end of the study treatment).
•
Underlying disease that led to HSCT or SOT, including relapse/progression, will be
assessed at all visits throughout the follow-up phase.
•
CMV DNA test: all CMV DNA tests (quantitation, genotyping) at all visits during the
follow-up phase will be tested in the central specialty laboratory.
•
Symptomatic CMV infection status (no change, improvement, worsening, or resolution
of disease/syndrome and associated symptoms) will be assessed at all visits until
resolution during the follow-up for subjects with CMV tissue-invasive disease or CMV
syndrome (SOT subjects only) present at Visit 2/Day 0 (Baseline).
•
Development of new tissue-invasive disease or CMV syndrome will be assessed at all
visits during the follow-up. Any new tissue-invasive disease or CMV syndrome status
(no change, improvement, worsening, or resolution of disease/syndrome and associated
symptoms) will be assessed at all visits until resolution.
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•
Graft outcomes (acute rejection or graft loss in both SOT and HSCT subjects) and GVHD
(for HSCT subjects only) assessments will be done at all visits through the follow-up
phase.
•
Comorbidity status evaluation at Visit 14/Study Week 12, Visit 16/Study Week 16, and
Visit 18/Study Week 20.
•
Concomitant medications, therapies, and procedures will be assessed through the
follow-up phase.
•
AE/SAE monitoring will be assessed through the follow-up phase according to
Section 8.2.3.2.
All AEs and SAEs that are not resolved at the time of end of study (Visit 18/Study
Week 20/Follow-up Week 12) will be followed to closure (see Appendix 3.2). 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.
Subjects who have a CMV tissue-invasive disease or CMV syndrome (SOT subjects only) at 
Visit 2/Day 0 (Baseline) and who have no change, worsening, or improvement of 
disease/syndrome and associated symptoms at the time of end of study (Visit 18/Study 
Week 20/Follow up Week 12) will be followed until the resolution. 
Subjects who develop new CMV tissue-invasive disease or CMV syndrome during the treatment 
period and who have no change, worsening or improvement of disease/syndrome and associated 
symptoms at the time of end of study (Visit 18/Study Week 20/Follow up Week 12) will be 
followed until the resolution.
8.1.4 Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.2 Study Assessments
All study evaluations and procedures are specified in SoA 1 (Table 1) and SoA 2 (Table 2).
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information including sex, age, race, and ethnicity will be collected prior to 
the subject receiving the first dose of study treatment. 
8.2.1.1 Height and Weight
Height and weight will be measured and recorded in the subject’s source documents. 
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8.2.1.2 Medical and Medication History
Medical and medication history will be collected and recorded in the subject’s source documents. 
A medical history will be taken during the screening period and updated at Visit 2/Study
Week 0/Day 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/Study Week 0/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. 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. 
Specific information regarding the subject’s transplant history that will be collected, including 
but not limited to, are: the number of past transplants prior to the current transplant; the type of 
transplant and details for each, such as cell source and type for HSCT or organ for SOT; the 
human leukocyte antigen (HLA) matching level. The date and the history of the current 
transplant including complications, transplant related infections, induction and maintenance 
therapy received for transplant, history of relevant viral serology, history of antiviral 
prophylaxis, and status of the transplant at Baseline.
Specific information regarding the subject’s CMV infection will be collected (when available). 
The collected information will include but will not be limited to: CMV serology of donor and 
recipient, CMV infection episodes with viral loads and/or treatment, CMV resistance 
information (sequencing data), prophylactic treatment, if utilized. More details will be specified 
in the study manual. 
Subjects will be classified into 1 of the following categories with respect to hepatic function, 
based on baseline clinical and laboratory assessments (see Appendix 5). 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
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8.2.2 Efficacy
8.2.2.1 CMV DNA Quantitation (CMV infection)
Blood samples collected will be assessed at a central specialty laboratory for the quantification of 
CMV DNA in plasma using qPCR. Central specialty laboratory plasma CMV DNA results will 
be reported to the investigator site as available. Additional CMV DNA tests at central specialty 
laboratories may be performed and collected at more frequent intervals, or additional assay 
methods may be used at the discretion of the investigator. These results will also be collected 
when available. 
Confirmed CMV viremia clearance will be defined as plasma CMV DNA concentration 
below the lower limit of quantification (LLOQ) to be determined depending on the 
selected 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 to be determined depending on the selected central specialty 
laboratory in 2 consecutive plasma samples at least 5 days apart, after attaining viremia 
clearance. Every attempt should be made by the investigators to collect the 2 consecutive plasma 
samples and monitor results to confirm recurrence prior to initiating alternative available 
therapy.
8.2.2.2 CMV Genotyping and Phenotyping 
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 the subjects, it is not 
possible to wait for this central specialty laboratory assessment prior to a subject’s study 
treatment administration to confirm lack of resistance to any previously used agents. For 
asymptomatic subjects, 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.
During the study, CMV genotyping will be conducted at the central specialty laboratory when 
the CMV DNA viral load is above a predefined cut off level: in cases of failure to clear CMV 
viremia during treatment; cases of recurrence of viremia on and off treatment; and cases of 
viremia rebound if >1 log10 above nadir while on treatment (Rebound is defined as increase in 
viral DNA load for >1 log10 above nadir 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. 
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Additionally, virus susceptibility testing (phenotyping) could be performed on selected de-novo 
CMV mutations/variants of maribivir-treated subjects by recombinant phenotyping to define the 
association of these mutations with anti-CMV drug resistance. Details of the analysis would be 
specified in a resistance analysis plan.
The list of CMV mutations known to confer resistance to valganciclovir, and other commercially
available anti-CMV agents (ganciclovir, foscarnet, and cidofovir [not approved in Japan]) is 
presented in Appendix 6.
8.2.2.3 CMV Infection Symptomatic Assessment
Cytomegalovirus tissue-invasive disease will be defined as described by Ljungman et al., 2017. 
The gold standard for diagnosing CMV tissue-invasive disease is the identification of CMV 
inclusions in the infected cells of the tissues OR identification of CMV in biopsy tissue 
samples. However, in some cases both diagnostic methods are required when tissue samples 
have a high chance of being contaminated by body fluids that shed virus (bronchoalveolar lavage 
[BAL], urine or stool). 
In some subjects, when it is not possible to obtain a tissue biopsy, a culture of CMV from body 
fluids or CMV DNA quantitation (for selected cases) may be used to confirm diagnosis, with a 
lower level of confidence in diagnosis. CMV syndrome (in SOT subjects only) will also be 
defined as described by Ljungman et al., 2017, and requires at least 2 of 6 signs and symptoms to 
be present (see Appendix 7 for full description of criteria).
All subjects will be monitored for the occurrence of CMV tissue-invasive disease and CMV 
syndrome throughout the study. For symptomatic subjects who present with CMV 
tissue-invasive disease and CMV syndrome at Baseline, the investigator will document the initial 
diagnosis of CMV tissue-invasive disease and CMV syndrome at Visit 2/Day 0 (ie, absence or 
presence at Baseline) and all serial assessments of infection status (ie, no change, improvement, 
worsening, or resolution) at all subsequent visits in the study. 
The recurrence of symptomatic CMV infection will be defined as the presence of signs or 
symptoms of the CMV tissue-invasive disease or CMV syndrome (same or new 
symptomatology) confirmed as per Ljungman et al., 2017 after the period of resolution of 
symptomatic CMV infection in subjects symptomatic at Baseline.
In subjects asymptomatic at Baseline, the occurrence of new CMV tissue-invasive disease or 
CMV syndrome after start of study treatment will be assessed by the investigator at all scheduled 
study visits.
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8.2.2.4 Graft Outcomes
History of the current transplant and its status at screening and baseline will be collected for all 
transplant types, including dates of transplant, graft complications, and use of antirejection 
therapies for prophylaxis or treatment of graft rejection.
Assessment of the transplant throughout the study will include the status of the graft function, the 
presence of the episode(s) of acute rejection, or development of other relevant complications (eg, 
new onset diabetes). The outcome of graft loss is a clinical determination that the graft 
irreversibly and irrevocably ceases functioning (eg, in case of renal transplant, with the subject 
returning to permanent dialysis if dialysis-dependent prior to transplant or return to insulin 
dependency in the case of pancreas transplant) as determined by the investigator.
Detailed information will be collected in separate CRF forms for SOT (by organ) or HSCT, as 
specified in the study manual.
8.2.2.5 Graft-versus-host-disease (GVHD) Assessments
Graft-versus-host-disease is a well-recognized complication of transplantation, much more 
frequently in HSCT transplants. Graft-versus-host-disease occurs when the donor cells (the
“graft”) recognizes 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 HLAs and the incidence of acute GVHD is directly 
related to the degree of mismatch between HLA proteins expressed by the HSCT 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.
Chronic GVHD typically occurs later (>100 days after transplant) and is manifested on skin, 
appendages, mouth, eyes, lungs, genitalia, esophagus, and connective tissues. 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 patients with HSCT (such as 
mycophenolate mofetil [MMF] toxicity or the presence of GI CMV tissue-invasive disease).
Investigators are expected to consider recommendations for diagnosis provided in guidance in 
Appendix 9 and Appendix 10 (Jagasia et al., 2015; Shulman et al., 2015). Detailed information 
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on GVHD and its grading, at Baseline and during the study will be collected in separate eCRF 
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 8
(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. 
8.2.2.6 Comorbidity Status
Transplant subjects often have multiple other comorbidities, resulting from their 
immunosuppressed status (co-infections, GVHD, 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 at timepoints specified in Table 1 and Table 2.
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 subjects. Refer to
Appendix 11 for the KPS performance status scale.
8.2.3 Safety
8.2.3.1 Physical Examination
A physical examination will be performed by the investigator. A complete physical examination 
will include, at a minimum, assessments of the head, eyes, ears, nose, throat, neck, lymph nodes, 
and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.
Symptom-oriented physical examinations other than protocol-specified examinations will be 
performed when clinically indicated.
Abnormalities identified at the Screening visit (Visit 1) will be documented in the subject’s 
source documents and medical history CRF. Changes after the Screening visit (Visit 1) will be 
captured as AEs on the AE eCRF page, as deemed clinically relevant by the investigator and at 
subsequent study visits will be recorded in the subject’s source documents.
The investigator or designee will perform physical examinations at time points specified in 
Table 1 and Table 2. Body weight and height will be measured at time points specified in the 
SoA.
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8.2.3.2 Adverse Events
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?”). 
Adverse events are collected from the time informed consent is signed through 30 days after the 
dose of study treatment. Following the 30-day capture period for all AEs, only those AEs 
deemed related to study treatment or other protocol-mandated procedures and all SAEs 
(regardless of causality assessment) will be collected through the end of the study 
(Visit 18/Study Week 20/Follow-up Week 12). Refer to Appendix 3 for AE definitions, 
assessment, collection time frame, and reporting procedures. 
8.2.3.3 Vital Signs
Vital signs include pulse rate, respiration rate, blood pressure and temperature. 
Measurement of vital signs is always performed prior to drawing the blood samples at the 
timepoints specified in Table 1 and Table 2. The investigator will assess whether a change from
Baseline (Visit 2/Study Week 0/Day 0) in vital signs may be deemed clinically significant and 
whether the change should be considered and recorded as an AE.
8.2.3.4 Clinical Laboratory Tests
Clinical laboratory tests (hematology, chemistry, urinalysis, HBV, HCV, and pregnancy) will be 
performed by a central laboratory at the time points specified in Table 1 and Table 2. 
Immunosuppressant drug concentration testing will solely be done for subjects receiving 
immunosuppressive therapy with tacrolimus, cyclosporine, or everolimus (see Table 1 and 
Table 2). During screening, clinical laboratory tests will be performed by the central laboratory, 
however local laboratory results if available might be utilized for the assessment of the 
eligibility. If local laboratory results are used for the assessment of the eligibility, the reference 
ranges must be provided. However, for CMV DNA quantitation results, only central laboratory 
results will be used to confirm eligibility. At Baseline (Visit 2/Study Week 0/Day 0) blood 
samples will be taken for CMV DNA quantitation and genotyping, hematology and chemistry, 
and tested in the central specialty laboratory. All clinical laboratory assays will be performed 
according to the central laboratory’s standard procedures. 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.
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A complete list of the clinical laboratory tests to be performed is provided in Appendix 2.
8.2.3.5 Pregnancy Test
Aserum hCG pregnancy test will be performed on all females of childbearing potential at the 
Screening visit (Visit 1), Baseline visit (Visit 2/Study Week 0/Day 0), Visit 6/Study
Week 4/Day 28 and end of study treatment visit (Visit 10/Study Week 8/Day 56); if pregnancy is 
suspected; or on withdrawal of the subject from the study. Urine pregnancy tests may be done 
per institutional requirements; however, they are not sufficient for eligibility determination.
8.2.3.6 Electrocardiogram
A 12-lead ECG will be performed at Visit 2/Study Week 0/Day 0, Visit 10/Study
Week 8/Day 56 (end of treatment visit), Visit 18/Study Week 20/Day 84 (end of study visit), and 
at any additional time during the study, if clinically indicated. Each ECG 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.
8.2.4 Other
8.2.4.1 Clinical Pharmacology
For subjects entered to study treatment, the PK plasma samples will be collected on each of the 
study days specified in Table 1. The predose PK plasma sample will be obtained at all 3 PK 
visits. The postdose PK plasma samples at Visit 3/Study Week 1/Day 7 and at Visit 10/Study 
Week 8/Day 56 will be obtained any time between 2 to 4 hours after the morning dose. Any 
episode of vomiting occurring within 2 to 4 hours after the morning dose and before the postdose 
PK plasma sample collection must be documented. 
The following will be recorded in the CRF: 

Date and time of the last dose of study treatment before the predose PK plasma sample

Date and time of the predose PK plasma sample

Date and time of the last dose of study treatment before the postdose PK plasma sample

Date and time of the 2 to 4 hours postdose PK plasma sample

Date and time of vomiting within 2 to 4 hours after the morning dose and before the
postdose PK plasma sample collection
If a subject had study treatment interrupted for 2 consecutive days prior to the morning maribavir
dose on a PK visit, no PK plasma sample will be collected. If a subject has completed the 
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predose PK plasma sample collection but has missed the morning dose of maribavir on the day 
of the PK visit, then no postdose PK plasma sample will be collected.
Additional PK plasma samples will be collected from the subjects with biopsy-proven GI GVHD 
with diarrhea (>300 mL/day), biopsy-proven GI GVHD with nausea and vomiting, 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).
8.2.4.2 Pharmacodynamics
Not applicable.
8.2.4.3 Genetics
Not applicable.
8.2.4.4 Health-related Quality of Life 
Not applicable.
8.2.4.5 Healthcare Resource Utilization 
Not applicable.
8.2.5 Volume of Blood to Be Drawn from Each Subject
The volume of blood drawn from each subject during the study is provided in the Protocol 
Annex.
The amount of blood to be drawn for each assessment 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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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its designee. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy, safety, and PK data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, study treatment exposure, and prior and concomitant medications. The SAP will 
also include a description of how missing, unused, and spurious data will be addressed. A 
separate population PK analysis and report will be generated and a data analysis plan for the 
population PK analysis will be produced separately.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using statistical analysis system (SAS®) (SAS Institute, 
Cary, NC 27513) Version 9.4 or higher.
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis, adaptive design, or data monitoring committee is planned for this study.
9.3 Sample Size and Power Considerations
Post-transplant (SOT/HSCT) CMV infection is a rare condition and the number of patients 
expected to participate in this clinical trial in Japan is anticipated to be limited. For the start of 
domestic development of TAK-620, Takeda conducted a feasibility assessment for the planned 
clinical study. Specifically, a survey on the number of patients in university or large hospitals in 
Japan where HSCT or SOT are performed was carried out. The number of patients with 
asymptomatic CMV infection was estimated to be about 44 for HSCT and about 9 for SOT, for a 
total of about 53 patients. Assuming a dropout rate of 15%, approximately 44 patients with 
asymptomatic CMV infection are expected to be enrolled. On the other hand, the number of 
patients with resistant or refractory CMV infection is very small, and only a few patients 
(approximately 3) can be expected to be enrolled at the maximum.
From the standpoint of feasibility, approximately 44 asymptomatic patients and few resistant or 
refractory patients are expected to be enrolled in this study. 
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The target number of patients with asymptomatic CMV infection should be determined from the 
viewpoint of evaluating the similarities in outcome between the prospective study and the 
overseas Phase III study (Study SHP620-302) as well as the feasibility of the new study.
For the proportion of patients who achieved CMV clearance at Week 8 in the TAK-620 group in 
Study SHP620-302, since the results have not been available, we can assume 68%, which was 
used as the estimation for sample size justification in Study SHP620-302. Regarding the 
proportion of patients who achieved CMV clearance at Week 8 in this study, since it is the same 
target population and primary endpoint as Study SHP620-302, it is appropriate to assume 68% as 
Study SHP620-302.
In addition, we considered it appropriate to use -15% as a reference value for the difference in 
the point estimate between studies based on the noninferiority margin used in 2 noninferiority 
studies comparing valganciclovir and ganciclovir for CMV treatment (The study reported by 
Chawla et al., 2012 and VICTOR study [Asberg et al., 2007]).
With a sample size of 44 in asymptomatic patients, if the true response rates for this study is the 
same as that of the Study SHP620-302, the probability of observing a response rate similar to 
that of the Study SHP620-302 is high, that is, over 95% the point estimate from this study will be 
above the point estimate of Study SHP620-302 minus 15%.
Of note, the similarity between SHP620-302 study and Japan study will be based on both the 
primary endpoint and secondary endpoints.
9.4 Statistical Analysis Sets
Statistical analysis sets are as follows:
•
Enrolled Set: consists of all subjects who have signed an informed consent and have
begun some study procedures.
•
Full Analysis Set: consists of all subjects who have taken at least 1 dose of study
treatment; the Full Analysis Set will be used for efficacy analyses.
•
Per-Protocol Set: consists of all subjects in Full Analysis Set who do not have major
predefined protocol deviations that may affect the primary efficacy assessment.
•
Safety Set: consists of all subjects who have taken at least 1 dose of study treatment. The
Safety Set will be used for safety analyses.

Pharmacokinetic Set: consists of all subjects in the Safety Set who have plasma samples
drawn and tested for maribavir concentrations.
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9.5 Efficacy Analyses
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. Ninety-five percent confidence intervals (CIs) 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 at Visit 2/Study Week 0/Day 0.
9.5.1 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. 
For clearance of CMV viremia to be declared at the end of Study Week 8 during the treatment 
period, the subject must have received study treatment exclusively. 
Confirmed CMV viremia clearance at the end of Study Week 8 is defined as plasma CMV DNA 
concentrations <LLOQ with the assay at a central specialty laboratory, in 2 consecutive 
postbaseline samples, separated by at least 5 days at Study Week 8. Subjects who take alternative 
anti-CMV treatment before Study Week 8 or have missing data at Study Week 8 due to early 
discontinuation or any other reasons will be counted as nonresponders. 
Assessments of virological responders at Study Week 8 are described with examples in Table 7. 
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Table 7. Assessments of Virological Responders at Study Week 8
Scenario
CMV DNA Weeks on Study
Rationale
Week 6
Week 7
Week 8
Week 9a
Response
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; DNA=deoxyribonucleic acid; LLOQ=lower limit of quantification; NA=not available 
for evaluation of study drug effect; reason could be either not assessable by lab, by starting alternative anti-CMV 
treatment, 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
“+” = 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.
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Statistical Methodology for Primary Efficacy Endpoint:
The proportion of subjects achieving the confirmed CMV viremia clearance at Study Week 8 and 
the corresponding 95% exact CI will be calculated for the Full Analysis Set.
This analysis is also performed for the Per-Protocol Set. 
Details of the analysis will be specified in the statistical analysis plan.
9.5.2 Secondary Efficacy Endpoints
Secondary efficacy endpoints are as follows:
•
The maintenance of the confirmed CMV viremia clearance and infection symptom
control achieved at Study Week 8 through Study Week 12 (4 weeks of post-treatment
period), Study Week 16 (8 weeks of post-treatment/follow-up phase), and Study Week 20
(12 weeks post-treatment).
•
The time to first confirmed viremia clearance at any time during the study.

The recurrence of confirmed CMV viremia during the 12-week follow-up period in
subjects with confirmed viremia clearance at Study Week 8 requiring additional
anti-CMV treatment.

The time course of changes in plasma CMV viremia load from Baseline by study week.

Recurrence of CMV viremia during study treatment and in the follow-up period after the
subject is discontinued from study treatment.

Assessment of the profile of mutations in the CMV genes conferring resistance to
maribavir.

Confirmed plasma CMV DNA at the end of Study Week 8 to be less than 137 IU/mL.
Statistical Methodology for Secondary Efficacy Endpoint:
Secondary efficacy endpoints will be summarized descriptively. The denominator for the 
percentages will be based on the number of subjects in the Full Analysis Set, unless specified 
otherwise. Time-to-event endpoints will be summarized using Kaplan-Meier estimation. 
Ninety-five percent CIs for the estimated 25%, 50%, and 75% times will be presented.
Details of the analysis will be specified in the statistical analysis plan and the resistance analysis 
plan.
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9.5.3 Pharmacokinetic Analyses
The pharmacokinetic endpoint for this study is maribavir Cmin.
Individual maribavir plasma concentrations data will be presented in a listing. Maribavir Cmin
(predose maribavir concentration) will be summarized by Visit using descriptive statistics.
In a separate analysis and report, all maribavir concentrations obtained in this study will be 
combined with PK data from the Phase 1, Phase 2 and Phase 3 studies in adults conducted 
outside Japan, and analyzed by population PK analysis approach using a nonlinear mixed effect 
model approach using NONMEM Version 7 or above.
9.6 Safety Analyses
Safety and tolerability of maribavir for the treatment of CMV infection after HSCT or SOT will 
be assessed by evaluation of TEAEs (including instances of CMV disease), SAEs, AEs leading 
to interruption of study treatment, AEs leading to discontinuation of study treatment, AEs
leading to withdrawal from the study, number of subjects with clinically significant vital signs, 
number of subjects with abnormal clinical laboratory evaluations, number of subjects with 
clinically significant ECG parameters, and number of subjects with abnormal physical 
examination findings. New onset of acute or chronic GVHD, graft rejection, or graft loss will be 
reported and may be assessed as AE/SAE. Immunosuppression drug levels will be summarized 
over time.
Two observation periods are defined for the purpose of safety analyses: 1) On-treatment period: 
from the time of maribavir initiation through 7 days after the last dose of study treatment, and 2) 
Overall-study period: start of maribavir administration through the end of the study. 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 
the study treatment. 
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Treatment-emergent AEs 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.
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study drug; it does not have a causal relationship with study drug. The 
PTEs will not be evaluated in the safety analysis; they will be listed as pretreatment AEs.
The number of events, incidence, and percentage of TEAEs will be displayed by preferred terms 
(PTs) using the Medical Dictionary for Regulatory Activities (MedDRA®) for the on-treatment 
period and overall-study period. Summaries in terms of severity and relationship to study 
treatment will also be provided. Treatment-emergent SAEs will be summarized separately in a 
similar fashion. Summaries of AEs leading to interruptions of study treatment, discontinuation of 
study treatment, withdrawals, AEs leading to death, and SAEs will be provided.
Adverse events will be analyzed according to primary system organ classes (SOCs) and PTs. 
Summary tables with SOCs and PTs will be generated presenting the number and percentage of 
subjects by AE, severity, seriousness, and relationship to study treatment for the on-treatment 
period and overall-study period. 
Usage of concomitant medications will be summarized descriptively for the on-treatment period 
and overall-study period. Additionally, administration of hematopoietic growth factors, blood, 
and blood products will be summarized.
Baseline safety analyses is defined as the last value for the assessment prior to taking the first 
dose of study treatment. Change from Baseline in vital signs and clinical laboratory tests during 
on-treatment period and overall-study period will be summarized with descriptive statistics at 
each assessment visit. Potentially clinically important findings will also be summarized.
Maribavir dose interruptions for any AE will be summarized. Abnormal physical examination 
findings will be listed. A summary of ECG findings will be provided.
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10. REFERENCES
Asberg, A., Humar, A., Rollag, H., Jardine, A. G., Mouas, H., Pescovitz, M. D., et al. 2007. Oral
valganciclovir is noninferior to intravenous ganciclovir for the treatment of 
cytomegalovirus disease in solid organ transplant recipients. Am J Transplant, 7, 2106-
13.
Avery, R. K., Marty, F. M., Strasfeld, L., Lee, I., Arrieta, A., Chou, S., et al. 2010. Oral 
maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant 
recipients. Transpl Infect Dis, 12, 489-96.
Biron, K. K., Harvey, R. J., Chamberlain, S. C., Good, S. S., Smith, A. A., 3rd, Davis, M. G., et 
al. 2002. Potent and selective inhibition of human cytomegalovirus replication by 
1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob Agents 
Chemother, 46, 2365-72.
Boeckh, M. & Ljungman, P. 2009. How we treat cytomegalovirus in hematopoietic cell 
transplant recipients. Blood, 113, 5711-9.
Boeckh, M., Nichols, W. G., Papanicolaou, G., Rubin, R., Wingard, J. R. & Zaia, J. 2003. 
Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known 
challenges, and future strategies. Biol Blood Marrow Transplant, 9, 543-58.
Busca, A., de Fabritiis, P., Ghisetti, V., Allice, T., Mirabile, M., Gentile, G., et al. 2007. Oral 
valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem 
cell transplantation. Transpl Infect Dis, 9, 102-7.
Chawla, J. S., Ghobadi, A., Mosley, J., 3rd, Verkruyse, L., Trinkaus, K., Abboud, C. N., et al. 
2012. Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients 
after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of 
the literature. Transpl Infect Dis, 14, 259-67.
Chulay, J., Biron, K., Wang, L., Underwood, M., Chamberlain, S., Frick, L., et al. 1999. 
Development of novel benzimidazole riboside compounds for treatment of 
cytomegalovirus disease. Adv Exp Med Biol, 458, 129-34.
de la Hoz, R. E., Stephens, G. & Sherlock, C. 2002. Diagnosis and treatment approaches of 
CMV infections in adult patients. J Clin Virol, 25 Suppl 2, S1-12.
Drew, W. L., Miner, R. C., Marousek, G. I. & Chou, S. 2006. Maribavir sensitivity of 
cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. J Clin Virol, 37, 
124-7.
Emery, V. C., Sabin, C. A., Cope, A. V., Gor, D., Hassan-Walker, A. F. & Griffiths, P. D. 2000. 
Application of viral-load kinetics to identify patients who develop cytomegalovirus 
disease after transplantation. Lancet, 355, 2032-6.
Harris, A. C., Young, R., Devine, S., Hogan, W. J., Ayuk, F., Bunworasate, U., et al. 2016. 
International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical 
Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. 
Biol Blood Marrow Transplant, 22, 4-10.
Hodson, E. M., Jones, C. A., Webster, A. C., Strippoli, G. F., Barclay, P. G., Kable, K., et al. 
2005. Antiviral medications to prevent cytomegalovirus disease and early death in 
recipients of solid-organ transplants: a systematic review of randomised controlled trials. 
Lancet, 365, 2105-15.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Takeda
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Clinical Study Protocol: TAK-620-3001 Amendment 1
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Humar, A., Gregson, D., Caliendo, A. M., McGeer, A., Malkan, G., Krajden, M., et al. 1999. 
Clinical utility of quantitative cytomegalovirus viral load determination for predicting 
cytomegalovirus disease in liver transplant recipients. Transplantation, 68, 1305-11.
Jagasia, M. H., Greinix, H. T., Arora, M., Williams, K. M., Wolff, D., Cowen, E. W., et al. 2015. 
National Institutes of Health Consensus Development Project on Criteria for Clinical 
Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working 
Group report. Biol Blood Marrow Transplant, 21, 389-401.e1.
Kanj, S., Sharara, A., Clavien, P. & Hamilton, J. 1996. Cytomegalovirus infection following 
liver transplantation: review of the literature. Clin Infect Dis, 22, 537-49.
Kern, E. R., Hartline, C. B., Rybak, R. J., Drach, J. C., Townsend, L. B., Biron, K. K., et al. 
2004. Activities of benzimidazole D- and L-ribonucleosides in animal models of 
cytomegalovirus infections. Antimicrob Agents Chemother, 48, 1749-55.
Komatsu, T. E., Pikis, A., Naeger, L. K.and Harrington, P. R. 2014. Resistance of human
cytomegalovirus to ganciclovir/valganciclovir: a comprehensive review of putative 
resistance pathways. Antiviral Res, 101, 12-25.
Krause, H., Hebart, H., Jahn, G., Muller, C. A. & Einsele, H. 1997. Screening for CMV-specific 
T cell proliferation to identify patients at risk of developing late onset CMV disease. 
Bone Marrow Transplant, 19, 1111-6.
Krosky, P., Baek, M. & Coen, D. 2003. The human cytomegalovirus UL97 protein kinase, an 
antiviral drug target, is required at the stage of nuclear egress. J Virol, 77, 905-14.
Legendre, C. & Pascual, M. 2008. Improving outcomes for solid-organ transplant recipients at 
risk from cytomegalovirus infection: late-onset disease and indirect consequences. Clin 
Infect Dis, 46, 732-40.
Ljungman, P., Boeckh, M., Hirsch, H. H., Josephson, F., Lundgren, J., Nichols, G., et al. 2017. 
Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in 
Clinical Trials. Clin Infect Dis, 64, 87-91.
Ljungman, P., Deliliers, G. L., Platzbecker, U., Matthes-Martin, S., Bacigalupo, A., Einsele, H., 
et al. 2001. Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell 
transplant recipients. The Infectious Diseases Working Party of the European Group for 
Blood and Marrow Transplantation. Blood, 97, 388-92.
Ljungman, P., Perez-Bercoff, L., Johnsson, J., Avetisyan, G., Sparrelid, E., Aschan, J., et al. 
2006. Risk factors for the development of cytomegalovirus disease after allogeneic stem 
cell transplantation. Haematologica, 91, 78-83.
Loiseau, P., Busson, M., Balere, M. L., Dormoy, A., Bignon, J. D., Gagne, K., et al. 2007. HLA 
Association with hematopoietic stem cell transplantation outcome: the number of 
mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall 
survival. Biol Blood Marrow Transplant, 13, 965-74.
Lu, H. & Rosenbaum, S. 2014. Developmental pharmacokinetics in pediatric populations. J 
Pediatr Pharmacol Ther, 19, 262-76.
Lurain, N. S.and Chou, S. 2010. Antiviral drug resistance of human cytomegalovirus. Clin
Microbiol Rev, 23, 689-712.
Paya, C., Hermans, P., Wiesner, R., Ludwig, J., Smith, T., Rakela, J., et al. 1989. 
Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive 
orthotopic liver transplantations. J Infect Dis, 160, 752-8.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Takeda
Page 87
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Clinical Study Protocol: TAK-620-3001 Amendment 1
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Peus, D., Newcomb, N. & Hofer, S. 2013. Appraisal of the Karnofsky Performance Status and 
proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak,
13, 72.
Razonable, R. R. & Emery, V. C. 2004. Management of CMV infection and disease in transplant 
patients. 27-29 February 2004. Herpes, 11, 77-86.
Reusser, P., Einsele, H., Lee, J., Volin, L., Rovira, M., Engelhard, D., et al. 2002. Randomized 
multicenter trial of foscarnet versus ganciclovir for preemptive therapy of 
cytomegalovirus infection after allogeneic stem cell transplantation. Blood, 99, 1159-64.
Rubin, R. H. 1989. The indirect effects of cytomegalovirus infection on the outcome of organ 
transplantation. Jama, 261, 3607-9.
Salzberger, B., Bowden, R. A., Hackman, R. C., Davis, C. & Boeckh, M. 1997. Neutropenia in 
allogeneic marrow transplant recipients receiving ganciclovir for prevention of 
cytomegalovirus disease: risk factors and outcome. Blood, 90, 2502-8.
Schag, C. C., Heinrich, R. L. & Ganz, P. A. 1984. Karnofsky performance status revisited: 
reliability, validity, and guidelines. J Clin Oncol, 2, 187-93.
Shulman, H. M., Cardona, D. M., Greenson, J. K., Hingorani, S., Horn, T., Huber, E., et al. 2015. 
NIH Consensus development project on criteria for clinical trials in chronic graft-versus-
host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow 
Transplant, 21, 589-603.
Singh, N., Wannstedt, C., Keyes, L., Wagener, M. M., de Vera, M., Cacciarelli, T. V., et al. 
2004. Impact of evolving trends in recipient and donor characteristics on cytomegalovirus 
infection in liver transplant recipients. Transplantation, 77, 106-10.
Strasfeld, L., Lee, I., Tatarowicz, W., Villano, S. & Chou, S. 2010. Virologic characterization of 
multidrug-resistant cytomegalovirus infection in 2 transplant recipients treated with 
maribavir. J Infect Dis, 202, 104-8.
The Japanese liver transplantation society 2019. Liver transplantation in Japan-registry by the 
Japanese liver transplantation society. Japanese journal of transplantation: jt, 54, 81-96.
The Japanese pancreas and islet transplantation association working group for pancreas 
transplantation 2019. The registry of Japanese pancreas and islet transplantation 2019. 
Japanese journal of transplantation: jt, 54, 111-19.
The Japanese society for heart transplantation 2019. The registry report of Japanese heart 
transplantation 2019. Japanese journal of transplantation: jt, 54, 97-104.
The Japanese society of lung and heart-lung transplantation 2019. Registry report of Japanese 
lung transplantation-2019. Japanese journal of transplantation: jt, 54, 105-10.
Williams, S. L., Hartline, C. B., Kushner, N. L., Harden, E. A., Bidanset, D. J., Drach, J. C., et al. 
2003. In vitro activities of benzimidazole D- and L-ribonucleosides against herpesviruses. 
Antimicrob Agents Chemother, 47, 2186-92.
Winston, D. J., Wirin, D., Shaked, A. & Busuttil, R. W. 1995. Randomised comparison of 
ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-
transplant recipients. Lancet, 346, 69-74.
Wolf, D. G., Courcelle, C. T., Prichard, M. N. & Mocarski, E. S. 2001. Distinct and separate 
roles for herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and 
encapsidation. Proc Natl Acad Sci U S A, 98, 1895-900.
Zaia, J. A., Gallez-Hawkins, G. M., Tegtmeier, B. R., ter Veer, A., Li, X., Niland, J. C., et al. 
1997. Late cytomegalovirus disease in marrow transplantation is predicted by virus load 
in plasma. J Infect Dis, 176, 782-5.
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Appendix 10 Diagnostic Criteria for Chronic GVHD
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Appendix 13 Protocol History 
Document
Date
Global/Country/Site Specific
Original Protocol
26 Jul 2021
Japan
Amendment 1
28 Oct 2021
Japan
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SAP_001.pdf: 
Statistical Analysis Plan 
NCT Number: NCT05137717 
Title: A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, Safety, and 
Pharmacokinetics of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection 
in Japanese Recipients of a Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ 
Transplant (SOT) 
Study Number: TAK-620-3001 
Document Version and Date: Version 3.0 / 26-Jul-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


STATISTICAL ANALYSIS PLAN
Study Number: TAK-620-3001
Study Title: A Phase 3, Open-Label, Single-Arm Study to Assess the Efficacy, Safety, and 
Pharmacokinetics of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection in 
Japanese Recipients of a Hematopoietic Stem Cell Transplant (HSCT) or Solid Organ Transplant 
(SOT)
Phase: 3
Version: 3.0
Date: 26-Jul-2023
Prepared by: 
Based on:
Protocol Version: Amendment 1.0
Protocol Date: 28-Oct-2021
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REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
1.0
16-Nov-2021
[Not Applicable]
2.0
23-May-2023
・Updated the wording throughout this document according to the protocol
amendment of v1.0.
・Updated the ABBREVIATIONS list.
・Section 1.1.2 and 1.2.2.1: Updated secondary objectives and endpoints
details as per protocol amendment 1.
・Section 5.0: Described PPS exclusion criteria to clarify the definition.
・Section 6.2.1: Updated analysis category because the classification dealing
with an item in the treatment phase incorrectly dealt with an item in the overall
study.
・Section 6.3, 6.4.2, 6.5, 6.6.1, 6.6.1.1, 6.6.2, 6.6.3, 6.6.4, 6.6.8: Added
analysis by subject type because it was needed to evaluate the results.
・Section 6.3.1: Updated analysis variables by reviewing related studies and
the data collected in this study.
・Section 6.4: Described the analysis set to clarify the analysis set used in the
relevant sections.
・Section 6.4.1: Described the dictionary used for coding and the analysis set to
be used in the listing for clarification.
・Section 6.4.2: Modified to add the missing analysis period and removed
unnecessary descriptions found during the review layouts of analysis results.
・Section 6.4.3: Added reference to the definition of “on-treatment period” for
clarification.
・Section 6.5.1.1: Maintained for clarity of description to show that the
condition is the same as in the related studies.
・Section 6.5.1.2: Added listing and table of reasons for non-responders to be
able to prepare the same type of analysis results as the related studies.
・Section 6.5.1.3: Added analysis (type 6-8) and clarified conditions for each
analysis to be able to prepare the same type of analysis results as the related
studies.
・Section 6.5.1.4: Clarified conditions for analysis to be able to prepare the
same type of analysis results as the related studies.
・Section 6.5.2.2: Maintained for clarity of description.
・Section 6.5.2.3: Clarified conditions for analysis to be able to prepare the
same type of analysis results as the related studies.
・Section 6.5.2.3: Corrected plot type to use an appropriate layout.
・Section 6.5.2.5: Changed analysis due to change of endpoint in protocol
amendment 1.
・Section 6.5.3.1: Deleted unnecessary analysis found during the review
layouts of analysis results.
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Version 
Approval Date
Primary Rationale for Revision
・Section 6.5.3.2: Deleted section due to deletion of endpoint in protocol
amendment 1.
・Section 6.5.4: Updated analysis subgroup to match Section 6.3.1 update.
・Section 6.6: Added the definition of “on-treatment period” for clarification.
・Section 6.6.1 and 6.6.1.1: Added and removed the required analysis types
found during the review layouts of analysis results.
・Section 6.6.1.2: Added section to be able to analyze AEs that were
specifically indicated in the protocol.
・Section 6.6.1.3: Added section for necessary analysis found during the
review layouts of analysis results.
・Section 6.6.2: Clarified conditions for analysis and added “Potentially
Clinically Significant (PCS) Laboratory Results” table needed in protocol.
・Section 6.6.3: Corrected an error.
・Section 6.6.6: Changed to refer to another section to be prepared separately
as an AEs table.
・Section 6.6.7 and 6.6.8: Deleted unnecessary analyses found during the
review layouts of analysis results.
・Section 6.7.1 and 6.7.2: Described contents of analysis.
・Section 9.2.6: Added for descriptions not appropriate to be included in
section 9.2.3.
・Section 9.3: Added section to define renal disorder TEAEs and AESIs.
3.0
26-Jul-2023
Modification in the results of the consistency check between SAP and layout 
of TLFs.
1.
Modification of analysis.
・Section 6.4.2: Changed the type of analysis table by time period.
・Section 6.6.6: Added analysis table using concentration data.
・Section 6.6.8: Modification of the compliance definition to match the study
design and data structure.
2.
Clarification of definitions and maintenance of terminology.
・Section 6.3.2: Modification of analysis item names.
・Section 6.4.2: Clarified that “blood” is included in “blood products”.
・Section 6.5: Delete the definition of “rebound” not used for analysis.
・Section 6.5.2: Added the definition of “infection symptom control”.
・Section 6.5.2.4: Deletion of duplicate description.
・Section 6.5.4: Modification to align with updates in Section 6.3.2 (deletion
of an unnecessary subgroup).
・Section 6.6.2: Corrected the test items for CTCAE grading.
・Section 6.6.2, Section 6.6.3, Section 6.6.4: Corrected the definition of the
denominator in the calculation of the percentage by visit.
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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................4
LIST OF IN-TEXT TABLES ..........................................................................................................7
ABBREVIATIONS .........................................................................................................................8
1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................9
1.1
Objectives ......................................................................................................................9
1.1.1
Primary Objectives ................................................................................................9
1.1.2
Secondary Objectives ............................................................................................9
1.1.3
1.2
Endpoints .......................................................................................................................9
1.2.1
Primary Endpoints.................................................................................................9
1.2.2
Secondary Endpoints...........................................................................................10
1.2.2.1
Efficacy Endpoints......................................................................................10
1.2.2.2
Pharmacokinetic Endpoint ..........................................................................10
1.2.3
1.3
Estimands.....................................................................................................................11
2.0
STUDY DESIGN...............................................................................................................11
3.0
STATISTICAL HYPOTHESES AND DECISION RULES.............................................13
3.1
Statistical Hypotheses ..................................................................................................13
3.2
Statistical Decision Rules ............................................................................................13
3.3
Multiplicity Adjustment...............................................................................................13
4.0
SAMPLE-SIZE DETERMINATION................................................................................13
5.0
ANALYSIS SETS .............................................................................................................14
6.0
STATISTICAL ANALYSIS .............................................................................................15
6.1
General Considerations................................................................................................15
6.1.1
Handling of Treatment Misallocations................................................................15
6.2
Disposition of Subjects ................................................................................................16
6.2.1
Disposition...........................................................................................................16
6.2.2
Protocol Deviations .............................................................................................16
6.3
Demographic and Other Baseline Characteristics .......................................................17
6.3.1
Demographics......................................................................................................17
6.3.2
Baseline Characteristics.......................................................................................17
6.4
Medical History and Concurrent Medical Conditions.................................................19
6.4.1
Medical History...................................................................................................19
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6.6.4
Electrocardiogram (ECG)....................................................................................44
6.6.5
Other Safety Data ................................................................................................45
6.6.6
Immunosuppressant Drug Concentration Level..................................................45
6.6.7
Extent of Exposure and Compliance ...................................................................46
6.6.8
Measurement of Treatment Compliance .............................................................46
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................46
6.7.1
Pharmacokinetic Analysis ...................................................................................46
6.7.1.1
Drug Concentration.....................................................................................47
6.7.1.2
Handling Below Lower Limit of Quantitation Values................................47
6.7.1.3
Analysis of Pharmacokinetic Endpoints .....................................................47
6.7.2
Pharmacodynamic Analysis ................................................................................48
6.7.3
Biomarker Analysis.............................................................................................48
6.8
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................48
6.8.1
PRO Analysis ......................................................................................................48
6.8.2
Health Care Utilization Analysis.........................................................................48
6.9
Other Analyses.............................................................................................................48
6.10
Interim Analyses ..........................................................................................................48
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees].................................................................................................................48
7.0
REFERENCES ..................................................................................................................49
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES...................................................50
9.0
APPENDIX........................................................................................................................50
9.1
Changes From the Previous Version of the SAP.........................................................50
9.2
Data Handling Conventions.........................................................................................50
9.2.1
Repeated or Unscheduled Assessments of Safety Parameters ............................50
9.2.2
Handling of Missing, Unused, and Spurious Data ..............................................50
9.2.2.1
Missing Date of Investigational Product.....................................................50
9.2.2.2
Missing Date Information for Prior or Concomitant Medications
(Therapies/Procedures) ...............................................................................50
9.2.2.3
Missing Date Information for Adverse Events ...........................................52
9.2.2.4
Missing Severity Assessment for Adverse Events......................................52
9.2.2.5
Missing Relationship to Investigational Product for Adverse Events ........53
9.2.2.6
Character Values of Clinical Laboratory Variables....................................53
9.2.3
Definition of Visit Windows ...............................................................................53
9.2.4
Derivation of Maintenance for Secondary Endpoints .........................................54
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9.2.5 
Definition of Baseline ..........................................................................................55 
9.2.6 
Definition of Treatment Period ...........................................................................56 
9.3 
Definition of renal disorder TEAEs and AESIs ...........................................................56 
9.3.1 
Definition of Renal Disorder TEAEs ..................................................................56 
9.3.2 
Definition of AESIs .............................................................................................56 
9.4 
Analysis Software ........................................................................................................59 
LIST OF IN-TEXT TABLES 
Table 1 
Estimand Framework .............................................................................................11 
Table 2 
Assessments of Virological Response at Study Week 8 ........................................22 
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) ............................................................................................30 
Table 4 
Criteria for Potentially Clinically Significant Laboratory Tests ............................42 
Table 5 
Criteria for Potentially Clinically Important Vital Signs .......................................43 
Table 6 
Criteria for Potentially Clinically Significant ECG Values ...................................44 
Table 7 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables ................................................................................................................53 
Table 8 
Definition of Visit Windows ..................................................................................53 
Table 9.1 
Renal disorder ........................................................................................................56 
Table 9.2 
Taste disturbance ...................................................................................................56 
Table 9.3 
Immunosuppressant drug level increased ..............................................................57 
Table 9.4 
Gastrointestinal disorders.......................................................................................57 
Table 9.5 
Neutropenia ............................................................................................................57 
Table 9.6 
Tissue-invasive CMV disease ................................................................................57 
Table 9.7 
Graft-versus-host Disease ......................................................................................58 
Table 9.8 
Graft rejection ........................................................................................................59 
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ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
CI
confidence interval
Cmin
minimum observed plasma concentration
CMV
cytomegalovirus
COVID-19
coronavirus disease 2019 
CTCAE
Common Terminology Criteria for Adverse Events
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
GVHD
graft-versus-host disease
HLA
human leukocyte antigen
HSCT
hematopoietic stem cell transplant
ICE
intercurrent event
ICF
informed consent form
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
PCI
potentially clinically important
PCS
potentially clinically significant
PDs
Protocol deviations
PK
pharmacokinetics
PRO
patient-reported outcomes
PT
Preferred Term (MedDRA)
Q1
25th percentile
Q3
75th percentile
QTc
corrected QT interval
QTcF
QT Interval Corrected for Heart Rate using Fridericia’s Formula
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
SOC
System Organ Class
SOT
solid organ transplant
TEAE 
treatment-emergent adverse event
WHO
World Health Organization
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1.3
Estimands
Table 1
Estimand Framework
Estimand: Primary efficacy endpoint 
Definition
Attributes
Treatment
Population
Variable (or 
Endpoint)
Strategy for Addressing 
Intercurrent Event
Population-
Level 
Summary
The primary 
estimand is the 
Confirmed 
clearance of 
plasma CMV 
DNA of 
TAK-620 at 
Study Week 8
in targeted 
patient 
population
During the 
treatment 
phase (Study 
Week 1 to 
Study 
Week 8), 
TAK-620
will be 
administered 
twice daily.
Japanese 
HSCT or
SOT 
recipients 
with CMV
infection 
Confirmed 
clearance of 
plasma CMV 
DNA 
(confirmed 
CMV viremia 
clearance) at 
Study Week 8
The following intercurrent 
events (ICEs) are considered:
1. Taking alternative
anti-CMV treatment before
Study Week 8 regarded as
ICE.
2. Study discontinuation
without data to confirm
viremia clearance at Study
Week 8 regarded as ICE.
For these two types of ICEs, 
apply the composite variable 
strategy and assume 
non-response.
Handling of missing data is 
described in Section 6.5.1.1.
The 
proportion of 
subjects 
achieving the 
confirmed 
CMV viremia 
clearance at
Study Week 8 
and the 
corresponding 
95% exact CI
2.0 
STUDY DESIGN
This is a Phase 3, multicenter, open-label study to evaluate the efficacy, safety and tolerability, 
and PK of maribavir in Japanese HSCT or SOT recipients with CMV infection, including 
subjects with symptomatic CMV infection who are resistant or refractory to ganciclovir, 
valganciclovir, or foscarnet. The study will assess the efficacy of maribavir by measuring the 
plasma CMV DNA clearance at Study Week 8. To be eligible for the study, subjects must have a 
documented CMV infection with a screening value of >455 IU/mL in plasma in 2 consecutive 
assessments, separated by at least 1 day, as determined by a central specialty laboratory 
quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. 
Results should be available prior to the first study treatment administration to confirm subject 
eligibility for the study. Both samples should be taken within 14 days prior to first dose of study 
treatment with the second sample obtained within 5 days prior to first dose of study treatment at 
Visit 2/Day 0.
As shown in Figure 1 of the Protocol, the study will have 3 phases: (1) 2-week screening phase; 
(2) 8-week 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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
Screening Phase:
As presented in the Schedule of activities (SoA) (Table 1 of the Protocol), subjects will be 
screened from Day -14 to Day 0 to establish eligibility for study participation. If applicable, 
subjects who meet eligibility requirements will undergo washout of any prohibited medications, 
the length of which is specified in Table 6 of the Protocol.

Study Treatment Phase:
Once all screening assessments following informed consent (and assent where applicable) are 
completed and eligibility is confirmed, the subject will receive maribavir 400 mg BID for
8 weeks starting at Visit 2/Day 0.
Assessments to be performed at weekly study visits during treatment include: CMV DNA 
quantification testing, evaluation of symptoms suggestive of CMV disease, underlying disease 
assessments, graft outcomes and GVHD assessments, resolution or improvement of
tissue-invasive CMV disease (symptomatic subjects only), clinical laboratory testing
(hematology and chemistry), and concomitant medications and AE review. Pharmacokinetic 
sample collection, physical examination, vital sign assessment, ECGs, immunosuppressive drug 
level monitoring, and urinalysis will be conducted at selected visits throughout the treatment 
phase.
Monitoring of concomitant immunosuppressant concentration levels (eg, tacrolimus, 
cyclosporine, and everolimus) will be conducted at designated study time points. 
Cytomegalovirus DNA genotyping will be performed on samples at Baseline and in cases of 
rebound, or lack of response to therapy. 
Historical laboratory results for tests specified in the SoA (Table 1 of the Protocol) may be used 
for eligibility assessment (HIV or hepatitis test results) provided that these 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 study treatment administration and all clinical laboratory 
results required for eligibility verification must be available prior to treatment administration, 
including 2 separate CMV DNA assessments. Initiation of study treatment (ie, first dose) will 
only occur after completion of all required Visit 2/Day 0 procedures and confirmation of 
eligibility. This will be done under the supervision of investigator site personnel. If the baseline 
sample analyzed by central specialty laboratory reports mutation, then the subject will continue 
receiving treatment but will be excluded from the Per Protocol Set for analysis.
All subjects will perform study-specific evaluations weekly during the 8-week study treatment 
phase (Table 1 of the Protocol).
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
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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.
For subjects that, in the investigator’s judgment, have a lack of response or are unable to tolerate
treatment and require discontinuation of study treatment, alternative anti-CMV treatment may be
administered as deemed necessary. Subjects who discontinue study treatment prior to Study
Week 8 will complete the end of treatment procedures described for Study Week 8 in the SoA.
These subjects will follow a modified SoA through the remaining weekly visits of the study
treatment phase and regular SoA through the 12-week follow-up phase.
All subjects who complete the study treatment phase through Visit 10/Study Week 8 will enter
the 12-week follow-up phase.

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 SoA 2 (Table 2 of the Protocol). See Section 7 of the 
Protocol for details regarding discontinuation and withdrawal. 
If a subject is unable to travel to the site for the follow-up visits, AEs and SAEs 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.
3.0
STATISTICAL HYPOTHESES AND DECISION RULES
3.1
Statistical Hypotheses
Not applicable.
3.2
Statistical Decision Rules
Not applicable.
3.3
Multiplicity Adjustment
Not applicable.
4.0
SAMPLE-SIZE DETERMINATION
Post-transplant (SOT/HSCT) CMV infection is a rare condition and the number of patients 
expected to participate in this clinical trial in Japan is anticipated to be limited. For the start of 
domestic development of TAK-620, Takeda conducted a feasibility assessment for the planned 
clinical study. Specifically, a survey on the number of patients in university or large hospitals in 
Japan where HSCT or SOT are performed was carried out. The number of patients with 
asymptomatic CMV infection was estimated to be about 44 for HSCT and about 9 for SOT, for a 
total of about 53 patients. Assuming a dropout rate of 15%, approximately 44 patients with 
asymptomatic CMV infection/infection are expected to be enrolled. On the other hand, the
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number of patients with refractory or resistant CMV infection is very small, and only a few
patients (approximately 3) can be expected to be enrolled at the maximum.
From the standpoint of feasibility, approximately 44 asymptomatic patients and few resistant or
refractory patients are expected to be enrolled in this study.
The target number of patients with asymptomatic CMV infection should be determined from the
viewpoint of evaluating the similarities in outcome between the prospective study and the
overseas Phase III study (Study SHP620-302) as well as the feasibility of the new study.
For the proportion of patients who achieved CMV clearance at Week 8 in the TAK-620 group in
Study SHP620-302, since the results have not been available, we can assume 68%, which was
used as the estimation for sample size justification in Study SHP620-302. Regarding the
proportion of patients who achieved CMV clearance at Week 8 in this study, since it is the same
target population and primary endpoint as Study SHP620-302, it is appropriate to assume 68% as
Study SHP620-302.
In addition, we considered it appropriate to use -15% as a reference value for the difference in
the point estimate between studies based on the noninferiority margin used in 2 noninferiority
studies comparing valganciclovir and ganciclovir for CMV treatment (The study reported by
Chawla et al. (2012) and VICTOR study (Asberg et al. 2007).
With a sample size of 44 in asymptomatic patients, if the true response rates for this study is the
same as that of the Study SHP620-302, the probability of observing a response rate similar to
that of the Study SHP620-302 is high, that is, over 95% the point estimate from this study will be
above the point estimate of Study SHP620-302 minus 15%.
Of note, the similarity between SHP620-302 study and Japan study will be based on both the
primary endpoint and secondary endpoints.
5.0
ANALYSIS SETS

Enrolled Set: consists of all subjects who have signed an informed consent and have begun
some study procedures.

Full Analysis Set: consists of all subjects who have taken at least 1 dose of study treatment;
the Full Analysis Set will be used for efficacy analyses.

Per Protocol Set: consists of all subjects in Full Analysis Set who do not have major
predefined protocol deviations that may affect the primary efficacy assessment.
The major protocol deviations that lead to exclusion from the Per Protocol Set include but
are not limited to the following:
o
Early discontinuation defined as discontinuation from study treatment within 72 hours
of first dose of study assigned treatment
o
Violations of inclusion criteria #2-5 or 7
o
Violations of exclusion criteria #1, 2 or 8
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o
Received prohibited concomitant anti-CMV medications for more than one day while
on treatment

Any of the following systemic anti-CMV therapies:

Ganciclovir

Valganciclovir

Foscarnet

CMV immune globulin

IVIG

Leflunomide

Artesunate

Letermovir

Use of other investigational anti-CMV agent such as CMV specific T-cell
transfer (considered investigational)
o
If the result of maribavir resistance mutation at baseline is positive after study treatment
has been initiated for an assumed asymptomatic subject.

Safety Set: consists of all subjects who have taken at least 1 dose of study treatment. The
Safety set will be used for safety analyses.

Pharmacokinetic Set: consists of all subjects in the Safety Set who have plasma samples
drawn and tested for maribavir concentrations.
6.0
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 and 95% exact confidence intervals (CIs) will be presented for the estimated 25%, 
50%, and 75% times estimates.
6.1.1
Handling of Treatment Misallocations
Not applicable.
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6.2
Disposition of Subjects
6.2.1
Disposition
A listing of all Screen Failures (i.e. subjects who were screened but not entered Study Treatment 
Phase) will be presented along with reasons for screen failure.
The number and percentage (calculated using the Enrolled Set as the denominator) of Screen 
Failures by reason will be presented.
The number of subjects included in each analysis set (i.e., Full Analysis Set, Per Protocol Set, 
Safety Set, and Pharmacokinetic Set) will be summarized. Percentages will be provided using the 
subject enrolled in the study treatment period as the denominator.
The number and percentage (calculated using the subject enrolled in the study treatment period
as the denominator) of subjects in the following categories will be presented.

Completed 8-week study treatment or discontinued study treatment early and by reason for
early discontinuation of study treatment

Completed the 8-week treatment phase (regardless of number of weeks of treatment) or did
not complete the 8-week treatment phase

Status of subjects who completed the 8-week treatment phase (entered follow-up phase, did
not enter the follow-up phase)

Final status (i.e. study completer vs discontinued early). Completed the study at the end of
study, or discontinued from the study and by reason
In addition, the number of subjects enrolled, taken at least 1 dose of study treatment and 
completed will be tabulated by site for the subject enrolled in the study treatment period.
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.
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.
Major/minor protocol deviations will be summarized for the Safety Set by category and site. 
Major/minor protocol deviations will be listed for the Safety Set. A summary and listing of PDs 
causing subjects to be excluded from the Per Protocol Set will be provided. A summary of the 
number and percentage of subjects with any COVID-19 pandemic related deviations, major and 
minor, will be produced using Safety Set.
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6.3
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be determined using the screening visit or last
observation on or prior to first dose of study treatment, whichever is later.
Descriptive summaries of demographic and baseline characteristics will be presented for the Full 
Analysis Set and Per Protocol Set.
The same analyses as for the Full Analysis Set will be performed by subject type 
("Asymptomatic CMV infection" and "Resistant or Refractory CMV infection"(R/R)).
6.3.1
Demographics
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.
Age will be calculated as following:

Age (years): Integer value of ((date of Informed consent – date of birth) / 365.25)
BMI will be calculated as following:

BMI (kg/m2) = weight (kg)/ (height (m))2
6.3.2
Baseline Characteristics
The following baseline characteristics including transplant history and CMV history will be
summarized.
Baseline characteristics will be treated as categorical variables:

Current transplant type (SOT/HSCT)
o
If SOT,

by organ type
o
If HSCT

Underlying condition for current transplantation

Is this recurrence of underlying disease

Type of transplant (autologous, allogeneic)

If allogenic haploidentical (yes/no)

If allogenic human leukocyte antigen (HLA), match type

Stem cell source for current HSCT

Current graft status at baseline

Type of preparative conditioning regimen

History of transplants prior to the current transplant type (yes/no)
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
Number of HSCT transplants prior to current transplant

T-cell depletion modality

Was a donor T-cell infusion given post-HSCT (yes/no)

CMV serostatus (Donor positive/ recipient positive (D+/R+), Donor negative/ recipient
positive (D-/R+), Donor positive/ recipient negative (D+/R-), Donor negative/ recipient
negative (D-/R-)) overall and by transplant type (SOT, HSCT)

Is current CMV infection the first episode post-transplant? (yes/no)

Have history of CMV tissue invasive disease (yes/no) and by type

Category of current CMV infection based on investigator’s assessment (CMV Syndrome for
SOT subjects only, tissue invasive disease, asymptomatic)

Current CMV infection (Asymptomatic / Refractory or Resistant)

Baseline CMV DNA category based on central laboratory results (high/intermediate/low)*

Does subject have resistance mutation according to central laboratory result (yes/no)

If yes, region (UL97, UL54, UL27)

Acute GVHD status at baseline (presence/absence)

Chronic GVHD status at baseline (presence/absence)

Baseline total leukocyte (<2.7, ≥2.7 and <7, ≥7 10^9/L)
Baseline characteristics treated as continuous variable:

The nucleated cell number transplanted in 10^6 for the current transplant

Days from onset of current CMV infection to first dose of study treatment

Days from the current transplant to the first dose of study treatment

Days from the current transplant to onset of current CMV infection

Baseline total leukocyte count

Baseline CMV DNA levels from central laboratory
*Baseline CMV DNA concentration levels, based on plasma CMV DNA concentration as
determined by the most recent central specialty laboratory qPCR results, are classified as
follows:

high viral load with CMV DNA ≥91000 IU/mL

intermediate viral load ≥9100 and <91000 IU/mL

low viral load CMV DNA <9100 IU/mL
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6.4
Medical History and Concurrent Medical Conditions
All analyses for medical history and concurrent medical conditions will be conducted on the 
Safety Set, unless stated otherwise.
6.4.1
Medical History
The medical history will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) at the start of the study. The medical history will be 
summarized by system organ class (SOC) and preferred term (PT) for the Safety Set. Listing will 
be provided for the Enrolled Set.
6.4.2
Prior, Concomitant, and Post-Treatment Medications
World Health Organization (WHO) Drug Dictionary dated March 2021 or newer 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) 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 by ATC Level III and preferred drug name 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 factor uses", "immunosuppression drug use", "other anti-CMV drugs" and 
"blood and blood products use" ("blood" is "whole blood" and "blood products" are otherwise) 
will be summarized using the Safety Set for the on-treatment period.
The same analyses as for the immunosuppression drug use will be performed by subject type 
("Asymptomatic CMV infection" and "Resistant or Refractory CMV infection"(R/R)).
All prior, concomitant, and post-treatment medications will be provided in the by subject listings. 
Additionally, "immunosuppression drug use" and "blood and blood products use" will be 
provided in separate data listings.
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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; the on-treatment period is defined in Section 9.2.6.
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 Full Analysis Set, unless stated otherwise.
For the primary endpoint, secondary endpoints and subgroup analyses, the same analyses as for 
the Full Analysis Set will be performed by subject type (“Asymptomatic CMV infection” and 
“Resistant or Refractory CMV infection”(R/R)).
All CIs will be 2-sided 95% exact CIs, unless stated otherwise. 
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 treatments unless otherwise specified. Efficacy 
measurements after initiation of alternative non-study 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.
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., <34.5 IU/mL for primary efficacy endpoint, <137 IU/mL for 
secondary efficacy endpoint) when assessed by COBAS® 8800/COBAS® CMV Test at selected 
central specialty laboratory, in 2 consecutive post-baseline samples, separated by at least 5 days.
Confirmed recurrence of CMV viremia: defined as plasma CMV DNA concentration ≥LLOQ 
when assessed by COBAS® 8800/COBAS® CMV Test at selected central specialty laboratory in 
2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance.
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6.5.1
Primary Endpoint Analysis
6.5.1.1
Derivation of Endpoints
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 treatment through Study Week 8 (i.e., did not receive alternative 
non-study 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., <34.5 IU/mL), in 2 consecutive post-baseline samples 
separated by at least 5 days, regardless of whether study treatment was discontinued before the 
end of the stipulated 8 weeks of therapy. This is further described in Table 2 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 treatment:

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

No alternative anti-CMV DNA treatment prior to the primary or confirmatory sample
These criteria will be assessed by an algorithm that initially chooses a potential confirmatory 
sample (sample B) within the scheduled Week 8 Visit window 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 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 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.
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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 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 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.
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 “-”
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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
CMV: Cytomegalovirus
NA=not available for evaluation of study treatment effect; reason could be not assessable by lab, starting 
alternative anti-CMV, or withdrawal from study etc.
a Week 6 data, if available to evaluate the effect of study treatment, only to be used if Week 7 data are unavailable 
or missing
b Week 9 data, if available to evaluate the effect of study treatment, 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 treatment will be included (ie, prior to the start 
of alternative anti-CMV treatment if any).
"-" = CMV DNA concentration <LLOQ (<34.5 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.
6.5.1.2
Main Analytical Approach
The proportion of subjects achieving the confirmed CMV viremia clearance at Study Week 8 and 
the corresponding 95% exact CI will be calculated for the Full Analysis Set.
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 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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6.5.1.3
Supportive Analysis
In Section 6.5.1.3 we propose some supportive analyses. Some subjects classified as
non-responders due to missing data will be re-classified as responders or non-responders in some
supportive analyses.
The following 8 types of supportive analyses will be performed for the primary efficacy 
endpoint. These analyses will be conducted using the Full Analysis Set unless specified 
otherwise.
Type
Analysis Type
1
Analysis using Per Protocol Set
2
Analysis using subset defined by baseline CMV DNA concentration
3
Analysis restricted to subjects not impacted by COVID-19 pandemic
4
Analysis restricted to subjects who received 8 weeks of study treatment
5
Analysis allowing for the use of non-study anti-CMV treatment
6
Analysis treating subjects with confirmed viremia clearance at the time of early 
treatment discontinuation as responders
7
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
8
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
1.
Supportive Analysis 1: Analysis restricted to subjects in Per Protocol Set
(a). Rationale
An analysis of primary endpoint using subjects in Per Protocol Set is of clinical interest.
(b). Derivation of Endpoint:
The primary efficacy analysis will be performed in subjects in Per Protocol Set. This 
analysis will be conducted following the same methods as described in the primary 
analysis.
(c). Analytical Approach
Same as primary analysis (does not include summary of reasons for non-responder)
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2.
Supportive Analysis 2: 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
Same as primary analysis (does not include summary of reasons for non-responder)
3.
Supportive Analysis 3: 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 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 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 and who have 
not discontinued the study prior to Week 8 due to the COVID-19 pandemic
(c). Analytical Approach
Same as primary analysis (does not include summary of reasons for non-responder)
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4.
Supportive Analysis 4: Analysis restricted to subjects in Full Analysis Set who received
8 weeks of study treatment
(a). Rationale
An analysis of primary endpoint on a subset of subjects in Full Analysis Set who received 
8 weeks of study treatment is of clinical interest.
(b). Derivation of Endpoint:
The primary efficacy analysis will be performed in the subset of subjects in Full Analysis 
Set who received 8 weeks of study 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 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 (does not include summary of reasons for non-responder)
5.
Supportive Analysis 5: 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 assessed following the same method as
described for the primary endpoint of response at Study Week 8.
(c). Analytical Approach
Same as primary analysis (does not include summary of reasons for non-responder)
6.
Supportive Analysis 6: 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 if available will be ignored in this analysis.
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(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 treatment 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 then the first reading at least 5 days after
treatment discontinuation through 10 days after treatment discontinuation 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 (does not include summary of reasons for non-responder)
7.
Supportive Analysis 7: 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
(a). Rationale
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).
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(c). Analytical Approach
Same as primary analysis (does not include summary of reasons for non-responder)
8.
Supportive Analysis 8: 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
(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 supportive analysis 6, 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 (does not include summary of reasons for non-responder)
6.5.1.4
Supplementary Analyses
In Section 6.5.1.4, we propose some supplementary analyses. Some subjects classified as
non-responders due to missing data will be re-classified as responders or non-responders in some
supplementary analyses.
The following 2 types of supplementary analyses will be performed for the primary efficacy 
endpoint. These analyses will be conducted using the Full Analysis Set unless specified 
otherwise.
Type
Analysis Type
1
Analysis assessing non-responder imputation for subjects who discontinue 
study early with confirmed clearance at the time of study discontinuation
2
Analysis using additional imputation by taking account of COVID-19
impact
1.
Supplementary Analysis 1: 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 
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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.
(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 supplementary
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 study 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 
study 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 the study early (during the treatment phase) and take alternative CMV 
treatment prior to discontinuation will be classified as non-responders. Subjects who 
discontinue the 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
2.
Supplementary Analysis 2: Taking Account of COVID-19 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 
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deviations and electronic case report form (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 below 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 below 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.
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
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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
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
6.5.2
Secondary Endpoints Analysis
The analysis of secondary efficacy endpoints will be conducted using the Full Analysis Set 
unless otherwise specified.
For the following 2 secondary endpoints (a) and (b), the proportion of subjects reaching the
endpoint and the corresponding 95% exact CIs will be calculated.
The maintenance of the confirmed CMV viremia clearance and infection symptom control
achieved at Study Week 8 through Study Week 12 (4 weeks of post-treatment period), Study
Week 16 (8 weeks of post-treatment/follow-up phase), and Study Week 20 (12 weeks
post-treatment)
Confirmed-plasma CMV DNA at the end of Study Week 8 to be less than 137 IU/mL (CMV 
viremia clearance).
Details of derivations of virological response maintenance for (a) and (c) are contained in
Section 9.2.4 of the Appendix.
For the following (c) secondary endpoints, the number and the proportion of subjects reaching 
the endpoints will be calculated.
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The recurrence of confirmed CMV viremia during the 12-week follow-up period in subjects 
with confirmed viremia clearance at Study Week 8.
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 study-assigned treatment was
discontinued before the end of the stipulated 8 weeks of therapy, and maintenance of such effect
through Week 20, the subject must have received exclusively a study-assigned treatment. CMV
infection symptom control include:

Resolution or improvement of tissue invasive disease or CMV syndrome for symptomatic
subjects at baseline,

no new symptoms for subjects asymptomatic at baseline.
The investigator will perform the initial diagnosis of tissue-invasive CMV disease or CMV
syndrome for the symptomatic subjects at baseline and new occurrence of tissue invasive CMV
disease or CMV syndrome for the asymptomatic subjects at baseline through the study and will
continue with the assessment of the infection status (ie, no change, improvement, worsening, or
resolution) at subsequent visits throughout the study. 
6.5.2.1
The maintenance of the confirmed CMV viremia clearance and infection symptom 
control achieved at Study Week 8 through Study Week 12 (4 weeks of post-treatment 
period), Study Week 16 (8 weeks of post-treatment/follow-up phase), and Study 
Week 20 (12 weeks post-treatment)
For maintenance effect to be achieved at a time point, the subjects must have received
exclusively study 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 treatment was discontinued before the end of the stipulated 8 weeks of therapy, through 
Weeks 12, 16 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 treatment was discontinued
before the end of the stipulated 8 weeks of therapy;

Subjects who maintain the effect achieved at Study Week 8 through Week 12 (16 or 20) will
be classified as responder for Week 12 (16 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, 16, 20 will be conducted
following the same method as described for the primary endpoint.
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6.5.2.2
The time to first confirmed viremia clearance at any time during the study
Time to first confirmed viremia clearance is defined as time from the start date of first dose of 
study treatment to the date of confirmed viremia clearance (event), or the date of last CMV 
DNA assessment on study before the initiation of alternative anti-CMV treatment (censored). 
The date of confirmed viremia clearance is the first of two consecutive samples with plasma 
CMV DNA <LLOQ that meet the criteria of confirmed CMV viremia clearance. Patients who 
start alternative treatment prior to CMV viremia clearance will be censored at the day before the 
initiation of alternative treatment. Patients who never achieve viremia clearance and do not 
initiate alternative therapy will be censored at the last CMV assessment day on study.
Time to confirmed viremia clearance on study will be measured in days and is calculated as stop
(event or censored) date minus date of dosing plus 1 day.
The time to confirmed viremia clearance any time on study will be summarized using 
Kaplan-Meier method, and will also be summarized descriptively (minimum, median, and 
maximum).
Additionally, time to confirmed viremia clearance within Week 8 will be summarized.
6.5.2.3
The recurrence of confirmed CMV viremia requiring treatment during the 12-week 
follow-up period in subjects with confirmed viremia clearance at Study Week 8
All CMV DNA measurements after achieving confirmed viremia clearance will be included in 
the assessment.
The following recurrence of CMV viremia will be provided.

Of the number of subjects who achieved viremia clearance at Week 8, the number and
percentage of subjects who had recurrence requiring alternative anti-CMV treatment
afterwards
6.5.2.4
The time course of changes in plasma CMV viremia load from Baseline by study 
week
The CMV viral load, i.e., plasma CMV DNA concentration assessed by the central laboratory 
will be summarized and reported. The number (%) of subjects with plasma CMV DNA (Not 
Detected, detected <LLOQ, ≥LLOQ) by week on study after receiving study treatment and prior 
to non-study anti-CMV medication, will be provided.
Additionally, baseline and change from baseline in log10 plasma CMV DNA concentration from 
the central laboratory prior to receiving non-study anti-CMV therapy will be summarized 
descriptively. For analysis purpose, results reported as “Not detected” or “<LLOQ” will be 
imputed as half of the LLOQ value (i.e. 34.5/2=17.25) in the calculation. In addition, the viral 
load change over time will be presented using the plots by subject.
All CMV viral load data will be provided in data listing. CMV viral load data collected after the 
initiation of non-study anti-CMV treatment will be indicated in the data listing.
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6.5.4
Subgroup Analyses
The following list of subgroup analyses will be performed for the primary efficacy endpoint. The 
proportion of responders and the corresponding 95% exact CI for each endpoint will be 
summarized. Subgroup analysis results will be summarized in a forest plot.
Subgroup:

Transplant type (HSCT, SOT)
o
If SOT, by organ type

Symptomatic CMV Infection (CMV syndrome (SOT) or CMV tissue invasive disease)
(Yes/No)

CMV DNA viral load (high/intermediate/low)

Acute GVHD presence/absence at baseline

Age group, adjacent groups may be collapsed to have adequate sample size
o
<18 years of age
o
≥18 to <45 years of age
o
≥45 to <65 years of age
o
≥65 years of age

Gender

CMV serostatus (D+/R+, D-/R+, D-/R-, D+/R-)
6.6
Safety Analysis
The analysis of safety will be based on the “treatment-emergent” principle.
The safety analysis will be performed using the Safety Set, unless specified otherwise.
The safety analyses will include evaluation and procedures to meet the primary objective of
assessing the safety and tolerability of maribavir. Safety evaluation will be made during the
periods as illustrated in Figure 1 of the Protocol, 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 observation 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.
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
The overall-study observation 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 absolute
neutrophil count (ANC) <500/mm3 [0.5×109/L] or ANC <1,000/mm3 [1.0×109/L] at any
time during the study [on-treatment (defined as last dose date+7), and overall study period],
and time to neutropenia development).
Safety assessments will also include vital sign measurements, physical examination, and ECG.
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 Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 dated March 2021 or later.
An AE (classified by system organ class and preferred term) that has a start date on or after the 
first dose of study treatment or if it has a start date before the date of first dose of study treatment 
but increases in severity after first dose of study 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 
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 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, Section 9.2.2.4 and Section 9.2.2.5, 
respectively.
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 study treatment.
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
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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
TEAEs, any serious treatment-emergent adverse events (TESAEs), any severe TEAEs,
TEAEs and TESAEs causing discontinuation of study medication, TEAEs and TESAEs
leading to withdrawals from study and fatal AEs as well as the total number of events for
each category

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

Summary of frequently occurring in >= 10% TEAEs by PT in descending order

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

Summary of TEAEs by maximum severity, SOC, and PT

Summary of TEAEs related to study treatments by maximum severity, SOC, and PT

Summary of TESAEs by SOC and PT

Summary of TESAEs by maximum severity, SOC and PT

Summary of TESAEs considered related to study treatments by SOC and PT

Summary of TEAEs leading to study treatment discontinuation by SOC and PT

Summary of TEAEs leading to study discontinuation by SOC and PT

Summary of TEAEs related to study treatments leading to study treatment discontinuation
by SOC and PT

Summary of TEAEs related to study treatments leading to study discontinuation 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
TEAEs, any TESAEs, any severe TEAEs, TEAEs causing discontinuation of study
medication, TEAEs leading to withdrawals from study and fatal AEs, related TESAEs
leading to death as well as the total number of events for each category
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
Summary of TEAEs by SOC and PT, including the number and percentage of subjects with
a TEAE, as well as the total number of events

Summary of TEAEs related to study treatments by SOC and PT

Summary of TESAEs by SOC and PT

Summary of TEAEs leading to death by SOC and PT

Summary of related TESAEs by SOC and PT
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 and fatal AEs.
The following analyses as for the Safety Set for the on-treatment period will be performed by 
subject type ("Asymptomatic CMV infection" and "Resistant or Refractory CMV 
infection"(R/R)).

An overall summary of TEAEs, including the number and percentage of subjects with any
TEAEs, any TESAEs, any severe TEAEs, TEAEs and TESAEs causing discontinuation of
study medication, TEAEs and TESAEs leading to withdrawals from study and fatal AEs as
well as the total number of events for each category

Summary of TEAEs by SOC and PT, including the number and percentage of subjects with
a TEAE, as well as the total number of events

Summary of TEAEs related to study treatments by SOC and PT

Summary of TESAEs by SOC and PT

Summary of TESAEs considered related to study treatments by SOC and PT

Summary of TEAEs by maximum severity, SOC, and PT

Summary of TEAEs leading to study treatment discontinuation by SOC and PT

Summary of TEAEs related to study treatments leading to study treatment discontinuation
by SOC and PT
6.6.1.1
Renal Disorder TEAEs
The following summaries of sponsor-defined renal disorder TEAEs will be provided using the 
Safety Set for the on-treatment period, including the number and percentage of subjects as well 
as the total number of events:

Summary of renal disorder TEAEs by SOC and PT, including the number and percentage of
subjects with a renal disorder TEAE, as well as the total number of events

Summary of renal disorder TEAEs related to study treatments by SOC and PT

Summary of renal disorder TEAEs by maximum severity, SOC, and PT

Summary of renal disorder TEAEs related to study treatment by PT and maximum severity
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
Summary of serious renal disorder TEAEs by maximum severity, SOC, and PT

Summary of serious renal disorder TEAEs related to study treatment by PT and maximum
severity
The following analyses as for the Safety Set for the on-treatment period will be performed by 
subject type ("Asymptomatic CMV infection" and "Resistant or Refractory CMV 
infection"(R/R)).

Summary of renal disorder TEAEs by SOC and PT, including the number and percentage of
subjects with a renal disorder TEAE, as well as the total number of events

Summary of renal disorder TEAEs related to study treatments by SOC and PT
The list of renal disorder TEAEs is provided in respective tables in Appendix 9.3.
6.6.1.2
Adverse Events of Special Interest
The following summaries of adverse event of special interest (AESI) will be provided using the 
Safety Set for the on-treatment period and the overall study, including the number and 
percentage of subjects as well as the total number of events:

Summary of AESIs by category of AESI and PT, including the number and percentage of
subjects with a TEAE, as well as the total number of events

Summary of AESIs related to study treatments by category of AESI and PT
Class of AESIs:
•
Taste disturbance
•
Immunosuppressant drug level increased
•
Gastrointestinal disorders
•
Neutropenia
•
Tissue-invasive CMV disease
•
Graft-versus-host Disease
•
Graft rejection
The list of AESIs is provided in respective tables in Appendix 9.3.
The above analyses as for the Safety Set for the on-treatment period will be performed by 
subject type ("Asymptomatic CMV infection" and "Resistant or Refractory CMV 
infection"(R/R)).
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6.6.1.3
Subgroup Analysis for Adverse Events
The following list of subgroup analyses will be performed for the Safety Set.
Subgroup:

Transplant type (HSCT, SOT)

Age group, adjacent groups may be collapsed to have adequate sample size
•
<18 years of age
•
≥18 to <45 years of age
•
≥45 to <65 years of age
•
≥65 years of age

Gender
The following summaries of TEAEs will be provided for the on-treatment period for the 
subgroups:

Summary of TEAEs by SOC and PT

Summary of TEAESI by SOC and PT

Summary of TESAEs by SOC and PT
6.6.2
Clinical Laboratory Data
The clinical laboratory assessments are described in Section 8.2.3.4 of the study protocol at the 
time points specified in Table 1 and Table 2 of protocol. The L/H ratio (low-density lipoprotein/
high-density lipoprotein ratio) will be calculated as following:
 L/H ratio = low-density lipoprotein (mg/dL) / high-density lipoprotein results (mg/dL)
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 baseline. 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 separate data listings. 
Laboratory data during the follow-up period after initiation of non-study 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 
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.
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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
The following hematology and chemistry laboratory results will be graded according to the
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
version 5.0 or higher.

Hematology: White blood cell and differential counts (WBC), Hemoglobin, Platelet count,
International normalized ratio

Chemistry: Serum sodium, potassium, Bicarbonate/carbon dioxide, Glucose, Creatinine,
Calcium, Magnesium, Albumin, Direct bilirubin, ALT, AST, gamma-glutamyl transferase,
Alkaline phosphatase, Total cholesterol, Triglycerides
Shift tables showing the shift in NCI CTCAE 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.
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. 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 (last dose date +7) 
and the overall-study period will be provided. 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. For creatinine, an 
analysis of time from a lower grade to a maximum grade of 2, 3 or 4 post-baseline will be 
provided.
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Table 5
Criteria for Potentially Clinically Important Vital Signs
Vital Sign Parameter
Criteria
Observed Value
Change from Baseline
Pulse rate (beats per minute)
≤50
≥100
≥120
Weight (kg)
-
Increase of ≥7%
-
Decrease of ≥7%
Temperature (°C)
<35.0
>39.0
The above PCI analysis as for the Safety Set will be performed by subject type ("Asymptomatic 
CMV infection" and "Resistant or Refractory CMV infection"(R/R)).
All vital signs data will be listed for the Safety Set.
6.6.4
Electrocardiogram (ECG)
A 12-lead ECG will be performed at Visit 2/Week 0, Visit 10/Week 8 (end of treatment visit),
Visit 18/Week 20 (the on-treatment period and the overall-study period will be provided), and at 
any additional time during the study, if clinically indicated. ECG data will include heart rate, 
RR duration, PR duration, QT duration, and 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 visit. 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 assessment value
at each visit. A listing of all subjects with post-baseline PCS values will be provided including 
the subject number, site, baseline, and post-baseline PCS values.
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
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Table 6
Criteria for Potentially Clinically Significant ECG Values
ECG Parameter
Criteria
Observed Value
QT Interval Corrected for Heart 
Rate using Fridericia’s Formula 
(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
The above PCS analysis as for the Safety Set will be performed by subject type ("Asymptomatic 
CMV infection" and "Resistant or Refractory CMV infection"(R/R)).
All ECG data will be presented in a by-subject listing.
6.6.5
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.
The number and percentage of subjects receiving hemopoietic growth factors, blood, blood
products at least once and by type during the on-treatment period and overall-study period for the 
study treatment will be provided.
All blood and blood products transfusions will be provided in a data listing. A data listing
including the hemopoietic growth factors will be provided.
6.6.6
Immunosuppressant Drug Concentration Level
The analysis of immunosuppressant drug concentration level increased will be summarized for 
the Safety Set. 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: cyclosporine, tacrolimus and everolimus.
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6.6.7
Extent of Exposure and Compliance
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 DOSING ORAL
eCRF. The dose adjustment and dose interruption for study treatments will be collected on the 
eCRF. Available data collected on eCRF will be used in assessing the treatment exposure.

Exposure duration will be calculated as the number of days from the date of first dose of
study treatment to the date of the last dose of study treatment plus 1.

Actual exposure days to study treatment will be calculated as the number of days on which
at least 1 dose of study treatment was taken.
The measures of exposure will be summarized using descriptive statistics and will be reported.
All drug exposure and compliance information, study treatment administrations will be presented 
chronologically by subject in data listings.
6.6.8
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 total number of doses is calculated as total number of 
dispensed tablets - total number of returned tablets. 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 for 
the Safety Set.
Dose interruptions due to adverse events is allowed.
The following summaries for dose interruption will be provided:

Dose interruption:
o
The number and percentage of subjects with at least one interruption, total number of
interruption, and reason of interruption.
The above analyses as for the Safety Set will be performed by subject type ("Asymptomatic 
CMV infection" and "Resistant or Refractory CMV infection"(R/R)).
6.7
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses
6.7.1
Pharmacokinetic Analysis
All summaries and analyses of the pharmacokinetic data will be based on the Pharmacokinetic 
Set. Individual maribavir concentrations will be listed. Maribavir Cmin (predose maribavir 
concentration) will be summarized using descriptive statistics (n, mean, standard deviation (SD), 
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median, minimum, maximum, coefficient of variation, geometric mean, and geometric 
coefficient of variation) by Visit.
Additional analysis may be conducted and will be described in a separate pharmacokinetic data 
analysis plan if applicable.
6.7.1.1
Drug Concentration
Predose at Week 1, Week 4 and Week 8 and between 2 to 4 hour postdose at Week 1 and 
Week 8 will be collected.
Additional PK plasma samples will be collected from the subjects with biopsy-proven 
gastrointestinal graft-versus-host disease (GI GVHD) with diarrhea (>300 mL/day), 
biopsy-proven GI GVHD with nausea and vomiting, 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).
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 listings, but will be excluded from PK 
concentration summaries. Only pre-dose Cmin will be summarized.
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 descriptive statistics
(e.g. mean, SD, etc.) for the plasma concentrations at individual time points except for
geometric mean. Concentrations that are LLOQ will be excluded from the computation of
geometric mean.

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.

Missing 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 after last dosing. Planned pre-dose PK sample which were collected at post-dose 
time will be included in the listing with flag and exclude from descriptive statistics. Additionally, 
a by-subject listing of maribavir concentrations in subjects with GI GVHD will be generated. A 
by-subject listing of week 8 viremia response and recurrence of CMV viremia at any time due to 
low Maribavir concentrations during the treatment phase will be generated for subjects with Cmin 
(predose maribavir concentration) below LLOQ at one or more PK visits. 
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Maribavir Cmin will be summarized by visit using descriptive statistics (number of observations,
mean, SD, coefficient of variation, median, maximum, minimum and geometric mean, and
geometric coefficient of variation) using Pharmacokinetic Set. Planned pre-dose PK samples
which were collected at post-dose time will not be used in Cmin summary.
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. Cmin values that were below the 
LLOQ were imputed with ½ LLOQ.
Box plot of average Cmin by confirmed CMV viremia clearance response at Week 8 for all
subjects will be provided.
6.7.2
Pharmacodynamic Analysis
Not applicable.
6.7.3
Biomarker Analysis
Not applicable.
6.8
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis
6.8.1
PRO Analysis
Not applicable.
6.8.2
Health Care Utilization Analysis
Not applicable.
6.9
Other Analyses
Not applicable.
6.10
Interim Analyses
Not applicable.
6.11
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees]
No Data Monitoring Committee or Internal Review Committee is planned.
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7.0
REFERENCES
Asberg, A., Humar, A., Rollag, H., Jardine, A. G., Mouas, H., Pescovitz, M. D., et al. 2007. Oral 
valganciclovir is noninferior to intravenous ganciclovir for the treatment of 
cytomegalovirus disease in solid organ transplant recipients. Am J Transplant, 7(9), 
2106-13.
Chawla, J. S., Ghobadi, A., Mosley, J., 3rd, Verkruyse, L., Trinkaus, K., Abboud, C. N., et al. 
2012. Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients 
after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of 
the literature. Transpl Infect Dis, 14(3), 259-67.
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8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
Not applicable.
9.0
APPENDIX 
9.1
Changes From the Previous Version of the SAP
See “REVISION HISTORY”.
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 treatment, then the results from the 
most recent assessment prior to the start of study treatment will be used as baseline. If the end of 
study assessments is 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 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 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 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 treatment 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 presented 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 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. Coding of Special Character 
Values for Clinical Laboratory Variables are described in Table 7. However, the actual values as
reported in the database will be presented in data listings.
Table 7
Examples for Coding of Special Character Values for Clinical Laboratory
Variables
Clinical Laboratory
Possible Results (in SI units) 
Coded Value for Analysis
Chemistry: ALT
<5
0
Chemistry: AST
<5
0
Chemistry: Total Bilirubin
<2
0
Urinalysis: Glucose
≥55
Positive
≤0
Negative
Urinalysis: pH
≥8.0
8.0
9.2.3
Definition of Visit Windows
For the purpose of analysis, 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 analysis visits.
Visit windows are described in Table 8. If two measurements end up in one week, the
measurement closest to the scheduled visit study start will be used for the summary by week.
Assessments done on or before the first study treatment administration are considered baseline.
Table 8
Definition of Visit Windows
Analysis Visit
FROM
TO
Week 0
-x
0
Week 1
1
9
Week 2
10
16
Week 3
17
23
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Table 8
Definition of Visit Windows
Analysis Visit
FROM
TO
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
For the purpose of analysis, the week on study (Study Week 0 through Study Week 20) for all
efficacy measurements on treatment phase and follow-up phase will be determined based on the
analysis visits. If two measurements end up in one week, the measurement closest to the
scheduled visit study start will be used for the summary by week. The earlier measurement will
be classified as unscheduled. Measurements after day 146 will be classified as unscheduled.
Assessments done on or before the first study treatment administration are considered baseline.
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 (a) and (c) of Section 6.5.2, 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
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Statistical Analysis Plan v3.0
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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
Definition of Baseline 
The baseline value for efficacy variables is defined as the last available value before or on the
first dose date of study treatment on Visit 2/Week 0/Day 0.
Baseline safety analyses is defined as the last value for the assessment prior to taking the first
dose of study treatment.
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