Clinical trial NCT04497883
Conditions: Healthy Volunteers
Sponsor: Shire
Start date: 2020-08-07; Completion date: 2020-11-12
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare the pharmacokinetics (PK), safety, and tolerability of maribavir administered as a single oral dose in healthy, adult participants of Japanese descent and matched, healthy, adult, non-Hispanic, Caucasian participants. In addition, this study will assess the dose-proportionality of PK of maribavir in healthy, adult participants of Japanese descent.

Detailed description:
The study will be conducted in two cohorts, Cohort A and Cohort B. Cohort A consists of 12 participants of Japanese Descent. Cohort B consists of 12 non-Hispanic, Caucasian participants.

For Japanese participants there will be three treatment periods. In Treatment Period 1, they will receive maribavir as a single 400 mg oral dose. In Treatment Periods 2 and 3, all Japanese participants will receive maribavir as a single oral dose of either 200 mg or 800 mg, depending upon randomization assignment. For the non-Hispanic, Caucasian group there will be only one treatment period and they will receive maribavir as a single 400 mg oral dose.

Arms: arm 1: Non-Hispanic, Caucasian group participants will receive 400 milligram (mg) maribavir tablets orally once on Day 1 during treatment period 1. arm 2: Japanese descent group participants will receive 400 mg maribavir tablets orally once on Day 1 during treatment period 1 followed by 200 mg or 800 mg maribavir tablets orally once on Day 1 during treatment period 2 followed by 800 mg or 200 mg maribavir tablets orally once on Day 1 during treatment period 3 in cross-over fashion. A washout period of 72 hours will be maintained between treatment period 1, 2, and 3.
Interventions: intervention 1: Maribavir (400 mg) intervention 2: Maribavir (200 mg) intervention 3: Maribavir (800 mg)
Intervention descriptions: intervention 1: Non-Hispanic, Caucasian group and Japanese descent group participants will receive 400 mg maribavir tablets orally once on Day 1 during treatment period 1. intervention 2: Japanese descent group participants will receive 200 mg maribavir tablets orally once on Day 1 during treatment period 2 or 3. intervention 3: Japanese descent group participants will receive 800 mg maribavir tablets orally once on Day 1 during treatment period 2 or 3.

Protocol documents:
Prot_000.pdf: 
PROTOCOL: TAK-620-1020
TITLE:
A Phase 1, Open-label, Randomized, Cross-over Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of 
Maribavir Administered in Healthy Japanese Subjects Compared with 
Matched, Healthy, Non-Hispanic, Caucasian Subjects and to Assess 
Dose-Proportionality of 3 Doses of Maribavir in the Japanese Subjects
DRUG:
TAK-620 (Maribavir)
IND:
051001
EUDRACT NO.:
Non-EUDRACT
SPONSOR: 
Shire ViroPharma LLC (Shire, [and affiliates]); Shire is a wholly owned 
subsidiary of Takeda Pharmaceutical Company Limited 300 Shire Way, 
Lexington, MA 02421 USA 
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, DO, FACP
PROTOCOL 
HISTORY:
Protocol Amendment 1: 08 July 2020
Original Protocol: 03 April 2020
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.












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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the "Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious adverse 
events (AEs) as Required by the Protocol" within 24 hours to the Shire Global Drug Safety 
Department. The fax number and e-mail address are provided on the form (sent under separate 
cover). A copy of this form must also be sent to the contract research organization (CRO) 
(as applicable) and Shire Medical Monitor using the details below.
For protocol- or safety-related questions the investigator must contact the Shire Medical 
Monitor:
, MD, PhD, MPH
Shire Study Medical Monitor
Telephone: 
Cell phone: 
 (24-hour coverage)
E-mail: 
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the Shire Medical Monitor.


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire 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 Shire 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

Bottle/vial fill shortage or overage

Tablet damaged/broken

Vial cracked/broken

Product discoloration
Labeling

Label missing

Leaflet or Instructions For Use 
(IFU) 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

Particulate in packaging
Please report the product quality complaint using the “Product Quality Complaint Data 
Collection Form” via the email address:


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
EMERGENCY CONTACT INFORMATION................................................................................7
PRODUCT QUALITY COMPLAINTS..........................................................................................8
TABLE OF CONTENTS.................................................................................................................9
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
LIST OF APPENDICES................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
1.
BACKGROUND INFORMATION.......................................................................................28
1.1
Indication and Current Treatment Options...............................................................28
1.2
Product Background.................................................................................................29
1.2.1
Preclinical Information ..........................................................................................29
1.2.2
Clinical Information...............................................................................................29
1.2.3
Pharmacokinetics and metabolism.........................................................................29
1.2.4
Efficacy..................................................................................................................30
1.2.5
Safety .....................................................................................................................31
1.3
Risk/Benefit and Ethical Assessment.......................................................................32
1.4
Compliance Statement..............................................................................................32
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................33
2.1
Rationale for the Study.............................................................................................33
2.2
Study Objectives ......................................................................................................33
2.2.1
Primary Objective..................................................................................................33
2.2.2
Secondary Objectives.............................................................................................33
2.2.3
Exploratory Objective............................................................................................33
3.
STUDY DESIGN ...................................................................................................................34
3.1
Study Design and Flow Chart ..................................................................................34
3.2
Maximum Duration of Participation and Study Completion ...................................38
3.3
Sites and Regions .....................................................................................................38
4.
STUDY POPULATION.........................................................................................................39
4.1
Inclusion Criteria......................................................................................................39
4.2
Exclusion Criteria.....................................................................................................39
4.3
Restrictions...............................................................................................................41
4.4
Reproductive Potential .............................................................................................41
4.4.1
Female Contraception............................................................................................41


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4.4.2
Male Contraception................................................................................................42
4.5
Discontinuation of Subjects .....................................................................................42
4.5.1
Reasons for Discontinuation..................................................................................43
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................43
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................44
5.1
Prior Treatment ........................................................................................................44
5.2
Concomitant Treatment............................................................................................44
5.2.1
Permitted Treatment...............................................................................................44
5.2.2
Prohibited Treatment .............................................................................................44
6.
INVESTIGATIONAL PRODUCT ........................................................................................45
6.1
Identity of Investigational Product...........................................................................45
6.1.1
Blinding the Treatment Assignment......................................................................45
6.1.2
Unblinding the Treatment Assignment..................................................................45
6.2
Administration of Investigational Product(s)...........................................................45
6.2.1
Allocation of Subjects to Treatment ......................................................................45
6.2.2
Dosing....................................................................................................................46
6.2.3
Administration .......................................................................................................46
6.3
Labeling, Packaging, Storage, and Handling ...........................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................47
6.3.3
Storage ...................................................................................................................47
6.4
Drug Accountability.................................................................................................47
6.5
Subject Compliance..................................................................................................48
6.6
Retention of Bioavailability and Bioequivalence Testing Samples.........................48
7.
STUDY PROCEDURES........................................................................................................49
7.1
Study Schedule.........................................................................................................49
7.1.1
Screening Period....................................................................................................49
7.1.1.1
Screening Failure....................................................................................49
7.1.1.2
Rescreening of Subjects .........................................................................49
7.1.2
Predose Assessments .............................................................................................50
7.1.3
Treatment Periods..................................................................................................50
7.1.3.1
Treatment Period 1 (Non-Hispanic, Caucasian Subjects)......................50
7.1.3.2
Treatment Period 1 (Japanese Subjects).................................................50
7.1.3.3
Treatment Period 2 (Japanese Subjects).................................................50
7.1.3.4
Treatment Period 3 (Japanese Subjects).................................................50
7.1.4
Follow-up Period (All Subjects)............................................................................50
7.1.5
Additional Care of Subjects After the Study .........................................................51
7.2
Study Evaluations and Procedures ...........................................................................51


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7.2.1
Demographic and Other Baseline Characteristics .................................................51
7.2.1.1
Height and Weight .................................................................................51
7.2.2
Safety .....................................................................................................................51
7.2.2.1
Medical and Medication History............................................................51
7.2.2.2
Physical Examination (Including Height and Weight) ..........................52
7.2.2.3
Adverse Event Collection.......................................................................52
7.2.2.4
Vital Signs..............................................................................................52
7.2.2.5
Electrocardiogram ..................................................................................54
7.2.2.6
Clinical Laboratory Tests.......................................................................55
7.2.2.7
Pregnancy Test .......................................................................................56
7.2.2.8
Drug and Alcohol Screen .......................................................................56
7.2.2.9
Serology Screen......................................................................................57
7.2.3
Pharmacokinetic Procedures..................................................................................57
7.2.3.1
Blood Sample Collection and Handling Procedures..............................57
7.2.3.2
Plasma Drug Assay Methodology..........................................................57
7.2.4
Volume of Blood to be Drawn from Each Subject................................................57
8.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................59
8.1
Data Collection.........................................................................................................59
8.2
Clinical Data Management.......................................................................................59
8.3
Data Handling ..........................................................................................................59
8.4
Statistical Analysis Process......................................................................................59
8.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......60
8.6
Study Population ......................................................................................................60
8.7
Pharmacokinetic Analyses .......................................................................................60
8.7.1
Pharmacokinetic Endpoint(s).................................................................................60
8.7.1.1
Statistical Analysis of Pharmacokinetic Parameters ..............................61
8.8
Safety Analyses........................................................................................................62
8.9
Sample Size Calculation and Power Considerations................................................63
9.
REFERENCES .......................................................................................................................64
10. PROTOCOL HISTORY.........................................................................................................66


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LIST OF TABLES
Table 1
Schedule of Assessments for Subjects of Japanese Descent.........................21
Table 2
Detailed Schedule of Assessments for Subjects of Japanese Descent 
for Days 1 and 2 of Treatment Period 1 ........................................................23
Table 3
Detailed Schedule of Assessments for Subjects of Japanese Descent 
for Days 1 and 2 of Treatment Period 2 ........................................................24
Table 4
Detailed Schedule of Assessments for Subjects of Japanese Descent 
for Days 1 and 2 of Treatment Period 3 ........................................................25
Table 5
Schedule of Assessments for Non-Hispanic, Caucasian Subjects.................26
Table 6
Detailed Schedule of Assessments for Non-Hispanic Caucasian 
Subjects for Days 1 and 2 of Treatment Period 1..........................................27
Table 7
Volume of Blood to be Drawn from Each Subject........................................58
LIST OF FIGURES
Figure 1
Study Design Flow Chart ..............................................................................37
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations ............................67
Appendix 2
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .........................................................74


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ABBREVIATIONS
AE
adverse event
AUC
area under the curve
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-inf
area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration
AUC0-inf%extrap
The percent of AUC0-inf extrapolated, calculated by (1-AUClast/AUC0-inf)*100
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
BID
twice daily
Cmax
maximum concentration 
CL/F
oral clearance 
CMV
cytomegalovirus
CRA
clinical research associate
CRC
clinical research center
CRF
case report form
CRO
contract research organization
CV
coefficient of variation
CV%
percent coefficient of variation
CYP
cytochrome P450
DNA
deoxyribonucleic acid
EC
Ethics Committee
ECG
electrocardiogram
EMA
European Medicines Agency
EU
European Union
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
hepatitis B surface antibody
HCV
hepatitis C virus
HDPE
high density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplants 
IB
Investigator’s Brochure


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IP
investigational product (investigational drug)
IRB
Institutional Review Board
IV
intravenous
z
first order rate constant associated with the terminal (log linear) portion of the 
curve
P-gp
P-glycoprotein
PK
pharmacokinetics
PT
preferred term
QTc
corrected QT interval
QTcF
The corrected QT interval by Fredericia Correction Formula
SAE
serious adverse event
SAP
statistical analysis plan
SOT
solid organ transplant
SUSAR
Suspected Unexpected Serious Adverse Reaction 
t1/2
terminal half-life
TEAE
treatment-emergent adverse event
TID
3 times daily
Tlag
Delay between the time of dosing and time of appearance of drug
(investigational) in plasma in the employed sampling scheme
tmax
time of maximum observed concentration sampled during a dosing interval
TSH
thyroid-stimulating hormone
US
United States
US FDA
United States Food and Drug Administration
US CFR
United States Code of Federal Regulations 
Vdz/F
Apparent volume of distribution 




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Rationale:
This study is being conducted to compare the PK, safety, and tolerability of maribavir administered as a single 
oral dose in healthy adult subjects of Japanese descent and matched, healthy, adult non-Hispanic, Caucasian 
subjects. In addition, this study will assess the dose-proportionality and PK of maribavir in healthy, adult 
subjects of Japanese descent.
In accordance with the ICH-E5, this study is designed to evaluate whether there is any ethnic difference in PK 
and safety of maribavir between Japanese and non-Japanese subjects. These data will inform the bridging of 
safety and efficacy data from non-Japanese subjects to the Japanese population.
The results from this study will be utilized to guide dose selection for a future Phase 3 study in Japanese 
transplant patients with cytomegalovirus (CMV) infection.
Investigational product, dose, and mode of administration:
Maribavir is the investigational product (IP) for this study and will be administered orally as a single 200 mg 
(1×200 mg tablet, current Phase 3 formulation), 400 mg (2×200 mg tablets), and 800 mg (4×200 mg tablets) 
dose.
Methodology:
This is a Phase 1, open-label, randomized, crossover, partially fixed sequence, single-center study to evaluate 
the PK profile, safety, and tolerability of maribavir administered in healthy, adult subjects of Japanese descent 
and matched, healthy, adult, non-Hispanic, Caucasian subjects. The non-Hispanic, Caucasian subjects will 
receive a single oral dose of 400 mg maribavir on Day 1. For this cohort there will be one treatment period 
(Table 5 and Table 6).The Japanese subjects will receive 3 doses of maribavir separated by a 72-hour washout 
period between doses: in Treatment Period 1 on Day 1, they will receive a single oral dose of 400 mg of 
maribavir; in Treatment Period 2 and Treatment Period 3 on Day 1, they will be randomized to receive a single 
oral dose of either 200 mg followed by 800 mg of maribavir or vice versa (Table 1, Table 2, Table 3, and 
Table 4). A total of 24 subjects will be enrolled: 12 subjects of Japanese descent and 12 non-Hispanic, 
Caucasian subjects. Non-Hispanic, Caucasian subjects will be matched to Japanese subjects based on age 
(years), sex, and BMI (15%). 
The study will comprise a 28-day screening period, Treatment Period 1 for the non-Hispanic, Caucasian cohort, 
and Treatment Periods 1, 2, and 3 for the subjects of Japanese descent. There will be a post-treatment follow-up 
telephone call at 7 (±4) days after the last dose of IP for all subjects. Screening will occur within 28 days of the 
first dose. Subjects will be admitted to the clinical research center (CRC) on Day -1. All subjects (Japanese and 
Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive 
identical meals on Day 1 (up to 24 hours post dose) in all treatment periods to maintain control. Doses will be 
administered with a glass (240 mL) of room temperature water after at least a 10-hour overnight fasting, with 
water restricted 1 hour before and 1 hour after dosing. Food will be provided to subjects approximately 4 hours 
after study drug administration. Vomiting occurring within 4 hours after dosing will be recorded. There will be 
at least a 72-hour washout between maribavir doses for the subjects of Japanese descent.
The total number of nights subjects will be expected to stay at the CRC is approximately 2 for the non-Hispanic, 
Caucasian subjects and approximately 8 for the subjects of Japanese descent. The maximal total duration of 
study participation for a non-Hispanic, Caucasian subject is approximately 37 days and approximately 47 days 
for the subjects of Japanese descent, if the maximum screening period, treatment, washout, and follow-up visit 
durations are used. 
Treatment Period:

In Treatment Period 1, all study subjects (both Japanese and Caucasian) will receive maribavir as a 
single oral dose of 400 mg.

In Treatment Periods 2 and 3, all subjects of Japanese descent will receive maribavir as a single oral 
dose of either 200 mg or 800 mg, depending upon randomization assignment.


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Assessments

Serial blood samples for PK analysis will be collected in each treatment period for the determination of 
maribavir and 
 plasma concentrations at pre-dose and up to approximately 24 hours post dose. 
These blood samples will be collected according to the Schedules of Assessments (Table 1, Table 2, 
Table 3, Table 4, Table 5, and Table 6).

Safety and tolerability will be determined through assessment of treatment-emergent adverse events 
(TEAEs) from the first dose to the post-treatment follow-up telephone call at 7 (±4) days after the last 
dose of IP, and vital signs, electrocardiogram (ECG), and clinical laboratory evaluations on Day 1 
pre-dose and up to 24 hours post dose in each treatment period.
Follow-up

A post-treatment follow-up telephone call will occur at 7 (±4) days after the last dose of IP for each 
subject. Subjects who experience AEs will be followed longer if needed, including an unscheduled 
clinic visit if appropriate, depending on the nature, severity, and seriousness of the AE.
Inclusion and exclusion criteria:
Inclusion Criteria:
1.
An understanding, ability, and willingness to fully comply with study procedures and restrictions. 
2.
Ability to voluntarily provide written, signed, and dated (personally or via a legally-authorized 
representative) informed consent/assent as applicable to participate in the study.
3.
Healthy subjects of Japanese descent must have been born in Japan and must not have lived outside of 
Japan for >10 years; both parents and all 4 grandparents must be of Japanese origin. Healthy, 
non-Hispanic, Caucasian subjects must have both parents and all 4 grandparents of non-Hispanic, 
Caucasian origin.
4.
Age 18 years to 55 years, inclusive at the time of consent. The date of signature of the informed 
consent is defined as the beginning of the screening period. This inclusion criterion will only be 
assessed at the first screening visit.
5.
Male, or non-pregnant, non-breastfeeding female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential. 
6.
Healthy as determined by the investigator on the basis of screening evaluations. Healthy status is 
defined by absence of evidence of any active or chronic disease following a detailed medical and 
surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, 
blood chemistry (includes thyroid stimulating hormone [TSH] and free T4 at screening only), and 
urinalysis.
7.
Hemoglobin for males 135.0 g/L and females 120.0 g/L at screening and on Day -1.
8.
BMI between 18.5 and 28.0 kg/m2 inclusive and a body weight >45 kg (99 lbs.). This inclusion 
criterion will only be assessed at the first screening visit.
9.
Ability to swallow a dose of IP.
Exclusion Criteria:
1.
History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological, or psychiatric 
disease, gall bladder removal, or current recurrent disease that could affect the action, absorption, or 
disposition of the IP, or clinical or laboratory assessments.
2.
Current or relevant history of physical or psychiatric illness, any medical disorder that may require 
treatment or make the subject unlikely to fully complete the study, or any condition that presents undue 
risk from the IP or procedures.
3.
Known or suspected intolerance or hypersensitivity to maribavir, closely-related compounds, or any of 
the stated ingredients.
4.
Significant illness, as judged by the investigator, within 2 weeks of the first dose of IP.
5.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first 
dose of IP.
6.
Have taken another IP within 30 days or five half-lives of that IP, whichever is greater, prior to the first 
dose of maribavir.
7.
Have been enrolled in a clinical study (including vaccine studies) within 30 days prior to the first dose 


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of IP that, in the investigator’s opinion, may impact this study.
8.
Have had any substantial changes in eating habits within 30 days prior to the first dose of IP, as 
assessed by the investigator.
9.
Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood pressure 
>89 mmHg or <49 mmHg.
10. Twelve-lead ECG demonstrating corrected QT interval (QTc) >450 msec at screening. If QTc exceeds 
450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be 
used to determine the subject’s eligibility. 
11. Known history of alcohol or other substance abuse, including synthetic cannabinoids within the last 
year.
12. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. Female subjects 
who consume more than 14 units of alcohol per week or 2 units per day. (1 alcohol unit=1 beer or 
1 wine [5 oz/150 mL] or 1 liquor [1.5 oz/40 mL] or 0.75 oz alcohol).
13. A positive urine test for drugs of abuse, alcohol, or cotinine at screening or on Day -1.
14. A positive human immunodeficiency virus (HIV), hepatitis B surface antibody (HBsAg), or hepatitis C 
virus (HCV) antibody screen.
15. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form 
(eg, gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to 
receiving the first dose of IP.
16. Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine 
withdrawal headaches. (1 caffeine unit is contained in the following items: one 6 oz [180 mL] cup of 
coffee, two 12 oz [360 mL] cans of cola, one 12 oz cup of black tea, and three 1 oz [85 g] chocolate 
bars. (Decaffeinated coffee, herbal tea, or cola are not considered to contain caffeine).
17. Prior screen failure, randomization, enrollment, or participation in this study.
18. Current use of any prescription medication (with the exception of hormonal replacement therapy) 
within 30 days of the first dose of IP. Current use of any over the counter medication (including herbal 
preparations like St. John’s wort and ginkgo biloba, or homeopathic preparations) within 14 days of the 
first dose of IP.
19. Ingestion of known cytochrome P450 (CYP)3A modulators within 7 days of Day 1, Period 1 (includes 
grapefruit or grapefruit juice, oranges, Seville oranges, vegetables from the mustard green family [eg, 
kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard], charbroiled meats, and 
products containing these ingredients).
20. History of active or chronic oral/nasal cavity infections, gastroesophageal reflux, asthma treatment with 
albuterol, zinc supplementation.
21. Subjects with dry mouth syndrome or burning mouth syndrome or menopausal women suffering from 
dysgeusia.
22. Subjects who have acute gastrointestinal symptoms at screening or admission (eg, nausea, vomiting, 
diarrhea, and heartburn).
Maximum duration of subject involvement in the study:

Planned duration of screening period: Subjects will be screened within 28 days prior to the first dose of the 
IP.

Planned duration of treatment period: All subjects will be admitted to the CRC on Day -1. Caucasian 
subjects will be administered a single oral dose of maribavir 400 mg on Day 1 and will be discharged on 
Day 2. They will spend a total of approximately 3 days and 2 nights at the CRC. Subjects of Japanese 
descent will receive a single oral dose of 400 mg maribavir on Day 1 in Treatment Period 1, and will be 
dosed in a crossover fashion with a single dose of maribavir of either 200 mg or 800 mg based on their 
randomization assignment on Day 1 in Treatment Periods 2, and 3. They will spend in total approximately 
9 days and 8 nights at the CRC.

Planned duration of washout period between single doses of maribavir for the subjects of Japanese descent: 
There will be a 72-hour washout period from single dose to single dose of maribavir. This is not applicable 
for Caucasian subjects, as they will receive one single dose of maribavir. 

Planned duration of follow-up: There will be a post-treatment follow-up telephone call at 7 (±4) days after 
the last dose of IP for each subject. Subjects who experience AEs will be followed longer if needed, 




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parameters will be presented as well. 
Figures of individual and mean (±SD) maribavir concentration-time profiles will be generated on linear and 
semi-log scales. The mean plots will be generated and presented by overlaying the Japanese cohort and 
non-Hispanic, Caucasian cohort. Figures of PK parameters and dose-normalized Cmax, AUClast, and AUC0-inf vs. 
dose in Japanese subjects will be generated. Box-Whisker plots for selected PK parameter will be generated 
with Japanese cohort and non-Hispanic Caucasian side by side. 
In order to compare the PKs of maribavir between subjects of Japanese descent and matched, non-Hispanic, 
Caucasian subjects, the differences of log-transformed PK parameters (AUClast, AUC0-inf, and Cmax) from the 
maribavir 400 mg oral dose will be examined between cohorts using an analysis of variance model. The 
geometric mean ratio and its 90% CI of PK parameters will be provided from the model. In addition, the 
difference of log-transformed dose-normalized AUC0-inf, AUClast and Cmax will be examined between the 
Japanese cohort estimated at the 200 mg dose and the non-Hispanic, Caucasian cohort estimated at the 400 mg 
dose, as well as between the Japanese cohort estimated at the 800 mg dose and the non-Hispanic, Caucasian 
cohort estimated at 400 mg dose, using an analysis of variance model. The geometric mean ratio and its 90% CI
of PK parameters will be provided from the model. Forest plots of geometric mean ratios for selected PK 
parameters between Japanese cohort and the non-Hispanic Caucasian cohort at 400 mg will be generated. 
 
Dose proportionality will also be examined for maribavir PK parameters for the Japanese subjects. Dose 
proportionality will be assessed for Cmax and AUC (AUClast and AUC0-inf) using the power model. The power 
model assumes a linear relationship between the natural log transformed PK parameter and the natural log 
transformed dose.
ln (Parameter) = α + β × ln (Dose) + Random error
Where α is the intercept, β is the slope, and Random error is a random residual error. Dose proportionality will 
be assessed by estimating mean slope with the corresponding two-sided 90% CI from the power model. The fold 
increase in PK parameters and associated 90% CI when doubling the dose will be presented. 
 
Safety Endpoints:
Safety will be assessed for the following evaluations:

Number, severity, seriousness, and causality of TEAEs

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and urinalysis) 
from baseline to post-baseline time points. Baseline is defined as the last non-missing assessment prior 
to the first dose.
Statistical Methodology for Safety Endpoints:
Safety data, including TEAEs, laboratory tests, ECGs, and vital signs, will be summarized. Quantitative safety 
data, as well as the difference from baseline, if applicable, will be summarized by descriptive statistics. 
Frequency counts will be compiled for classification of qualitative safety data. Direct safety comparisons 
between the two cohorts will be presented from the maribavir 400 mg dosing data. All other safety data from the 
200 mg and 800 mg doses in the subjects of Japanese descent will be summarized and listed. 
Sample Size Justification:
The sample size consideration for the primary objective of evaluating the PK profile of maribavir, administered 
as a single oral dose at 400 mg, between Japanese subjects and matched, healthy, adult, non-Hispanic, 
Caucasian subjects is based on feasibility and comparable studies. A total of 24 subjects (12 subjects of 
Japanese descent and 12 matched, non-Hispanic, Caucasian subjects) will be targeted to be enrolled in the study.


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Maribavir
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Table 1
Schedule of Assessments for Subjects of Japanese Descent
Visit
Screening
Pre-dose 
Assessments
Treatment 
Period 1
Washout 
Periodi
Treatment 
Period 2
Washout 
Periodi
Treatment 
Period 3
Early 
Termination
Follow-upj
Study Day
–28 to -02
-1
1
2
3-5
1
2
3-5
1
2
7 (±4)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographya
X
Medical/medication 
history
X
X
Physical examination
X
Xb
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
temperature, and 
respiratory rate)c
X
X
X
X
X
X
X
X
X
Height and weightd
X
X
X
X
X
X
X
Electrocardiogram 
(12-lead)
X
X
X
X
X
X
X
X
X
Biochemistry, 
hematology, and 
urinalysis
X
X
X
X
X
X
X
X
X
HIV, HBsAg, and 
HCV antibodies
X
Serum β-HCG 
pregnancy test 
(females only)e
X
X
Urine pregnancy test 
(females only)e
X
X
X
X
Urine drug, alcohol, 
and cotinine screeningf
X
X
IP administrationg
X
X
X
PK blood samplingh
X
X
X
X
X
X
Check-in to the CRC
X
Discharge from the 
CRC
X


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TAK-620-1020 Protocol Amendment 1
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Table 1
Schedule of Assessments for Subjects of Japanese Descent
Visit
Screening
Pre-dose 
Assessments
Treatment 
Period 1
Washout 
Periodi
Treatment 
Period 2
Washout 
Periodi
Treatment 
Period 3
Early 
Termination
Follow-upj
Study Day
–28 to -02
-1
1
2
3-5
1
2
3-5
1
2
7 (±4)
Adverse 
events/serious adverse 
eventsi
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
β-hCG=β-human chorionic gonadotropin; BP=blood pressure; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; IP=investigational product; PK=pharmacokinetic
a Subjects must have been born in Japan and must not have lived outside of Japan for >10 years; both parents and all 4 grandparents of must be of Japanese 
origin. 
b If more than 2 days have passed since screening, a physical examination should be repeated on Day -1.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) 
arm with the higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d Height will be recorded at the screening visit only.
e Serum β-hCG testing is required at screening and on Day -1 for all female subjects. 
f Tests for drugs of abuse, alcohol, and cotinine will be performed at screening and on Day -1. Testing for alcohol on Day -1 will be performed using an on-site 
breathalyzer test. 
g All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before 
and 1 hour after dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive 
identical meals on Day 1 (up to 24 hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP 
administration. Vomiting occurring within 4 hours after dosing will be recorded.
h PK samples will be collected pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours post dosing with the IP on Day 1 of all 3 treatment periods.
i Washout period of a minimum of 72 hours and a maximum of 73 hours after administration of the IP on Day 1. Following the washout period, subjects will be 
asked regarding concomitant medications and any AEs.
jThere will be a post-treatment follow-up telephone call at 7 (±4) days after the last dose of IP. Subjects who experience AEs will be followed longer if needed, 
including an unscheduled clinic visit if appropriate, depending on the nature, severity, and seriousness of the AE.


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Table 2
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 1
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xe
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,c
Xe
X
X
Weightb
Xe
Electrocardiogram (12-lead)b,d
Xe
X
X
Biochemistry, hematology, and urinalysisb
Xe
X
IP administrationf
X
PK blood samplingg
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xe
X
X
X
Concomitant medicationb
Xe
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 1 and Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the 
last dose of investigational product in Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications 
and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) 
arm with the higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. 
The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
eBlood sampling assessments should be performed within 30 minutes prior to dose administration.  All other predose assessments should be completed within 60
minutes of dose administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration. 
f All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before 
and 1 hour after dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive 
identical meals on Day 1 (up to 24 hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP 
administration. Vomiting occurring within 4 hours after dosing will be recorded.
g The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK 
blood collection must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-
dose or by more than 15 minutes for samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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Table 3
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 2
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xf
Randomizationc
Xf
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,d
X f
X
X
Weightb
Xf
Electrocardiogram (12-lead)b,e
Xf
X
X
Biochemistry, hematology, and urinalysisb
Xf
X
IP administrationg
X
PK blood samplingh
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xf
X
X
X
Concomitant medicationb
Xf
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in Treatment Period 1 and 
Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Randomization will occur in Treatment Period 2, Day -1 or Day 1.
d Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the 
higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
e If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. The subject must be 
resting in the supine position for at least 5 minutes prior to collecting the ECG.
f Blood sampling assessments should be performed within 30 minutes prior to dose administration.  All other predose assessments should be completed within 
60 minutes of dose administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration. 
g All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before and 1 hour after 
dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive identical meals on Day 1 (up to 
24 hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours 
after dosing will be recorded.
h The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-dose or by more than 15 minutes for 
samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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TAK-620-1020 Protocol Amendment 1
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Table 4
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 3
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xe
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,c
Xe
X
X
Weightb
Xe
X
Electrocardiogram (12-lead)b,d
Xe
X
X
Biochemistry, hematology, and urinalysisb
Xe
X
IP administrationf
X
PK blood samplingg
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xe
X
X
X
Concomitant medicationb
Xe
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 1 and Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the 
last dose of investigational product in Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications 
and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) 
arm with the higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. 
The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Blood sampling assessments should be performed within 30 minutes prior to dose administration.  All other predose assessments should be completed within
60 minutes of dose administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration.
f All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before 
and 1 hour after dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive 
identical meals on Day 1 (up to 24 hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP 
administration. Vomiting occurring within 4
hours after dosing will be recorded.
g The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK 
blood collection must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-
dose or by more than 15 minutes for samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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Table 5
Schedule of Assessments for Non-Hispanic, Caucasian Subjects
Visit
Screening
Predose Assessments
Treatment Period 1
Early Termination
Follow-upi
Study Day
–28 to -02
-1
1
2
7 (±4)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographya
X
Medical/medication history
X
X
Physical examination
X
Xb
X
X
X
Vital signs (BP, pulse, temperature, and respiratory rate)c
X
X
X
X
X
Height and weightd
X
X
X
X
X
Electrocardiogram (12-lead)
X
X
X
X
X
Biochemistry, hematology, and urinalysis
X
X
X
X
X
HIV, HBsAg, and HCV antibodies
X
Serum β-HCG pregnancy test (females only)e
X
X
Urine pregnancy test (females only)e
X
X
Urine drug, alcohol, and cotinine screening f
X
X
IP administrationg
X
PK blood samplingh
X
X
Check-in to the CRC
X
Discharge from the CRC
X
Adverse events/serious adverse eventsi
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
β-hCG=β-human chorionic gonadotropin; BP=blood pressure; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; IP=investigational product; PK=pharmacokinetic
a Subjects must have both parents and all 4 grandparents of non-Hispanic, Caucasian descent. 
b If more than 2 days have passed since screening, a physical examination should be repeated on Day -1.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the 
higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d Height will be recorded at the screening visit only.
e Serum β-hCG testing is required at screening and on Day -1 for all female subjects. Urine pregnancy tests will be performed prior to dosing on Day 1 for all female subjects. 
f Tests for drugs of abuse, alcohol, and cotinine will be performed at screening and on Day -1. Testing for alcohol on Day -1 will be performed using an on-site breathalyzer test.
g All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before and 1 hour after 
dosing. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours after dosing will be recorded. 
h Collection time points for PK sampling will include pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours post dosing with the IP on Day 1.
i There will be a post-treatment follow-up telephone call at 7 (±4) days after the last dose of IP. Subjects who experience AEs will be followed longer if needed, including an 
unscheduled clinic visit if appropriate, depending on the nature, severity, and seriousness of the AE.


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Table 6
Detailed Schedule of Assessments for Non-Hispanic Caucasian Subjects for Days 1 and 2 of Treatment Period 1
Study Day
Day 1
Day 2
Hour (relative to dosing 
time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
Xd
Vital signs (BP, pulse, 
temperature, and respiratory 
rate)a,b
Xd
X
X
Weighta
Xd
X
Electrocardiogram (12-lead)a,c
Xd
X
X
Biochemistry, hematology, 
and urinalysisa
Xd
X
IP administratione
X
PK blood samplingf
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious 
adverse eventsa
Xd
X
X
X
Concomitant medicationa
Xd
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) 
arm with the higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
c If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. 
The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.  
d Blood sampling assessments should be performed within 30 minutes prior to dose administration.  All other predose assessments should be completed within 
60 minutes of dose administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration.
e All maribavir doses will be administered with a glass (240 mL) of room temperature water after a 10 hour overnight fasting, with water restricted 1 hour before 
and 1 hour after dosing. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours after dosing will be 
recorded.
f The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK 
blood collection must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-
dose or by more than 15 minutes for samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Cytomegalovirus (CMV) is a beta herpesvirus that commonly infects humans; serologic 
evidence of prior infection can be found in 40% to 100% of various adult populations (de la Hoz 
et al. 2002). However, symptomatic CMV infection or CMV disease occurs almost exclusively 
in individuals with compromised immune systems. CMV 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).
It has been found that CMV infection increases incidence of opportunistic infections and graft 
rejection, and decreased allograft and patient survival (Rubin 1989; Hodson et al. 2005; 
Ljungman et al. 2006). Organ-specific associations with CMV infection include bronchiolitis 
obliterans in lung recipients, vanishing bile duct syndrome in liver recipients, accelerated 
transplant vasculopathy in heart recipients and transplant glomerulopathy, transplant renal artery 
stenosis or increased risk of transplant rejection (Razonable and Emery 2004; Legendre and 
Pascual 2008; Richardson et al. 1981; Pouria et al. 1998; Farrugia and Schwab 1992). These 
effects are believed to be mediated by the ability of the virus to modulate the immune system, 
either directly or secondary to the host antiviral response through regulation of cytokine, 
chemokine, and/or growth factor production.
CMV prevention strategies (prophylaxis) for various high-risk transplant subjects exist, however, 
CMV infection or disease can still occur within the early (initial ~3 months) or later 
post-transplantation time periods (Boeckh et al. 2003; Legendre and Pascual 2008). 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 
(D+/R-) (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 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 (Boeckh et al. 2003; 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 (HSCT patients), who receive ongoing 
immunosuppressants to prevent organ rejection (SOT patients) or graft-versus host disease (in 
HSCT patients), or who may require the use of other therapies that are potentially toxic to the 
kidneys or other organs (SOT and HSCT patients). 
Development of anti-viral resistance to currently available anti-CMV agents is also an ongoing 
clinical problem in solid organ and stem cell transplantation leading to graft loss and even 
mortality for some transplant patients. As described by Limaye et al. 2000, ganciclovir resistance 
developed in 7% D+/R- kidney, liver, and pancreas recipients who were prophylaxed with 
3 months of oral ganciclovir. Ganciclovir resistant disease accounted for 20% of CMV disease, 


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occurred late (a median of 10 months after transplantation), was associated with higher intensity 
of immunosuppression, and was considered a clinically serious concern (Avery 2007).
There are no approved therapies for the treatment of CMV infection or CMV disease in 
transplant recipients, and no approved treatment for CMV infection or disease that is resistant or 
refractory to currently available therapies in any population. Maribavir is currently in Phase 3 
clinical development for the treatment of CMV infection or disease, including those resistant or 
refractory to ganciclovir, valganciclovir, foscarnet, or cidofovir, in transplant recipients. 
1.2
Product Background
1.2.1
Preclinical Information
Refer to the latest version of the maribavir (SHP620/TAK-620) Investigator’s brochure (IB).
1.2.2
Clinical Information
Maribavir is a potent and selective, orally bioavailable antiviral drug with a novel mechanism of 
action against CMV (Chulay et al. 1999) and a favorable nonclinical and clinical safety profile. It 
is a potent member of a new class of drugs, the benzimidazole ribosides (Williams et al. 2003). 
In side-by-side in vitro assays maribavir is 3-fold to 20-fold more potent than ganciclovir and 
cidofovir, and at least 100-fold more potent than foscarnet (Biron et al. 2002; Drew et al. 2006). 
Maribavir is active in vitro against strains of CMV that are resistant to ganciclovir, foscarnet, or 
cidofovir.
Unlike currently available anti-CMV agents that inhibit CMV deoxyribonucleic acid (DNA) 
polymerase, maribavir inhibits the CMV UL97 serine/threonine kinase by competitively 
inhibiting the binding of adenosine triphosphate (ATP) to the kinase ATP-binding site (Biron et 
al. 2002; Williams et al. 2003; Krosky et al. 2003; Wolf et al. 2001; Kern et al. 2004); the 
dominant phenotypic inhibitory effect of maribavir is on viral DNA assembly and egress of viral 
capsids from the nucleus of infected cells (Biron et al. 2002). Except for ganciclovir, maribavir 
does not antagonize the effects of other anti-viral (anti-CMV) agents. Since ganciclovir is 
dependent on its initial phosphorylation by the viral UL97 kinase, maribavir may antagonize its 
clinical efficacy. 
1.2.3
Pharmacokinetics and metabolism
Results from the Phase 1 studies demonstrated that following oral administration of the adult 
tablet formulation, maribavir was rapidly and well absorbed with mean peak plasma 
concentrations generally achieved between 1 and 3 hours post dose. After administration of 
single and multiple doses (both twice daily [BID] and 3 times daily [TID] regimens) over 
28 days, total maribavir plasma concentrations increased with increasing dose proportionally up 
to 900 mg. At dose levels ≥900 mg BID, there was no apparent increase in maximum observed 
plasma concentration (Cmax) levels, and above this level, the increase in area under the plasma 
concentration versus time curve (AUC) may be less than dose proportional. Maribavir 
demonstrates time-independent pharmacokinetics (PK). Pharmacokinetics data obtained in 
Phase 2 studies were similar to the data observed in healthy volunteers.


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Administration of maribavir in conjunction with food resulted in a 28% decrease in Cmax without 
a significant effect on AUC when compared to 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 and 0.96% in transplant patients. The apparent plasma elimination 
half-life for unchanged maribavir was approximately 5-7 hours. Maribavir is metabolized 
primarily in the liver through cytochrome P450 (CYP)3A4 pathway with the formation of the 
primary metabolite, VP44469. VP44469 does not have anti-CMV activity and does not affect 
major CYP enzymes or transporter activity. Renal clearance is a minor route of elimination of 
maribavir. Data from a Phase 1 study demonstrated no gender differences in maribavir PK. A 
population PK analysis conducted using pooled PK data from HP620-202 and SHP620-203 did 
not show apparent PK differences in Asian vs. non-Asian subjects; however, the sample size of 
Asian subjects was small (n=7).
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-glycoprotein (P-gp), resulted in increased tacrolimus Cmax and AUC by 
38% and 51%, respectively.

Maribavir does not have a clinically significant effect on the activity of CYP1A2, 
CYP3A, CYP2C9, or CYP2D6; however, it inhibits CYP2C19 activity (based on 
plasma omeprazole/5-OH omeprazole ratio). A follow-up clinical study indicates 
maribavir had no effect on the PK of voriconazole (a CYP2C19 substrate).

In vivo, maribavir 400 mg BID did not affect digoxin AUC; however, it increased Cmax
by 24.8%.

Concurrent administration of rifampin, an inducer of CYP3A4 and P-gp, and maribavir 
significantly reduced plasma concentrations of maribavir, resulting in a 61% reduction 
in AUC, reduced half-life, and significantly increased clearance, most likely due to 
induction of hepatic and intestinal CYP3A4, and possible enhancement of P-gp 
transport.

Concomitant administration of antacid has no effect on maribavir exposure.

Concomitant administration of ketoconazole increased maribavir AUC and Cmax by 
46% and 10%, respectively.
1.2.4
Efficacy
Two Phase 2 studies were conducted to assess the safety, tolerability, and anti-CMV activity of 
maribavir for treatment of CMV infections: Study 1262-202 (SHP620-202) in transplant subjects 
with CMV infections or disease that are resistant or refractory to treatment with anti-CMV 
agents conducted in the US and Study 1262-203 (SHP620-203) in transplant recipients with 
wild-type CMV infections who do not have CMV organ disease (asymptomatic) conducted in 
Europe. In both these studies subjects received maribavir at 1 of 3 dose strengths, 400, 800, or 
1200 mg BID, and both studies demonstrated favorable anti-CMV activity for maribavir, besides 
showing that maribavir was well tolerated with no safety concerns at all doses evaluated.


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Phase 3 registration trials are underway based on the results from these Phase 2 studies for CMV 
treatment.
1.2.5
Safety
Maribavir has been administered across a broad range of oral doses from 50 mg/day to 
2400 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. These 
studies included adult subjects only. Maribavir has been administered across a broad range of 
oral doses from 50 mg/day to 2400 mg/day. The most common TEAE in single- and multiple-
dose Phase 1 studies was taste disturbance (dysgeusia). A definitive corrected QT interval (QTc) 
study demonstrated no clinically significant repolarization effect of maribavir administered 
orally at single doses of 100 mg and 1200 mg in healthy subjects. In addition, no other 
significant electrocardiographic effects of maribavir were found.
Maribavir was safe and well tolerated in Phase 1 studies. The most common treatment-emergent 
adverse event (TEAE) in single- and multiple-dose Phase 1 studies was taste disturbance 
(dysgeusia). Among maribavir-treated subjects, dysgeusia was reported by up to 80% of subjects 
across the single-dose studies (dose range, 50 mg to 600 mg) and by 64% to 92% of subjects 
across the multiple-dose studies (dose range, 300 mg/day to 2400 mg/day). Of the 259 cases of 
dysgeusia reported by maribavir-treated subjects in Phase 1, 252 were mild or moderate and 
7 were of severe intensity. Dysgeusia was generally reported as a bitter or metallic taste that was 
considered related to maribavir administration. In a few cases, the taste disturbance was reported 
as more noticeable with liquids, especially cold beverages. Dysgeusia usually started within 
1 hour after maribavir dosing and resolved within approximately 8 hours after dosing in the 
single-dose studies (range, 0.5 hours to 25 hours) and within 1 day after the last dose in the 
multiple-dose studies. No subjects were withdrawn from treatment because of taste disturbance. 
Among maribavir-treated subjects, 94% (778/831) of TEAEs were of mild or moderate intensity; 
62% (517/831) of TEAEs were considered by the investigator to be related to maribavir. 
Maribavir had a favorable safety and tolerability profile in both the Phase 2 and Phase 3 trials for 
CMV prophylaxis. The most common TEAEs that appeared to be associated with maribavir 
treatment were dysgeusia and gastrointestinal (GI)-related events (eg, diarrhea, 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 1200 mg BID, and both studies 
demonstrated that maribavir was well-tolerated with no safety concerns at all doses evaluated. In 
Study SHP620-202, 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 cohorts.


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To date, maribavir has shown an overall favorable safety profile in placebo-controlled studies, 
open-label studies, and in studies that compared maribavir with other CMV therapies 
(ganciclovir, valganciclovir) for prophylaxis and for CMV treatment in HSCT and SOT patients.
Refer to the latest version of the maribavir IB for the most detailed and most current information 
regarding the drug metabolism, PK, efficacy and safety of maribavir.
1.3
Risk/Benefit and Ethical Assessment
To date, maribavir has been safe and well tolerated 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 stem cell transplant and SOT patients. 
Treatment effect on viral load reduction (confirmed undetectable plasma CMV DNA: 67% of 
subjects within 6 weeks in Study SHP620-202; 60.5% of subjects in 3 weeks and 77.3% of 
subjects in 6 weeks in Study SHP620-203) seen in Phase 2 treatment studies coupled with 
acceptable safety and tolerability establish the positive benefit-risk profile and warrant 
continuation of maribavir development in the Phase 3 treatment studies.
Always refer to the latest version of the maribavir IB for the overall benefit/risk assessment and 
the most accurate and current information regarding drug metabolism, PK, efficacy, and safety of 
maribavir. 
1.4
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; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the European Union (EU) Directives 
(2001/20/EC; 2005/28/EC), and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.




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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 1, open-label, randomized, crossover, partially fixed sequence, single-center 
study to evaluate the PK profile, safety, and tolerability of maribavir administered in healthy, 
adult subjects of Japanese descent and matched, healthy, adult, non-Hispanic, Caucasian 
subjects. A total of 24 subjects will be enrolled: 12 subjects of Japanese descent and 
12 non-Hispanic, Caucasian subjects. Non-Hispanic, Caucasian subjects will be matched to 
Japanese subjects based on age (years), sex, and body mass index (BMI) (15%).
The study design flow chart is presented in Figure 1.
Subjects will be screened within 28 days prior to the first dose of the investigational product (IP). 
Subjects will be admitted to the Clinical Research Center (CRC) on Day -1. 
For the non-Hispanic, Caucasian group, the study will comprise a 28-day Screening Period and 
Treatment Period 1. These subjects will receive a single oral dose of 400 mg maribavir on Day 1 
and will be discharged on Day 2. For this cohort there will be one treatment period (Table 5 and 
Table 6).
For the subjects of Japanese descent, the study will comprise a 28-day Screening Period and 
3 treatment periods. These subjects will receive 3 doses of maribavir separated by a least a 
72-hour washout period between doses: in Treatment Period 1 on Day 1, they will receive a 
single oral dose of 400 mg of maribavir; in Treatment Period 2 and Treatment Period 3 on Day 1, 
they will be randomized to receive a single oral dose of 200 mg followed by 800 mg of maribavir 
or a single oral dose of 800 mg followed by 200 mg maribavir (Table 1, Table 2, Table 3, and 
Table 4). 
All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects 
(Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 hours post dose) in all 
treatment periods to maintain control. All maribavir doses will be administered with a glass 
(240 mL) of room temperature water after at least a 10-hour overnight fasting, with water 
restricted 1 hour before and 1 hour after dosing. Food will be provided to subjects approximately 
4 hours after study drug administration. (Assessing the Effects of Food on Drugs in INDs and 
NDAs – Clinical Pharmacology Considerations, 2019). Vomiting occurring within 4 hours after 
dosing will be recorded. There will be at least a 72-hour washout between maribavir doses for 
the subjects of Japanese descent.
The study duration for the non-Hispanic, Caucasian cohort will comprise a 28-day screening 
period and Treatment Period 1. For the subjects of Japanese descent, the study duration will 
comprise a 28-day screening period and Treatment Periods 1, 2, and 3. For both groups 
(Japanese and Caucasian subjects), there will be a post-treatment follow-up telephone call at 
7 (±4) days after the last dose of IP.
The total number of nights subjects will be expected to stay at the CRC is approximately 2 for 
the non-Hispanic, Caucasian subjects and approximately 8 for the subjects of Japanese descent. 


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The maximal total duration of study participation for a non-Hispanic, Caucasian subject is 
approximately 37 days and approximately 47 days for the subjects of Japanese descent, if the 
screening, treatment, washout, and follow-up visit durations are used.
Treatment Period:

In Treatment Period 1, all study subjects (both Japanese and Caucasian) will receive 
maribavir as a single 400 mg oral dose. For the non-Hispanic, Caucasian group there 
will be only one treatment period.

In Treatment Periods 2 and 3, all subjects of Japanese descent will receive maribavir 
as a single oral dose of either 200 mg or 800 mg, depending upon randomization 
assignment.
Pharmacokinetic Assessments

Serial blood samples for PK analysis will be collected in each treatment period for the 
determination of maribavir and 
 plasma concentrations at pre-dose and up to 
approximately 24 hours post dose. These blood samples will be collected according to 
the Schedules of Assessments (Table 1, Table 2, Table 3, Table 4, Table 5, and 
Table 6).
Safety Assessments

Safety and tolerability will be determined through assessment of TEAEs from the first 
dose to the post-treatment follow-up telephone call at 7 (±4) days after the last dose 
of IP, and vital signs, ECG, and clinical laboratory evaluations on Day 1 pre-dose and 
up to 24 hours post dose in each treatment period. 
Follow-up

A post-treatment follow-up telephone call will occur at 7 (±4) days after the last dose 
of IP for each subject. Subjects who experience AEs will be followed longer if 
needed, including an unscheduled clinic visit if appropriate, depending on the nature, 
severity, and seriousness of the AE.
Rationale for Study Design and Dose Selection

Maribavir 400 mg BID is the clinical dose currently being evaluated in the ongoing 
pivotal Phase 3 studies; therefore, a single oral dose of 400 mg maribavir was 
selected for evaluating the primary objective of this study – to compare maribavir PK 
between Japanese and Caucasian subjects. Maribavir has demonstrated 
time-independent PK and a favorable safety profile in previous Phase 1 studies. 
Therefore, evaluating PK following repeated dosing, eg, 400 mg BID, is not 
necessary in this study. Although dose proportionality of PK for doses from 50 mg up 
to 900 mg was demonstrated in previous studies in Caucasian subjects, to explore the 
appropriate clinical dosage in Japanese subjects the lower and higher dosages were 
also selected to assess dose proportionality and to support the future Phase 3 clinical 


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development of maribavir in Japanese subjects. Therefore, the secondary objective of 
the study was to evaluate dose proportionality of maribavir PK in subjects of 
Japanese descent. The doses of 200, 400, and 800 mg were selected for evaluating 
dose proportionality as a more than two-fold differences in systemic exposure to 
maribavir is not expected in Japanese subjects as compared to Caucasian subjects. As 
the primary objective is to compare maribavir PK at 400 mg, the 400 mg dose is to be 
evaluated in Treatment Period 1 in both Japanese and Caucasian subjects to avoid 
treatment period effects on this comparison. 


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Figure 1
Study Design Flow Chart
This is an open-label study to evaluate the PK, safety, and tolerability of single doses of maribavir in healthy, adult subjects of 
Japanese descent and matched, healthy, adult, non-Hispanic, Caucasian subjects. These cohorts of healthy, non-Hispanic, Caucasian 
subjects and healthy Japanese subjects need not be dosed at the same time.
*Washout period of 72 to 73 hours after treatment on Day 1.


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3.2
Maximum Duration of Participation and Study Completion
The maximum duration of participation for non-Hispanic, Caucasian subjects is expected to be 
approximately 37 days, and the maximum duration of participation for subjects of Japanese 
descent is expected to be approximately 47 days, if the maximum screening, treatment, washout, 
and follow-up durations are used. The study will be completed in approximately 1 month to 
2 months.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). Please note that this includes the follow-up 
visit or contact, whichever is later (refer to Section 7.1.4 for the defined follow-up period for this 
protocol).
3.3
Sites and Regions
This study will be conducted at a single site in the United States (US).


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The screening period starts with the signing of the informed consent. During the screening 
period, inclusion/exclusion criteria for study participation will be checked/tested. The subject 
will not be considered eligible for the study without meeting all of the criteria below.
Subjects cannot be enrolled or randomized before all inclusion criteria (including test results) are 
confirmed.
1. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions. 
2. Ability to voluntarily provide written, signed, and dated (personally or via a 
legally-authorized representative) informed consent/assent as applicable to participate in 
the study.
3. Healthy subjects of Japanese descent must have been born in Japan and must not have 
lived outside of Japan for >10 years; both parents and all 4 grandparents must be of 
Japanese origin. Healthy, non-Hispanic, Caucasian subjects must have both parents and 
all 4 grandparents of non-Hispanic, Caucasian origin.
4. Age 18 to 55 years inclusive, at the time of consent. The date of signature of the informed 
consent is defined as the beginning of the screening period. This inclusion criterion will 
only be assessed at the first screening visit.
5. Male, or non-pregnant, non-breastfeeding female who agrees to comply with any 
applicable contraceptive requirements of the protocol or females of non-childbearing 
potential. 
6. Healthy as determined by the investigator on the basis of screening evaluations. Healthy 
status is defined by absence of evidence of any active or chronic disease following a 
detailed medical and surgical history, a complete physical examination including vital 
signs, 12-lead ECG, hematology, blood chemistry (includes thyroid stimulating hormone 
[TSH] and free T4 at screening only), and urinalysis.
7. Hemoglobin for males 135.0 g/L and females 120.0 g/L at screening and on Day -1.
8.
BMI between 18.5 and 28.0 kg/m2 inclusive with a body weight >45 kg (99 lbs.). This 
inclusion criterion will only be assessed at the first screening visit.
9. Ability to swallow a dose of IP.
4.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met. 


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1. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological, or 
psychiatric disease, gall bladder removal, or current recurrent disease that could affect the 
action, absorption, or disposition of the IP, or clinical or laboratory assessments.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that 
may require treatment or make the subject unlikely to fully complete the study, or any 
condition that presents undue risk from the IP or procedures.
3. Known or suspected intolerance or hypersensitivity to maribavir, closely-related 
compounds, or any of the stated ingredients.
4. Significant illness, as judged by the investigator, within 2 weeks of the first dose of IP.
5. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of IP.
6. Have taken another IP within 30 days or five half-lives of that IP, whichever is greater, 
prior to the first dose of maribavir.
7. Have been enrolled in a clinical study (including vaccine studies) within 30 days prior to 
the first dose of IP that, in the investigator's opinion, may impact this study.
8. Have had any substantial changes in eating habits within 30 days prior to the first dose of 
IP, as assessed by the investigator.
9. Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood 
pressure >89 mmHg or <49 mmHg.
10. Twelve-lead ECG demonstrating QTc >450 msec at screening. If QTc exceeds 450 msec, 
the ECG should be repeated 2 more times and the average of the 3 QTc values should be 
used to determine the subject’s eligibility. 
11. Known history of alcohol or other substance abuse, including synthetic cannabinoids 
within the last year.
12. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. 
Female subjects who consume more than 14 units of alcohol per week or 2 units per day. 
(1 alcohol unit=1 beer or 1 wine [5 oz/150 mL] or 1 liquor [1.5 oz/40 mL] or 0.75 oz 
alcohol).
13. A positive urine test for drugs of abuse, alcohol, or cotinine at screening or on Day -1.
14. A positive HIV, hepatitis B surface antibody (HBsAg), or hepatitis C virus (HCV) 
antibody screen.
15. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing 
products in any form (eg, gum, patch). Ex-users must report that they have stopped using 
tobacco for at least 30 days prior to receiving the first dose of IP.
16. Routine consumption of more than 2 units of caffeine per day or subjects who experience 
caffeine withdrawal headaches. (1 caffeine unit is contained in the following items: one 
6 oz [180 mL] cup of coffee, two 12 oz [360 mL] cans of cola, one 12 oz cup of black 
tea, and three 1 oz [85 g] chocolate bars. (Decaffeinated coffee, herbal tea, or cola are not 
considered to contain caffeine).
17. Prior screen failure, randomization, enrollment, or participation in this study.
18. Current use of any prescription medication (with the exception of hormonal replacement 
therapy, hormonal contraceptives, and occasional use of ibuprofen and/or 
acetaminophen) within 30 days of the first dose of IP. Current use of any over the counter 
medication (including herbal preparations like St. John’s wort and ginkgo biloba, or 
homeopathic preparations) within 14 days of the first dose of IP.


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19. Ingestion of known CYP 3A modulators within 7 days of Day 1, Period 1 (includes 
grapefruit or grapefruit juice, oranges, Seville oranges, vegetables from the mustard green 
family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, 
mustard], charbroiled meats, and products containing these ingredients).
20. History of active or chronic oral/nasal cavity infections, gastroesophageal reflux, asthma 
treatment with albuterol, zinc supplementation.
21. Subjects with dry mouth syndrome or burning mouth syndrome or menopausal women 
suffering from dysgeusia.
22. Subjects who have acute GI symptoms at screening or admission (eg, nausea, vomiting, 
diarrhea, and heartburn).
4.3
Restrictions
All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects 
(Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 hours post dose) in all 
treatment periods to maintain control.
Subjects should refrain from the following:
1. Strenuous physical exercise 48 hours prior to admission to the CRC and during the 
in-house stays at the CRC.
2. Consuming grapefruit or grapefruit juice, oranges, Seville oranges, and products 
containing these items, vegetables from the mustard green family [eg, kale, broccoli, 
watercress, collard greens, kohlrabi, Brussels sprouts, mustard], charbroiled meats, and 
products containing these ingredients) and products containing these items from 7 days 
prior to Day 1 of the first treatment period through the completion of the last treatment 
period. 
3. Consuming pine nuts 7 days prior to Day 1 of the first treatment period through the 
completion of the last treatment period.
4.
Consuming alcohol 48 hours prior to admission to the CRC and during the in-house stay 
at the CRC.
5. Use of tobacco or any products containing nicotine within 30 days of Day 1 of the first 
treatment period through the completion of the last treatment period.
6. Taking or regularly using any prescription medication with the exception of those listed 
in Section 5.2.1 from 30 days prior to receiving the first dose of the IP through the 
completion of the discharge assessments and procedures, and over the counter 
medications (including over-the counter multi-vitamin, herbal, or homeopathic 
preparations) from 14 days prior to receiving the first dose of the IP through the 
completion of the discharge assessments and procedures. Subjects should not use 
antacids, proton pump inhibitors, H2 antagonists, or zinc supplementation. 
7. Foods or beverages containing caffeine/xanthine 48 hours prior to admission to the CRC 
and during the in-house stay at the CRC.
4.4
Reproductive Potential
4.4.1
Female Contraception
There is no clinical experience with maribavir in pregnant subjects.  


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Sexually active females of child-bearing potential must be advised to use an acceptable method 
of contraception throughout the study period and for 30 days following the last dose of IP. 
Females of child-bearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of IP. 
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea and 
age 50 years), or

Surgically sterile (having undergone one of the following surgical procedures: 
hysterectomy, bilateral tubal ligation, bilateral oophorectomy or bilateral 
salpingectomy) and at least 6 weeks post-sterilization, or

All females of child-bearing potential with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the screening visit and prior to randomization 
or enrollment. Females of child-bearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use acceptable methods of 
contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for 
at least 30 days prior to the first dose of IP, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days. If hormonal contraceptives are used they should be administered according to 
the package insert.
4.4.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 3 months after the last dose of IP. 
Childbearing female partners of male study participants will be required to follow the acceptable 
methods of contraception for this study (described in Section 4.4.1) from the time of first dosing 
until 3 months after the last dose of IP. 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 of the first dose until 3 months after the last dose of IP. Male subjects must not donate 
sperm until 3 months after the last dose of IP.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time 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 


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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.
If IP is discontinued, regardless of the reason, the early withdrawal evaluations listed in Table 1
and Table 5 are to be performed as completely as possible. Whenever possible, all discontinued 
subjects should also undergo follow-up evaluations. 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 IP, and the total amount of IP administered must 
be recorded in the source documents and the case report form (CRF). 
Subjects who discontinue early without completing all planned PK assessments for Treatment 
Period 1 may be replaced at the sponsors discretion to ensure at least 24 subjects (12 subjects of 
Japanese descent and 12 matching, non-Hispanic, Caucasian subjects) with evaluable PK for the 
statistical analysis of the primary objective (PK comparison between Japanese and non-Hispanic, 
Caucasian subjects). If subjects discontinue early during Treatment Period 2 or 3, there is no 
need for replacement. 
4.5.1
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject discontinued for more than 1 reason, each reason should 
be documented in the source document and the most clinically relevant reason should be 
indicated.
Reasons for discontinuation include but are not limited to:

AE

Protocol deviation

Withdrawal by subject 

Lost to follow-up

Other (The investigator must specify on the CRF)
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused IP.


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5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins 
non-pharmacological treatments such as psychotherapy as appropriate) received within 30 days 
(or PK equivalent of 5 half-lives, whichever is longer) of the date of first dose of IP. Prior 
treatment information must be recorded on the appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of IP and 
the end of the follow-up period, inclusive. Concomitant treatment information must be recorded 
on the appropriate CRF page.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study. Any medication which is considered necessary for the subject’s 
safety and wellbeing may be given at the discretion of the investigator. The administration of all 
medications (including IPs) must be listed on the appropriate CRF page.
Medications permitted during the study are listed below:

Hormonal contraceptives for females of child-bearing potential administered according to the 
package insert (Section 4.4.1)

Hormone replacement therapy

Occasional use of ibuprofen and/or acetaminophen
5.2.2
Prohibited Treatment
Refer to Section 4.3 on restrictions for prohibited treatments.


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The IP is maribavir, which will be provided in tablet form. 
Maribavir tablets are blue, film-coated tablets containing 200 mg of maribavir. The tablets are 
packaged in a 60 cc, white, high-density polyethylene (HDPE) bottle containing 40 tablets. 
Additional information and detailed instructions are provided in the maribavir IB, and in a 
Pharmacy Manual that will be provided.
The sponsor will provide the IP.
6.1.1
Blinding the Treatment Assignment
Not applicable. This is an open-label study.
6.1.2
Unblinding the Treatment Assignment
Not Applicable. This is an open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment
This is an open-label, randomized study. The actual treatment given to individual subjects is 
determined by a randomization schedule.
The subjects of Japanese descent will receive 3 doses of maribavir separated by a 72-hour 
washout period between doses: in Treatment Period 1 on Day 1, they will receive a single oral 
dose of 400 mg of maribavir; in Treatment Period 2 and Treatment Period 3 on Day 1, they will 
be randomized to receive a single oral dose of either 200 mg followed by 800 mg of maribavir in 
a crossover study design.
Subject numbers are assigned to all subjects as they consent to take part in the study. The subject 
number is assigned to subjects according to the sequence of presentation for study participation. 
A 4-digit randomization number, 
, will be allocated immediately prior to dosing 
after eligibility has been determined. Once a randomization number has been assigned, that 
number must not be used again if, for example, a subject is withdrawn from the study. For 
randomized subjects, the randomization number will be the identifying number used throughout 
CRF.  If a randomization number/unique identifier is allocated incorrectly, the clinical research 
associate (CRA)/study monitor must be notified as soon as the error is discovered.
Screen failures will not be captured for this study.
The randomization number represents a unique number corresponding to IP allocated to the 
subject prior to dosing after eligibility has been determined.


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6.2.2
Dosing
The non-Hispanic, Caucasian subjects will receive a single oral dose of 400 mg maribavir 
(2×200 mg maribavir tablets) on Day 1. The Japanese subjects will receive 3 doses of maribavir: 
on Day 1 of Treatment Period 1, they will receive a single oral dose of 400 mg of maribavir 
(2×200 mg maribavir tablets); on Day 1 of Treatment Period 2, they will be randomized to 
receive a single oral dose of either 200 mg (1×200 mg tablets) or 800 mg of maribavir 
(4×200 mg maribavir tablets); and on Day 1 of Treatment Period 3, they will receive a single oral 
dose of whichever dosage they did not receive on Day 1 of Treatment Period 2 (200 mg or 
800 mg).  
6.2.3
Administration
All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects 
(Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 hours post dose) in all 
treatment periods to maintain control. All maribavir doses will be administered with a glass 
(240 mL) of room temperature water after at least a 10-hour overnight fasting, with water 
restricted 1 hour before and 1 hour after dosing. Food will be provided to subjects approximately 
4 hours after study drug administration. Vomiting occurring within 4 hours after dosing will be 
recorded. There will be at least a 72-hour washout between maribavir doses for the subjects of
Japanese descent (Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical 
Pharmacology Considerations, 2019).
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the IP container.
All IP (maribavir) is labeled with a minimum of the protocol number, medication identification 
number (if applicable), dosage form (including product name and quantity in pack), directions 
for use, storage conditions, batch number and/or packaging reference, the statements “For 
clinical trial use only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to 
Investigational Use” and “Keep out of reach of children,” and the sponsor’s name and address.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the IP in order to satisfy local or institutional requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.


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6.3.2
Packaging
Investigational product is packaged in the following labeled container:

Maribavir tablet: 60 cc, white, square, HDPE bottle
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited 
access location. Limited responsibility may be delegated to the pharmacy or member of the study 
team, but this delegation must be documented. Investigational products are distributed by the 
pharmacy or nominated member of the study team. The pharmacist/nominated team member will 
enter the unique subject identifier (if allowed by law/regulations) on the IP bottle/carton labels as 
they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the IP 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 IP 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 IP 
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 IP to carry out this protocol for the 
agreed number of subjects. The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition. Accurate records of all IP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing IP. 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.


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The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IP only to subjects included in this study 
following the procedures set out in the study protocol. Each subject will be given only the IP 
carrying his/her treatment assignment. All dispensed medication will be documented in the 
subject's source and/or other IP record. 
No IP stock or returned inventory from a Shire-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 stock and 
empty/used IP packaging may be destroyed at the site or a local facility. In this case, destruction 
records identifying what was destroyed, when and how, must be obtained with copies provided 
to the sponsor. Destruction of IP 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 IP 
delivered with those used and returned. All IP must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction.
6.5
Subject Compliance
Compliance must be assessed by observation of dosing by the investigator or designee. In 
addition, the CRC personnel should perform a hand and mouth check of the subject to assure the 
IP has been ingested. The investigator/nominated person will record details on the drug 
accountability log(s) and/or source documents. In addition, details of the dosing time (time, date, 
dose level) will be captured in the appropriate CRF.
6.6
Retention of Bioavailability and Bioequivalence Testing Samples
Not applicable.


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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6 for study procedures. 
The following “priority order” will be in effect when more than 1 procedure or assessment is 
required at a particular time point.

Spontaneous or solicited AE reporting

ECG

Vital signs

PK blood sampling

Clinical laboratory tests

Physical examination.
NOTE: Blood sampling for PK evaluation must be performed at the precise protocol-scheduled 
time. Actual sampling time(s) must be accurately recorded in the source document and 
appropriate CRF.
7.1.1
Screening Period
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent and assent form must be given to the subject for their records.
Screening procedures must be completed within 28 days of Day 1 as appropriate, prior to 
receiving the first dose of IP. All screening assessments and procedures are to be performed by 
the principal investigator or a qualified designee. See Table 1 and Table 5 for a complete list of 
screening procedures to be performed.
7.1.1.1
Screening Failure
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered IP.
For purposes of data collection, all subjects who give consent to the study, but are not enrolled 
and/or randomized will be reported as screen failures even if they were otherwise fully eligible 
for the study, for example alternates/reserve subjects.
7.1.1.2
Rescreening of Subjects
Subjects who fail to meet all inclusion/exclusion criteria may be permitted to be rescreened for 
the study at the discretion of the study Principal Investigator in consultation with the Shire Study 
Medical Monitor. 


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Eligible subjects who meet all inclusion/exclusion criteria, but are unable to participate in the 
study due to scheduling conflicts/timing, may be rescreened based on investigator discretion and 
Sponsor approval should their availability to participate fall outside the screening window. In 
these cases, a new screening number must be assigned for each subject who is rescreened and a 
new informed consent form must be signed.
7.1.2
Predose Assessments
Following the screening visit, eligible subjects will return to the CRC on Day -1 of the study. 
Predose assessments, including check-in to the CRC will be performed on Day -1, as described 
in Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6.
7.1.3
Treatment Periods 
The non-Hispanic, Caucasian subjects will have one Treatment Period. The Japanese subjects 
will have Treatment Periods 1, 2, and 3. 
7.1.3.1
Treatment Period 1 (Non-Hispanic, Caucasian Subjects)
Study assessments for non-Hispanic, Caucasian Subjects Days 1 and 2 in Treatment Period 1 are 
outlined in Table 5 and Table 6. Administration of maribavir will occur on Day 1 as described in 
Section 6.2.2. Non-Hispanic, Caucasian subjects will be discharged from the CRC on Day 2. 
7.1.3.2
Treatment Period 1 (Japanese Subjects)
Study assessments for Japanese subjects on Days 1 and 2 in Treatment Period 1 are outlined in 
Table 1 and Table 2. Administration of maribavir will occur on Day 1, as described in 
Section 6.2.2. There will be a 72-hour washout period after administration of the IP on Day 1. 
7.1.3.3
Treatment Period 2 (Japanese Subjects)
Study assessments for Japanese subjects on Days 1 and 2 in Treatment Period 2 are outlined in 
Table 1 and Table 3. Administration of maribavir will occur on Day 1, as described in 
Section 6.2.2. There will be a 72-hour washout period after administration of the IP on Day 1. 
7.1.3.4
Treatment Period 3 (Japanese Subjects)
Study assessments for Japanese subjects on Days 1 and 2 in Treatment Period 3 are outlined in 
Table 1 and Table 4. Administration of maribavir will occur on Day 1, as described in 
Section 6.2.2. Japanese subjects will be discharged from the CRC on Day 2.
7.1.4
Follow-up Period (All Subjects)
There will be a follow-up telephone call at 7 (±4) days after the last dose of IP to query for 
SAEs, AEs, and concomitant treatments. Subjects who experience AEs will be followed longer if 
needed, including an unscheduled clinic visit if appropriate, depending on the nature, severity, 
and seriousness of the AE. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (Appendix 2.2).


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7.1.5
Additional Care of Subjects After the Study
No after care is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Subject demographic information including date of birth, sex, age, race, and ethnicity will be 
collected at the initial screening visit, prior to the subject receiving the first dose of IP. 
7.2.1.1
Height and Weight
Height and weight will be measured and recorded in the subject’s source documents. 
7.2.2
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is that 
the investigator will ensure that every effort is made to perform all assessments at the 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than 15 minutes will be considered a protocol deviation.
Adverse events (defined as AEs occurring from the time of informed consent signature to first 
dose of IP), TEAEs (all AEs occurring after the first treatment or worsening after the first 
treatment), prior medication, and concomitant medication use will be assessed and monitored 
from the time the subject signs the informed consent form to completion of study (including to 
time of screen failure or dropout/discontinuation). While confined in the CRC, subject safety will 
also be closely monitored through blood pressure measurements, ECG measurement, clinical 
safety labs, and physician oversight.
7.2.2.1
Medical and Medication History
A complete medical and medication history, as well as demographic information, will be 
performed at the Screening Visit/time points described in Table 1, Table 2, Table 3, Table 4, 
Table 5, and Table 6 by a qualified licensed physician, physician’s assistant, or a nurse 
practitioner. The medical and medication history will be collected and recorded in the subject’s 
source documents. The medical history will include:

History of respiratory, cardiovascular, renal, GI, hepatic, endocrine, hematological, 
neurological, psychiatric, and other diseases

Recent ingestion of medication (30 days prior to entering the Screening Period)
Record medications taken via Injection/Infusion (IV, IM, SQ) ie, insulin, vaccine, etc. 


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7.2.2.2
Physical Examination (Including Height and Weight)
A complete physical examination will be performed at the time points described in Table 1, 
Table 2, Table 3, Table 4, Table 5, and Table 6 by a qualified licensed physician, physician’s 
assistant, or a nurse practitioner.
The physical examination will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys).
If more than 2 days have passed since screening, a physical examination should be repeated on 
Day -1. Abnormalities identified at the Screening Visit will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the Screening Visit will be 
captured as AEs on the AE CRF page, as deemed appropriate by the investigator.
7.2.2.3
Adverse Event Collection
At each study visit and at the post-treatment follow-up telephone call, 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. (Refer to Appendix 2 for AE definitions, assessment, collection time frame, 
and reporting procedures.)
7.2.2.4
Vital Signs
Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in Table 1, Table 2, Table 3, 
Table 4, Table 5, and Table 6. Additional blood pressure and pulse rate measurements may be 
performed, as determined by the investigator, in order to ensure appropriate monitoring of 
subject safety and accurate recording of vital sign measurements. Any changes from baseline 
which are deemed clinically significant by the investigator are to be recorded as an AE.
The same method for obtaining blood pressure measurement (auscultatory or oscillometric) 
should be used throughout the study (and documented) for all subjects. In addition, the 
conditions of vital sign measurements should be controlled and as consistent as possible during 


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the study, in order to minimize external variability of the readings. It is advised that 
measurements be collected at a comfortable room temperature with little to no background noise, 
using the same (appropriately sized) cuff placed at the same location of the same arm during the 
study. The bladder should be deflated (calibrated for oscillometric method or manually by 
auscultatory method) at a rate of 2-3 mmHg/s (and the first and last audible sounds recorded as 
systolic and diastolic pressure) after at least 5 minutes of rest in the supine position.
The cuff should have a bladder length that is 80% and a width that is at least 40% of arm 
circumference (a length-to-width ratio of 2:1). 
The subject should be asked to remove all clothing that covers the location of cuff placement. 
The subject should not have exercised or consumed coffee, black tea, cola, chocolate, alcohol, or 
nicotine within 30 minutes of collection. The subject should be instructed to relax as much as 
possible for at least 5 minutes prior to collection. The subject should remain quiet during this 
time and through the measurement.
The subject should be lying comfortably, with the legs uncrossed. The arm should be supported 
with a pillow, such that the middle of the cuff on the upper arm is at the level of the right atrium 
(approximately halfway between the bed and the level of the sternum).
At the Screening Visit, blood pressure should be compared between both arms. 
One reading in a supine position should be taken. When there is a consistent inter-arm difference 
in either SBP/DBP confirmed over 3 consecutive measurements (>10mmHg), the arm with the 
higher blood pressure should be used for inclusion at screening and the last measurement 
recorded in the CRF. The same (right or left) arm with the higher blood pressure will be used 
throughout the study. 
The use of automated devices for measuring pulse rate is acceptable although, when done 
manually, pulse rate will be measured in the brachial/radial artery for at least 30 seconds. When 
the timing of these measurements coincides with a blood collection, blood pressure and pulse 
rate should be obtained prior to the nominal time of the blood collection.
Respiratory Rate
The subject should be in a comfortable position. The observer should hold the extremity of the 
subject as a distraction for the patient (ie, pretending he/she is taking the subject’s radial pulse) 
and count the respiration for 1 minute. 
Body Temperature
Oral temperature should be taken by placing a digital thermometer under the tongue for at least 
30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be 
used. 


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7.2.2.5
Electrocardiogram
Twelve-lead ECGs will be performed at the times specified in Table 1, Table 2, Table 3, Table 4, 
Table 5, and Table 6. All ECGs will be performed using the equipment supplied by the CRC.
The following parameters will be recorded on the appropriate CRF page: heart rate, PR, RR, 
QRS, and QT intervals. The Fridericia's correction for QT interval (QTcF) will be derived from 
the data in the database. The investigator’s assessment of the ECG tracing as normal or abnormal 
must be documented, and if abnormal, his/her determination of whether the abnormality is 
clinically significant or not, will be documented on the tracing and recorded in the CRF.
The subject should be asked to remove all clothing that covers the location of lead placement.
The subject should not have exercised or consumed coffee, black tea, cola, chocolate, alcohol, or 
nicotine within 30 minutes prior to collection. The subject must be resting in the supine position 
for at least 5 minutes prior to collecting the ECG.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. 
Electrocardiogram recording, including a 10 second rhythm strip, will be obtained approximately 
2 minutes to 4 minutes apart for all assessments. The recordings should be immediately assessed 
and if not valid, should be repeated in order to obtain a valid recording.
If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 
3 QTc values and the average of other triplicate ECG measurements should be used and recorded 
in the CRF. Invalid recordings will not be entered in the CRF.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.
If the QTcF interval (calculated online on site) is increased by >45 msec from the baseline, or an 
absolute QTcF value is >500 msec for any scheduled ECG, then 2 additional ECGs will be 
collected, approximately 2 minutes to 4 minutes apart, to confirm the original measurement. If 
either of the QTcF values from these repeated ECGs remains above the threshold value 
(>45 msec from the baseline; or is >500 msec), then a single ECG must be repeated at least 
hourly until QTcF values from 2 successive ECGs fall below the threshold value that triggered 
the repeat measurement. When triplicate ECGs are collected, the mean of the triplicate 
measurements should be used to trigger the decision to collect follow-up ECGs.
If QTcF values remain above 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator); or QTcF intervals get progressively longer, the subject 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator).


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If a machine-read QTcF value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTcF values are in the 
acceptable range.
7.2.2.6
Clinical Laboratory Tests
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
The subject should not eat or drink anything for at least 8 hours to 10 hours before having 
clinical laboratory tests.
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. 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. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry
Blood samples for serum biochemistry will be collected into a serum separator tube at the time 
points described in Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6. The following 
parameters will be assessed: 
Sodium
Phosphate
-HCG a
Potassium
Protein
Glucose(fasting) 
Carbon dioxide
Urea nitrogen
Albumin
Creatinine
Aspartate transaminase 
Calcium
Alanine transaminase 
Chloride
Gamma glutamyl transferase 
Thyroid stimulating hormone (TSH)a
Alkaline phosphatase 
Thyroxine (free T4) 
Total bilirubin 
Triiodothyronine (T3) 
Uric acid
a Females only.


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Hematology
Blood samples for hematology will be collected into a K2EDTA tube at the time points described 
in Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6. The following parameters will be 
assessed:
Hemoglobin
Total neutrophils (absolute)
Hematocrit
Eosinophils (absolute)
Red blood cells
Monocytes (absolute)
Platelet count
Basophils (absolute)
White blood cell count; total and differential
Lymphocytes (absolute)
Urinalysis
A urine sample for urinalysis will be collected at the time points described in Table 1, Table 2, 
Table 3, Table 4, Table 5, and Table 6. The following parameters will be assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria. 
7.2.2.7
Pregnancy Test 
A pregnancy test is performed on all females as outlined in Table 1 and Table 5, or if pregnancy 
is suspected, or on withdrawal of the subject from the study.
7.2.2.8
Drug and Alcohol Screen
A urine screen for drugs of abuse and alcohol will be performed at the time points described in 
Table 1 and Table 5. Additional drug and alcohol screens may be performed at the investigator’s 
discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine.
Results of urine drug and alcohol screens will be reviewed and verified by the study monitor, but 
will not be collected in the CRF database.
Any positive result for drugs of abuse, cotinine, or alcohol at screening or on Day -1 will exclude 
the subject from further participation in the study.


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7.2.2.9
Serology Screen 
At the Screening Visit, a blood sample will be drawn into a serum separator tube to test for the 
presence of HIV, HBsAg, and HCV antibody. 
The test results must be confirmed negative prior to enrollment in the study. If a test result is 
positive, the subject will be excluded from entering the study. Results of the virology screen will 
be reviewed and verified by the study monitor, but will not be collected in the CRF database.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at the/each site and in the Trial Master File with the sponsor.
Actual PK blood sample collection times versus time of dosing will be recorded. The sponsor's 
expectation is that the investigator will ensure that every effort is made to collect all PK blood 
samples at the precise protocol scheduled time. Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than 5 minutes from 
samples drawn within 4 hours post-dose or by more than 15 minutes for samples drawn beyond 
4 hours post-dose. Samples drawn outside these parameters will be considered a protocol 
deviation. 
7.2.3.1
Blood Sample Collection and Handling Procedures
Blood samples will be collected at the time specified in Table 1, Table 2, Table 3, Table 4, 
Table 5, and Table 6 to measure plasma concentrations of maribavir and 
 
. 
Blood sample collection, processing and handling instructions are provided in the Laboratory 
Manual.
7.2.3.2
Plasma Drug Assay Methodology
Plasma concentrations of maribavir and 
 will be measured using the most current 
validated bioanalytical method. In addition, selected plasma samples may be used to investigate 
incurred sample reproducibility (full details will be described in the bioanalytical study plan). 
The presence of other metabolites or artifacts may be monitored or quantified as appropriate. 
Raw data will be stored in the archive of the designated bioanalytical contract laboratory. 
7.2.4
Volume of Blood to be Drawn from Each Subject
The volume of blood intended to be drawn from each subject is presented in Table 7.


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Table 7
Volume of Blood to be Drawn from Each Subject 
Assessment
Approximate 
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samples a
4
42 (Japanese) 
14 (Caucasian) 
168 mL (Japanese) 
56 mL (Caucasian) 
HBsAg, HIV, HCV
3.5
1 (Japanese) 
1 (Caucasian) 
3.5 mL (Japanese) 
3.5 mL (Caucasian)
Safety
Biochemistry and 
-HCG b
5
8 (Japanese)
4 (Caucasian)
68 mL (Japanese)
34 mL (Caucasian)
Hematology
4
8 (Japanese)
4 (Caucasian)
32 mL (Japanese)
16 mL (Caucasian)
Total mL
271.5 mL (Japanese)
109.5 mL (Caucasian)
-HCG=beta-human chorionic gonadotropin; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus
a If a catheter is used, the first 1mL is to be discarded; then take 2mL into appropriate tube for pharmacokinetic 
sample. A total of 3mL of blood drawn has been used in determination of sample volume.
b -HCG testing for females only.
During this study, it is expected that approximately 271.5 mL of blood will be drawn from 
Japanese subjects and approximately 109.5 mL of blood will be drawn from Caucasian subjects 
regardless of sex.
Note: 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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8.
DATA MANAGEMENT AND STATISTICAL METHODS
8.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the CRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the CRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. It is expected that site personnel will complete the CRF entry within approximately 
3 business days of the subject’s visit.
8.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
8.3
Data Handling
Not applicable to this study.
8.4
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.
The Statistical Analysis Plan (SAP) will provide the statistical methods and definitions for the 
analysis of the PK and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications. The SAP will also include a 
description of how missing, unused and spurious data will be addressed. 
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 SAS(SAS Institute, Cary, NC 27513). 


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8.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis, adaptive design, or Data Monitoring Committee in this 
study.
8.6
Study Population
The Enrolled Set will consist of all subjects who have signed informed consent and also passed 
inclusion/exclusion criteria.
The Safety Set will consist of all subjects who receive any amount of IP. Analysis will be 
performed according to the treatment regimen actually received regardless of the randomized 
treatment regimen.
The Pharmacokinetic (PK) Set will consist of subjects who receive at least 1 dose of study drug 
and have evaluable post-dose maribavir PK data (defined as complete concentration-time profile 
to obtain meaningful estimates of PK parameters). The PK analyses will be based on this 
analysis population.
Subjects who do not provide reliable concentration-time profile (in 1 or more periods) may be 
excluded from PK analysis (for the corresponding treatment period). 
8.7
Pharmacokinetic Analyses
8.7.1
Pharmacokinetic Endpoint(s)
A PK evaluation of maribavir concentrations and 
 will be performed 
based on the PK Set. Pharmacokinetics parameters will be estimated for maribavir and 
 
following the administration of maribavir 400 mg for non-Hispanic, Caucasian subjects and of 
200, 400, and 800 mg for subjects of Japanese descent.
Maribavir Cmax, AUClast, and AUC0-inf will be the primary endpoints. 
 
PK parameters will include, but not be limited to the following:

Cmax
Maximum observed plasma concentration 

tmax
Time of maximum observed concentration sampled during a 
dosing interval

AUClast
Area under the curve from the time of dosing to the last 
measurable concentration

AUC0-inf
Area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration


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
AUC0-inf%extrap The percent of AUC0-inf extrapolated, calculated by 
(1-AUClast/AUC0-inf)*100

λz elimination rate in the terminal phase 

t1/2 Terminal half-life

CL/F
Apparent total body clearance following extravascular 
administration calculated as dose divided by AUC0-inf

Vz/F
Apparent volume of distribution following extravascular 
administration calculated as CL/F divided by λz

Tlag
Delay between the time of dosing and time of appearance of drug 
(investigational) in plasma in the employed sampling scheme
In addition, dose-normalized (to 400 mg) AUClast, AUC0-inf, and Cmax will be calculated for 
Japanese subjects. 
8.7.1.1
Statistical Analysis of Pharmacokinetic Parameters
Maribavir Cmax, AUClast, and AUC0-inf will be the primary endpoints. 
 
 Individual concentrations and PK parameters (including 
dose-normalized) of maribavir and 
 will be listed and summarized by maribavir dose 
with descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient of 
variation [CV], median, minimum, maximum, geometric mean, and percent coefficient of 
variation (CV%) of geometric mean. The 95% CIs of the geometric means of Cmax, AUClast, and 
AUC0-inf parameters will be presented as well. Figures of individual and mean (±SD) maribavir 
concentration-time profiles will be generated on linear and semi-log scales. The mean 
concentration-time profiles will be generated and displayed by overlaying the Japanese cohort 
and Non-Hispanic Caucasian cohort. Figures of PK parameters and dose-normalized PK 
parameters vs. dose in Japanese subjects will be generated. Box-Whisker plots for selected PK 
parameter will be generated with Japanese cohort and Non-Hispanic Caucasian side by side.  
In order to compare the PKs of maribavir between subjects of Japanese descent and matched 
non-Hispanic, Caucasian subjects, the differences of log-transformed PK parameters (AUClast, 
AUC0-inf, and Cmax) from the maribavir 400 mg oral dose will be examined between cohorts 
using an analysis of variance model. The geometric mean ratio and its 90% CI of PK parameters 
for Japanese descent vs. Caucasian will be provided from the model. In addition, the difference 
of log-transformed dose-normalized AUClast, AUC0-inf, and Cmax will be examined between the 
Japanese cohort estimated at the 200 mg dose and the Non-Hispanic Caucasian cohort estimated 
at the 400 mg dose, as well as between the Japanese cohort estimated at the 800 mg dose and the 
Non-Hispanic Caucasian cohort estimated at 400 mg dose, using an analysis of variance model. 
The geometric mean ratio and its 90% CI will be provided from the model. Forest plots of 
geometric mean ratios for selected PK parameters between Japanese cohort vs. the Non-Hispanic 
Caucasian cohort at 400 mg will be generated. 
 




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Adverse events will be coded using the agreed-upon version of Medical Dictionary for 
Regulatory Activities, Version 23.0. or later. The number of events, incidence, and percentage of 
TEAEs will be calculated overall, by system organ class, and by PT. Treatment emergent 
adverse events will be further summarized by severity and relationship to investigational 
product. Adverse events related to investigational product, AEs leading to withdrawal, SAEs, 
and deaths will be similarly summarized/listed.
8.9
Sample Size Calculation and Power Considerations 
The sample size consideration for the primary objective of evaluating the PK profile of 
maribavir, administered as a single oral dose at 400 mg, between Japanese subjects and matched, 
healthy, adult, non-Hispanic, Caucasian subjects is based on feasibility and comparable studies. 
A total of 24 subjects (12 subjects of Japanese descent and 12 matched, non-Hispanic, Caucasian 
subjects) will be targeted to be enrolled in the study.


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9.
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Townsend, L. B. & Koszalka, G. W. 2002. Potent and selective inhibition of human 
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benzimidazole riboside compounds for treatment of cytomegalovirus disease. Adv Exp 
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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 
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Farrugia, E. & Schwab, T. R. 1992. Management and prevention of cytomegalovirus infection 
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Kern, E. R., Hartline, C. B., Rybak, R. J., Drach, J. C., Townsend, L. B., Biron, K. K. & 
Bidanset, D. J. 2004. Activities of benzimidazole D- and L-ribonucleosides in animal 
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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 
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Limaye, A. P., Corey, L., Koelle, D. M., Davis, C. L. & Boeckh, M. 2000. Emergence of 
ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ 
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Ljungman, P., Perez-Bercoff, L., Johnsson, J., Avetisyan, G., Sparrelid, E., Aschan, J., Barkholt, 
L., Larsson, K., Winiarski, J., Yun, Z. & Ringden, O. 2006. Risk factors for the 
development of cytomegalovirus disease after allogeneic stem cell transplantation. 
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Pouria, S., State, O. I., Wong, W. & Hendry, B. M. 1998. CMV infection is associated with 
transplant renal artery stenosis. Qjm, 91, 185-9.
Razonable, R. R. & Emery, V. C. 2004. Management of CMV infection and disease in transplant 
patients. 27-29 February 2004. Herpes, 11, 77-86.
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Link, H., Ljungman, P. & Infectious Diseases Working Party of the European Group for 
Blood and Marrow Transplantation 2002. Randomized multicenter trial of foscarnet 
versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic 
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Richardson, W. P., Colvin, R. B., Cheeseman, S. H., Tolkoff-Rubin, N. E., Herrin, J. T., Cosimi, 
A. B., Collins, A. B., Hirsch, M. S., McCluskey, R. T., Russell, P. S. & Rubin, R. H. 
1981. Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N 
Engl J Med, 305, 57-63.
Rubin, R. H. 1989. The indirect effects of cytomegalovirus infection on the outcome of organ 
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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.
Singh, N., Wannstedt, C., Keyes, L., Wagener, M. M., de Vera, M., Cacciarelli, T. V. & 
Gayowski, T. 2004. Impact of evolving trends in recipient and donor characteristics on 
cytomegalovirus infection in liver transplant recipients. Transplantation, 77, 106-10.
Williams, S. L., Hartline, C. B., Kushner, N. L., Harden, E. A., Bidanset, D. J., Drach, J. C., 
Townsend, L. B., Underwood, M. R., Biron, K. K. & Kern, E. R. 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.
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herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and 
encapsidation. Proc Natl Acad Sci U S A, 98, 1895-900.




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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
Appendix 1.1
Regulatory and Ethical Considerations
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
Appendix 1.2
Sponsor’s Responsibilities
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP guideline E6 (1996), EU Directive 2001/20/EC 
Guidelines, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IP for 
shipment to the site.
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.


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Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and Institutional Review Boards (IRBs)/Ethics committees (ECs) are notified as 
appropriate. Additionally, the discontinuation of a registered clinical study which has been 
posted to a designated public website will be updated accordingly.
Appendix 1.3
Investigator’s Responsibilities
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curricula vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
Agreement with the final clinical study report is documented by the signed and dated signature 
of the principal investigator, in compliance with Directive 2001/83/EC as amended by Directive 
2003/63/EC and ICH Guidance E3 (1995).


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Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all IP, containers, and other study materials to the sponsor. Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
Documentation and Retention of Records
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
All data sent to the sponsor must be endorsed by the investigator.
Once the CRA/study monitor has verified the contents of the completed CRF pages against the 
source data, the duplicate pages are retrieved and forwarded to the study sponsor (or designee) 
for data entry. If the data are unclear or contradictory, queries are sent for corrections or 
verification of data.


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Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports
All key data must be recorded in the subject’s source documents.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the United States 
Food and Drug Administration [US FDA], European Medicines Agency [EMA], United 
Kingdom Medicines and Healthcare products Regulatory Agency UKMHRA) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in IP; any significant equity interest 
in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).


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Compliance to all Local, State, and National Controlled-substance Biohazard and 
Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
Appendix 1.4
Ethical Considerations
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval. A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action. Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or the investigator for sites within the EU; 
for multicenter studies the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the clinical trial agreement.


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Investigational product supplied will not be released until the sponsor has received written 
IRB/EC approval.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC appraised of the 
progress of the study and of any changes made to the protocol, at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; or 
for multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures.
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market maribavir; national or local regulatory authorities; and the IRB/EC which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number.
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.


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Study Results / Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multi-site study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions:
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Shire is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Shire 
will require the submission of all Shire-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and 
self-archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.


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Appendix 2
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Appendix 2.1
Adverse Event Definitions
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this IP or 
medicinal product. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational)
product (ICH Guidance E2A 1995).
Treatment-emergent Adverse Event
A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment 
with an IP or medicinal product or any existing event that worsens in either intensity or 
frequency following exposure to the IP or medicinal product. 
Serious Adverse Event 
An SAE is any untoward medical occurrence (whether considered to be related to IP or not) that 
at any dose:

Results in death

Is life-threatening. Note: The term ‘life-threatening’ in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it was 
more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, that are the result of elective or previously scheduled investigations 
procedures or surgery for pre-existing conditions and have not worsened after 
initiation of treatment, should not be classified as SAEs. For example, an admission 
for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or 
previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s).

Results in persistent or significant disability/incapacity

Results in a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE 
when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent 1 of the outcomes listed 
in this definition. Examples of such medical events include bronchospasm associated 
with anaphylaxis requiring intensive treatment in an emergency room or at home; 
blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse.


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Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the IB. “Unexpected” also refers 
to the AEs that are mentioned in the maribavir IB and/or prescribing information as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the product, but are 
not specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB and/or prescribing 
information as the Reference Safety Information. This determination will include considerations 
such as the number of AEs previously observed, but not on the basis of what might be 
anticipated from the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect is any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the study 
protocol or product labeling; or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects.
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, vital sign measure, or ECG assessment 
can represent an AE if the change is clinically relevant or if, during administration of IP, a shift 
of a parameter is observed from a value in the normative range to a value that is outside the 
normal range and considered clinically significant, or a further waning of an already clinically 
significant value. When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing administration or 
after the end of administration with the IP, and the range of variation of the respective parameter 
within its reference range, should also be considered.


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If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
Appendix 2.2
Collection of Adverse Events
All AEs/SAEs are collected from the time the informed consent is signed until the defined 
follow-up period stated in Section 7.1.4. This includes events occurring during the screening 
phase of the study, regardless of whether or not IP is administered. 
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.
Appendix 2.3
Assessment of Adverse Events
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of IP, must be 
recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
IP, and the dyspepsia becomes severe and more frequent after first dose of a new AE of severe 
dyspepsia (with the appropriate date of onset) should be documented in the source.
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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Relationship Categorization
A physician/investigator must make the assessment of relationship to IP for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IP. If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related”. Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IP and the occurrence of the AE, then the AE should be considered 
“related”. The causality assessment must be documented in the source.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the IP is 
compelling and/or follows a known or suspected response pattern to that product, and 
the event cannot be explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the IP and the event.
Outcome Categorization
The outcome of AEs must be recorded in the source during the course of the study. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown.
If applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE CRF. 
Appendix 2.4
Safety Reporting
Reference Safety Information
The reference for safety information for this study is the maribavir IB, which the sponsor has 
provided under separate cover to all investigators.


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Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department, the CRO, and Shire Medical Monitor within 24 hours of becoming 
aware of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors (Appendix 2.9) unless they result in an SAE.
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
for SAEs and Non-serious AEs as Required by Protocol” Form and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested), and fax or e-mail the form to the Shire Global 
Drug Safety Department. A copy of the Shire Clinical Study Serious Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol (and any applicable follow-up reports) must 
also be sent to the CRO and Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol.
Appendix 2.5
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to IP) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Drug Safety Department and the CRO and Shire Medical Monitor within 
24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Shire Global Drug Safety
Department within 24 hours of the first becoming aware of the event.
Appendix 2.6
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets seriousness criteria. The 
resolution date is the date the event no longer meets seriousness criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital admission 
and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms reported by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
Appendix 2.7
Fatal Outcome
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.


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For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received IP or it is a single dose study). The IP action of withdrawn should not be selected 
solely as a result of the subject’s death.
Appendix 2.8
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO and Shire Medical Monitor using the details specified in 
the emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
β-HCG test or ultrasound result will determine the pregnancy onset date.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Shire Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
post-partum.
Appendix 2.9
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Appendix 2.4. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.


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
Abuse – Persistent or sporadic intentional intake of IP when used for a non-medical purpose 
(eg, to alter one’s state of consciousness or get high) in a manner that may be detrimental to 
the individual and/or society

Misuse – Intentional use of IP other than as directed or indicated at any dose (Note: this 
includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)

Overdose – Intentional or unintentional intake of a dose of IP higher than the 
protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an IP. Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of the unassigned treatment, or the administration and/or use 
of an expired IP is/are always reportable as a medication error.
Cases of subjects missing doses of the IP should be reported as missed dose.
Appendix 2.10
Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following:

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible IRB(s)/EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 


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Appendix 2.11 Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting
The sponsor is responsible for notifying the relevant regulatory authorities, IRBs and ECs of 
related, unexpected SAEs.
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the TAK-620 program. 
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings, or the relevant local regulatory authority of all SAEs that occur at his or her site as 
required by IRB/EC procedures.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
TAK-620-1020
PHASE 1
A Phase 1, Open-label, Randomized, Cross-over Study to Evaluate the Pharmacokinetics, Safety, 
and Tolerability of a Single Oral Dose of Maribavir Administered in Healthy Japanese Subjects 
Compared with Matched, Healthy, Non-Hispanic, Caucasian Subjects and to Assess Dose-
Proportionality of 3 Doses of Maribavir in the Japanese Subjects
PROTOCOL IDENTIFIER: TAK-620-1020
Study Sponsor(s):
Shire ViroPharma LLC (Shire, [and affiliates]); 
Shire is a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited 300 Shire Way, Lexington, MA 02421 USA
Author:
, PhD 
Protocol:
Original Protocol:  03 April 2020
Amendment 1:       08 July 2020
SAP Version #:
1.0
SAP Date:
06 August 2020
Status:
Final


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REVISION HISTORY
Version
Issue Date
Summary of Changes
1.0
06 Aug 2020
Final Version


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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................................5
LIST OF IN-TEXT FIGURES.........................................................................................................5
ABBREVIATIONS .........................................................................................................................6
1.
INTRODUCTION....................................................................................................................8
2.
OBJECTIVES AND ENDPOINTS..........................................................................................9
2.1
Objectives...................................................................................................................9
2.1.1
Primary Objective....................................................................................................9
2.1.2
Secondary Objectives...............................................................................................9
2.1.3
Exploratory Objective..............................................................................................9
2.2
Endpoints....................................................................................................................9
2.2.1
Pharmacokinetic Endpoints .....................................................................................9
2.2.2
Exploratory Pharmacokinetic Endpoints ...............................................................10
2.2.3
Safety Endpoints....................................................................................................10
3.
STUDY DESIGN ...................................................................................................................11
3.1
General Description..................................................................................................11
3.2
Randomization .........................................................................................................13
3.3
Blinding....................................................................................................................13
3.4
Sample Size and Power Considerations...................................................................13
4.
STATISTICAL ANALYSIS SETS........................................................................................14
4.1
Enrolled Set..............................................................................................................14
4.2
Safety Set..................................................................................................................14
4.3
Pharmacokinetic Set.................................................................................................14
5.
STUDY SUBJECTS...............................................................................................................15
5.1
Disposition of Subjects.............................................................................................15
5.2
Demographic and Other Baseline Characteristics....................................................15
5.3
Medical History........................................................................................................15
5.4
Prior Medications (Therapies), and Procedures .......................................................16
5.5
Concomitant Medications (Therapies) and Procedures ...........................................16
5.6
Exposure to Investigational Product ........................................................................16
5.7
Measurements of Treatment Compliance.................................................................17
5.8
Protocol Deviations..................................................................................................17
6.
EFFICACY ANALYSES.......................................................................................................18
7.
SAFETY ANALYSIS ............................................................................................................19
7.1
Adverse Events.........................................................................................................19
7.1.1
Selected Adverse Events........................................................................................20


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7.2
Clinical Laboratory Data..........................................................................................20
7.3
Vital Signs................................................................................................................23
7.4
Electrocardiogram (ECG).........................................................................................24
8.
PHARMACOKINETIC ANALYSIS.....................................................................................26
8.1
Drug Concentration..................................................................................................26
8.1.1
Handling Data with Below Limit of Quantitation (BLQ) Values..........................26
8.2
Pharmacokinetic Parameters ....................................................................................27
8.3
Statistical Analysis of Pharmacokinetic Data ..........................................................28
9.
PHARMACODYNAMIC ANALYSIS..................................................................................30
10. OTHER ANALYSES .............................................................................................................31
11. INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE.......................32
12. DATA HANDLING CONVENTIONS..................................................................................33
12.1
General Data Reporting Conventions ......................................................................33
12.2
Repeated or Unscheduled Assessments of Safety Parameters.................................33
12.3
Handling of Missing, Unused, and Spurious Data...................................................34
12.3.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..........................................................................................34
12.3.1.1
Incomplete Start Date.............................................................................34
12.3.1.2
Missing Day and Month.........................................................................34
12.3.1.3
Incomplete Stop Date.............................................................................34
12.3.2 Missing Date Information for Adverse Events......................................................35
12.3.2.1
Incomplete Start Date.............................................................................35
12.3.2.2
Incomplete Stop Date.............................................................................35
12.3.3 Missing Severity Assessment for Adverse Events.................................................36
12.3.4 Missing Relationship to Investigational Product for Adverse Events ...................36
12.3.5 Character Values of Clinical Laboratory Variables...............................................36
13. ANALYSIS SOFTWARE......................................................................................................37
14. CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ..................................................38
15. REFERENCES .......................................................................................................................39
16. APPENDICES ........................................................................................................................40
16.1
Schedule of Assessments .........................................................................................40


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LIST OF IN-TEXT TABLES
Table 1
Criteria for Potentially Clinically Significant Laboratory Tests............................21
Table 2
Criteria for Potentially Clinically Significant Vital Signs and Body Weight........23
Table 3
Criteria for Potentially Clinically Significant ECG Values...................................25
Table 4
Schedule of Assessments for Subjects of Japanese Descent..................................40
Table 5
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 
and 2 of Treatment Period 1...................................................................................42
Table 6
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 
and 2 of Treatment Period 2...................................................................................43
Table 7
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 
and 2 of Treatment Period 3...................................................................................44
LIST OF IN-TEXT FIGURES
Figure 1
Study Design Flow Chart.......................................................................................12


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ABBREVIATIONS
AE
adverse event
AUC
area under the curve
AUC0-inf
area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration
AUC0-inf%extrap
the percent of AUC0-inf extrapolated, calculated by (1-
AUClast/AUC0-inf)*100
AUClast
area under the curve from the time of dosing to the last measurable 
concentration
-HCG
beta-human chorionic gonadotropin
BLQ
below limit of quantification
BMI
body mass index
CI
confidence interval
Cmax
maximum concentration 
CL/F
oral clearance 
CRF
case report form
CV
coefficient of variation
CV%
percent coefficient of variation
ECG
electrocardiogram
IP
investigational product, maribavir
z
first order rate constant associated with the terminal (log linear) 
portion of the curve
PK
pharmacokinetics
PT
preferred term
QTc
corrected QT interval
QTcF
corrected QT interval by Fridericia's formula
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
t1/2
terminal half-life
TEAE
treatment-emergent adverse event


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TOST
two one-sided test
Tlag
delay between the time of dosing and time of appearance of drug 
concentration in plasma in the employed sampling scheme
tmax
time of maximum observed concentration sampled during a dosing 
interval
TSH
thyroid-stimulating hormone
Vz/F
apparent volume of distribution 


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1.
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of pharmacokinetic (PK), safety, and tolerability data as described in the TAK-620-
1020 protocol amendment 1 dated 08 July 2020. Specifications for tables, figures, and listings 
will be contained in a separate document. Methods used in the final analysis of pharmacokinetic 
(PK) parameters and the reporting of the results from these analyses will be described in Clinical 
Pharmacology Analysis Plan (CPAP).
Within this document, the term investigational product is used to refer to maribavir.




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
CL/F
Apparent total body clearance following extravascular administration 
calculated as dose divided by AUC0-inf

Vz/F
Apparent volume of distribution following extravascular 
administration calculated as CL/F divided by λz

Tlag
Delay between the time of dosing and time of appearance of plasma 
concentration in the employed sampling scheme
In addition, dose-normalized (to 400 mg) Cmax, AUClast, and AUC0-inf  will be calculated for 
Japanese subjects. 
2.2.2
Exploratory Pharmacokinetic Endpoints
2.2.3
Safety Endpoints
The safety analysis will be performed using the Safety Analysis Set. Safety endpoints include 
AEs, vital signs, ECG variables, and clinical laboratory variables. The following safety 
evaluations will be performed:

Number, severity, seriousness, and causality of treatment-emergent adverse events 
(TEAEs).

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and 
urinalysis) from baseline to post-baseline time points.
For each safety variable, the last value collected before the first dose of investigational product in 
that period will be used as baseline for all analyses of that safety variable in that period. 


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3.
STUDY DESIGN
3.1
General Description
This is a Phase 1, open-label, randomized, crossover, partially fixed sequence, single-center 
study. A total of 24 subjects will be enrolled: 12 subjects of Japanese descent and 
12 non-Hispanic, Caucasian subjects. Non-Hispanic, Caucasian subjects will be matched to 
Japanese subjects based on age (years), sex, and body mass index (BMI) (15%).
Treatment Period:
The non-Hispanic, Caucasian subjects will have one Treatment Period. The Japanese subjects 
will have Treatment Periods 1, 2, and 3. 

In Treatment Period 1, all study subjects (both Japanese and Caucasian) will receive 
maribavir as a single 400 mg oral dose.

Depending upon the randomization assignment on Day 1 of treatment period 2, all 
subjects of Japanese descent will be dosed in a crossover fashion in Treatment Periods 2 
and 3. They will receive a single oral dose of either 200 mg followed by 800 mg 
maribavir or a single oral dose of 800 mg followed by 200 mg maribavir.
The study design flow chart is presented in Figure 1.


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Figure 1
Study Design Flow Chart
*Washout period of 72 to 73 hours after treatment on Day 1.


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3.2
Randomization
Subjects of Japanese descent who meet all the inclusion criteria and none of the exclusion 
criteria will be randomized (1:1 ratio) to either maribavir 200 mg or 800 mg on Day 1 in 
treatment period 2. Subjects will then be dosed in a crossover fashion with a single dose of 
maribavir based on their randomization assignment on Day 1 in Treatment Periods 2, and 3.  
There is no stratification for this study.
3.3
Blinding 
This is an open-label study. Blinding is not applicable.
3.4
Sample Size and Power Considerations
The sample size consideration for the primary objective of evaluating the PK profile of 
maribavir, administered as a single oral dose at 400 mg, between Japanese subjects and matched, 
healthy, adult, non-Hispanic, Caucasian subjects is based on study feasibility and comparable 
studies. 
A total of 24 subjects (12 subjects of Japanese descent and 12 matched, non-Hispanic, Caucasian 
subjects) will be targeted to be enrolled in the study.


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4.
STATISTICAL ANALYSIS SETS
4.1
Enrolled Set
The Enrolled Set consists of all subjects who have signed informed consent and also met 
inclusion/exclusion criteria.
4.2
Safety Set
The Safety Set consists of subjects who are administered at least 1 dose of investigational 
product (maribavir) and have at least 1 post-dose safety assessment. Analysis will be performed 
according to the treatment regimen actually received regardless of the randomized treatment 
regimen.
4.3
Pharmacokinetic Set
The Pharmacokinetic (PK) Set will consist of subjects who receive at least 1 dose of study drug 
and have evaluable post-dose maribavir PK data (defined as complete concentration-time profile 
to obtain meaningful estimates of PK parameters). The PK analyses will be based on this 
analysis set.
Subjects who do not provide reliable concentration-time profile (in 1 or more periods) may be 
excluded from PK analysis (for the corresponding treatment period). 


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5.
STUDY SUBJECTS
5.1
Disposition of Subjects
The number of subjects who were included in each defined statistical analysis set (Enrolled, 
Safety, and PK) will be summarized by cohort and overall.
Summaries and listing of subject disposition will be based on the Enrolled Set.
The reasons for exclusion from the PK set will be presented in the listings with details of any 
AEs. 
The number and percentage of subjects who completed and prematurely discontinued the study, 
as well as subjects who completed dosing and prematurely discontinued the study drug, as 
recorded on the termination page of the electronic case report form (eCRF), will be presented for 
each cohort and overall for the Safety Set. Reasons for premature discontinuation from the study, 
as well as discontinuation from study drug, as recorded on the termination page of the eCRF will 
be summarized (number and percentage) by cohort and overall, for the Safety Set. All subjects 
who prematurely discontinued the study and/or discontinued the study drug will be listed by 
discontinuation reason. 
5.2
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by cohort 
and overall, for the Safety Set as well as the PK Set. Demographics and other baseline 
characteristics data will be listed for the Safety Set.
The following demographic characteristics will be summarized in the following order in the 
tables: age (years), sex, race, and ethnicity. The following baseline characteristics will be 
summarized in the following order in the baseline table: weight (kg), height (cm), and body mass 
index (BMI, kg/m2). 
Age, sex, race, and ethnicity will be summarized based on data obtained at the Screening Visit.  
Height and weight will be summarized from the last available measurement prior to the first 
single dose of IP, and BMI will be calculated.
Age will be calculated as the integer part of: (date of informed consent is signed – date of birth + 
1)/365.25. Body mass index will be calculated using the following formula: weight (kg) / (height 
[m])2.   
5.3
Medical History
Medical history will be collected at the Screening Visit and will be coded using agreed upon 
MedDRA Version 23.0 or newer. Listings will be provided using the Safety Set.
Medical history will be summarized by system organ class (SOC) and preferred term (PT) for 
each cohort, based on the Safety Set. The summary of medical history will include the number 


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and percentage of subjects who experienced the event and number of events experienced. System 
organ class will be sorted alphabetically, and within each SOC, PT will be sorted in the table 
Total column by descending order of frequency.
5.4
Prior Medications (Therapies), and Procedures
All prior medications, therapies, and procedures will be listed based on the Safety Set.
Prior medications will be coded using the World Health Organization Drug Dictionary Global 
B3 dated March 2020. 
Prior medications (therapies) and procedures are defined as the medications (therapies) and 
procedures with a start date prior to the date of the first single dose of IP. 
Prior medication usage presented by therapeutic class according to Anatomical Therapeutic 
Chemical (ATC) classification and PT will be summarized based on the number and proportion 
of subjects in each cohort and in overall subjects based on the Safety Set. Multiple medication 
usage by a subject in the same category will be counted only once. 
5.5
Concomitant Medications (Therapies) and Procedures  
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
Global B3 dated September 2019. 
Medications (therapies) and procedures taken during the study will be considered concomitant to 
the treatment(s) a subject has taken during the duration of the medications. Medications with 
start and stop dates and times during the wash-out period or the 7 days follow-up period after last 
single dose of IP will be considered concomitant to the prior treatment(s) subject received. Any 
medication/ therapy and procedure with a start date and time after 7 days following the date and 
time of the last single dose of IP will be considered post-treatment medication /therapy and 
procedure and not be considered a concomitant medication/therapy and procedure.
Concomitant medication usage presented by therapeutic class (according to Anatomical 
Therapeutic Chemical classification) and PT will be summarized based on the number and 
proportion of subjects by cohort, treatment group and overall, based on the Safety Set. Multiple 
medication usage by a subject in the same category will be counted only once.
All concomitant therapies, procedures and medication will be listed for the Safety Set.
5.6
Exposure to Investigational Product
Exposure to the IP (maribavir) will be summarized in terms of total planned dose in mg. 
Descriptive statistics (n, mean, standard deviation [SD], minimum, median, and maximum) will 
be presented to describe the exposure to IP by cohort and treatment group based on the Safety 
Set. 
Listings will be created by subject number and visit presenting the date and time of dose 
administration separately based on the Safety Set.


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5.7
Measurements of Treatment Compliance 
Treatment compliance will be summarized in terms of number of subjects who completed the 
drug administration, who fasted 10 hours before the investigational drug administration, and who 
fasted 4 hours after the investigational drug administration, by cohort and treatment group based 
on the Safety Set. 
5.8
Protocol Deviations
Protocol deviations will be recorded by the site separately from the clinical database using a 
Protocol Deviation tracker. Protocol deviations will be classified as major or minor per the 
agreed protocol deviation management plan and will be documented in the Protocol Deviation 
tracker. The Sponsor study team will review the protocol deviations and their classification 
throughout the study and before database lock.
Major/minor protocol deviations will be summarized by category for each cohort, each treatment
group, and overall based on the Safety Set. Major/minor protocol deviations will be listed based 
on the Safety Set.


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6.
EFFICACY ANALYSES
Not applicable. 


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7.
SAFETY ANALYSIS 
The safety analysis will be performed using the Safety Set. Safety variables include AEs, vital 
signs, ECG, and clinical laboratory variables. For each safety variable, the last value collected 
before the first dose of investigational product will be used as baseline for all analyses of that 
safety variable. Last Value on Treatment (LVOT) will be defined as the last valid assessment 
obtained after Baseline and until 7 days after last dose of investigational product. 
All safety analyses will be conducted according to the treatment the subject actually received.
7.1
Adverse Events 
Adverse events will be coded using MedDRA Version 23.0 or newer.
An AE (classified by preferred term) that occurs during the study will be considered a TEAE if it 
has a start date on or after the first dose of investigational product or if it has a start date before 
the date of the first dose of investigational product, but increases in severity on or after the date 
of the first dose of investigational product.  If more than 1 AE with the same preferred term is 
reported before the date of the first dose of investigational product, then the AE with the greatest 
severity will be used as the benchmark for comparison to the AEs occurring during the study 
under the preferred term. Adverse events during the study will be assigned to the treatment(s) a 
subject has taken at the onset of the event. An AE with start date and time during the wash-out 
period or the 7 days follow-up period after last single dose of IP will be assigned to the prior 
treatment subject received. An AE that occurs more than 7 days after the date of the last dose of 
investigational product will not be counted as a TEAE.
An overall summary of the number of subjects with TEAEs as well as the number of events will 
be presented, including the number and percentage of subjects with any TEAEs, serious TEAEs, 
TEAEs related to investigational product and TEAEs leading to discontinuation of 
investigational product.
The number and percentage of subjects reporting TEAEs, as well as the number of events, in 
each cohort, each treatment group, and overall will be tabulated by system organ class (SOC) 
and preferred term (PT); by SOC, preferred term (PT), and maximum severity. TEAEs 
considered related to investigational product will also be summarized by SOC and preferred 
term. If more than 1 AE occurs with the same preferred term for the same subject, then the 
subject will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by relationship to investigational product. 
Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC by 
descending incidence.
TEAEs and related TEAEs will be summarized by preferred term by descending frequency. 
Serious TEAEs, TEAEs leading to discontinuation of investigational product and serious TEAEs 
leading to death, will be summarized by SOC, preferred term, cohort, and treatment group. 


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7.1.1
Selected Adverse Events 
The following TEAEs and related TEAEs will be summarized by SOC, preferred term, cohort, 
and treatment group:

Dysgeusia

Nausea

Vomiting

Diarrhea

Neutropenia
These TEAEs and related TEAEs will also be summarized by PT by descending order of 
frequency.
7.2
Clinical Laboratory Data
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point as well as shift tables from baseline to each visit for quantitative 
variables will be presented by cohort and treatment group for the following clinical laboratory
variables (copy from the protocol). 
Hematology
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white blood cell 
count – total and differential (WBC), i.e. total neutrophils (absolute), 
eosinophils (absolute), monocytes (absolute), basophils(absolute), and 
lymphocytes (absolute).
Biochemistry
Sodium, potassium, glucose(fasting), urea nitrogen, creatinine, calcium, 
chloride, thyroid stimulating hormone (TSH) a, thyroxine (free 
T4)triiodothyronine (T3), phosphate, protein, carbon dioxide, albumin, 
aspartate transaminase, alanine transaminase, gamma glutamyl transferase, 
alkaline phosphatase, total bilirubin, uric acid, and -HCG a.
a Females only.
Urinalysis
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte esterase, and 
specific gravity.
Clinical laboratory test values are potentially clinically significant (PCS) if they meet either the 
low or high PCS criteria listed in Table 1. The number and percentage of subjects with post-
baseline PCS values will be tabulated by cohort and treatment group. The percentages will be 
calculated relative to the number of subjects with available baseline values and at least 1 post-
baseline assessment. The numerator is the total number of subjects with at least 1 post-baseline 




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Table 1
Criteria for Potentially Clinically Significant Laboratory Tests
Parameter
Classification 
Criteria: SI Units (Conventional Units)
Creatinine
High and Increase
>150 µmol/L AND
Increase > 30% from baseline value
Low and Decrease
NA
Calcium
High and Increase
Above ULN AND
Increase of ≥ 0.25 mmol/L (1.0 mg/dL) from baseline value
Low and Decrease
Below LLN AND
Decrease of ≥0.25 mmol/L (1.0 mg/dL) from baseline value
Carbon dioxide (Total)
High
>32 mmol/l (mEq/l) 
Low
< 20 mmol/l (mEq/l)) 
Phosphate
High
>0.162 mmol/L (0.5 mg/dL) above ULN
Low
>0.162 mmol/L (0.5 mg/dL) belowLLN
Chloride 
High
>110 mmol/L (>110 mEq/L)
Low
<98 mmol /L (<98 mEq/L)
Protein (Total)
High and Increase
Above ULN AND
Increase of ≥20 g/L (2.0 g/dL) from baseline value 
Low and Decrease
Below LLN AND
Decrease of ≥20 g/L (2.0 g/dL) from baseline value
Albumin
High and Increase 
Above ULN AND
Increase of ≥10 g/L (1.0 g/dL) from baseline value 
Low and Decrease 
Below LLN AND
Decrease of ≥10 g/L (1.0 g/dL) from baseline value
Aspartate transaminase
High
>2 × ULN
Alanine transaminase 
(ALT)
High
>2 × ULN
Gamma glutamyl 
transferase (GGT)
High
>1.5 × ULN
Alkaline phosphatase 
(ALP)
High
>1.5 × ULN
Total bilirubin
High and Increase 
>1.5 × ULN
Uric acid (with normal 
diet)
High and Increase 
Above ULN AND
Increase of >0.119 mmol/L (2.0 mg/dL) from baseline value
Low and Decrease
Below LLN AND
Decrease of >0.119 mmol/L (2.0 mg/dL) from baseline 
value
Thyroid stimulating 
hormone (TSH)
High
>5.0 μU/L (>5.0 μU/mL)
Low
<0.5 μU/L (<0.5 μU/mL)




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Table 2
Criteria for Potentially Clinically Significant Vital Signs and Body Weight
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline Value
(beats per minute)
Low
45
Decrease of 15
Weight (kg)
High
-
Increase of 5%
Low
-
Decrease of 5%
Body temperature
High
> 38.3°C or > 100.9°F
Low
< 35°C or < 95°F
Respiratory rate (breaths/min)
High
> 25
Low
< 10
a A post-baseline value is considered as a PCI value if its meets both criteria for observed value and change from baseline.
All vital signs data will be listed for the Safety Set.
7.4
Electrocardiogram (ECG)
Descriptive statistics for ECG variables (eg, heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc interval) and their changes from baseline at each assessment time point 
will be presented by cohort and treatment group. QTc interval will be calculated using both 
Bazett (QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not 
available, it will be replaced with 60/hr in the correction formula. ECG interpretation will be 
summarized by visit. A shift table from baseline to each visit for qualitative ECG results will be 
presented. If the QTcF interval is increased by >45 msec from the baseline, or an absolute QTcF 
value is >500 msec for any scheduled ECG, then ECG should be repeated 2 more times and the 
average of the 3 QTc values will be recorded in the CRF and used to generate descriptive 
summary.
Electrocardiogram variable values will be considered PCS if they meet or exceed the normal 
limit values listed in Table 3. The number and percentage of subjects with post-baseline PCS 
values will be tabulated by cohort and treatment group. The percentages will be calculated 
relative to the number of subjects with available non-PCS baseline and at least 1 post-baseline 
assessment. The numerator is the total number of subjects with at least 1 PCS post-baseline ECG 
value. A listing of all subjects with post-baseline PCS value will be provided including the 
subject number, baseline, and post-baseline PCS values.


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Table 3
Criteria for Potentially Clinically Significant ECG Values
Parameter
Classification 
Criteria
Overall evaluation
ABNORMAL
Overall evaluation is ABNORMAL
Heart rate (bpm)
LOW and DECREASE
≤45 and decrease of >15 from baseline value
HIGH and INCREASE
≥100 and increase of >15 from baseline value
PR interval (msec)
HIGH and INCREASE
≥200 and increase of ≥20 from baseline value
QRS interval (msec)
HIGH
≥120
QTc interval (men) 
(msec)*
HIGH
>430 and increase from baseline value >30
QTc interval (women) 
(msec)*
HIGH
>450 and increase from baseline value >30
Abbreviations: bpm=beats per minute; QTc=QT interval corrected.  
*Values noted refer to both Bazett’s (QTcB) and Fridericia’s (QTcF) formula
All ECG results will be presented in data listings.


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8.
PHARMACOKINETIC ANALYSIS 
All summaries and analyses of the PK data will be based on the Pharmacokinetic Set defined in 
Section 4.3.
Each subject’s data (eg, dosing records, sample collection records, protocol deviations, etc.) will 
be reviewed for data exclusion from the descriptive statistics and statistical analysis on a case-
by-case basis at the discretion of the pharmacokineticists. Rationale of data exclusion will be 
provided in a data listing.
Derivations of the PK parameters will be found in the Clinical Pharmacology Analysis Plan.
8.1
Drug Concentration
A PK evaluation of maribavir concentrations and 
 concentrations will be performed 
based on the PK Set. During this study, blood samples will be drawn from each subject for the 
determination of plasma concentration of maribavir and 
. Serial blood samples will be 
collected at the following time points. 
Collection of Blood Samples for Pharmacokinetic Analysis 
Cohort
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
A: Non-Hispanic 
Caucasian subjects
Maribavir 
and 
Plasma
Day1 of 
treatment 
period 1
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 
8, 12, 16, 20, and 24 hours post dose
B: Subjects of Japanese 
descent
Maribavir 
and 
Plasma
Day 1of all 
3 treatment 
periods
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 
8, 12, 16, 20, and 24 hours post dose
Plasma concentrations of maribavir and 
 will be measured using a validated analytical 
method.
The concentration of plasma maribavir and 
 will be summarized by cohort, treatment 
group, and scheduled sampling time using descriptive statistics (n, arithmetic mean, SD, 
geometric mean median, minimum, and maximum). Individual plasma concentration data will be 
presented in data listings by cohort and treatment group.
Individual concentrations of plasma maribavir and 
 will be plotted by actual time on 
linear and semilogarithmic scales for each subject, displaying all treatments. Plots of mean 
plasma maribavir and 
 concentrations versus nominal time for all treatments will also 
be provided on linear and semilogarithmic scales. 
8.1.1
Handling Data with Below Limit of Quantitation (BLQ) Values
The following procedures will be used for plasma maribavir concentrations below the lower limit 
of quantification (LLOQ):

Concentrations that are below limit of quantification (BLQ) are reported as <LLOQ on the 




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
Tlag
Delay between the time of dosing and time of appearance of drug 
concentration in plasma in the employed sampling scheme
In addition, dose-normalized (to 400 mg) AUClast, AUC0-inf, and Cmax will be calculated for 
Japanese subjects. 
Individual plasma PK parameters for maribavir and 
 will be summarized by cohort and 
treatment group using descriptive statistics (n, arithmetic mean, SD, median, minimum, 
maximum, and %CV). In addition, geometric mean, 95% CI of geometric mean and geometric 
CV% will be computed for original and dose-normalized Cmax, AUClast and AUC0-inf. Individual 
plasma PK parameters will be presented in a data listing for each cohort and treatment group. 
Scatter plots of individual plasma Cmax and AUCs for maribavir and 
 versus dose will 
be provided. Box-Whisker plots for selected dose-normalized PK parameters will be generated 
with Japanese cohort and Non-Hispanic Caucasian side by side at 400 mg. 
8.3
Statistical Analysis of Pharmacokinetic Data
In order to compare the PKs of maribavir between subjects of Japanese descent and matched 
non-Hispanic, Caucasian subjects, the differences of log-transformed PK parameters (Cmax , 
AUClast, and AUC0-inf) from the maribavir 400 mg oral dose will be examined between cohorts 
using an analysis of variance (ANOVA) model. The geometric mean ratio and its 90% CI of PK 
parameters for Japanese descent vs Caucasian will be provided from the model. 
In addition, the difference of log-transformed dose-normalized Cmax, AUClast, and AUC0-inf will 
be examined between the following dose groups using an ANOVA model.

the Japanese cohort estimated at the 200 mg dose and the Non-Hispanic Caucasian cohort 
estimated at the 400 mg dose

the Japanese cohort estimated at the 800 mg dose and the Non-Hispanic Caucasian cohort 
estimated at 400 mg dose
The geometric mean ratio and its 90% CI will be provided from the model. Forest plots of 
geometric mean ratios for selected PK parameters between Japanese cohort vs the Non-Hispanic 
Caucasian cohort at 400 mg will be generated. 
Dose proportionality
Dose proportionality will also be examined for maribavir PK parameters for the Japanese 
subjects. Dose proportionality will be assessed for Cmax and AUC (AUClast and AUC0-inf) using 
the power model. The power model assumes a linear relationship between the natural log 
transformed PK parameter and the natural log transformed dose.
ln (PK Parameter) = α + β × ln (Dose) + Random error


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where α is the intercept, β is the slope, and Random error is a random residual error. Dose 
proportionality will be assessed by estimating mean slope with the corresponding two-sided 90% 
CI from the power model. Dose proportionality is concluded when the 90% CIs of the slope β lie 
entirely within (1 + ln(0.8)/ln(r), 1 + ln(1.25)/ln(r)), where r is a ratio that describes the dose 
range and is defined as (highest dose/lowest dose). The fold increase in PK parameters and 
associated 90% CI when doubling the dose will be presented. 


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9.
PHARMACODYNAMIC ANALYSIS
Not applicable.


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10.
OTHER ANALYSES
No other analyses are planned for this study.


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11.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE 
Not applicable. 


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12.
DATA HANDLING CONVENTIONS
12.1
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, SD, minimum, and maximum. Categorical and count variables will be summarized by 
the number and the percent of subjects (n, %) in each category. 
The following rules will be applied for decimal places and rounding:
1. For measures of median and mean, 1 decimal place beyond those used for the measurement 
will be reported.
2. For measures of SD and standard error of the mean, 2 decimal places, beyond those used for 
the measurement, will be reported.
3. For measures of minimum and maximum values, the same number of decimal places will be 
used as those used for the measurement.
4. >=5 will be rounded up away from zero, whereas <5 will be rounded down toward zero to 
account for rounding of negative numbers.
5. For p-values, 3 decimal places will be used.
6. P-values that would round to 0.000 will be displayed as <0.001.
7. BMI should be rounded to 1 decimal place for reporting.
8. Averaged lab results (e.g. diastolic/systolic blood pressure and pulse [when taken in 
triplicate]) should be rounded to 1 decimal place for reporting.
9. For PK Related shells, display should be to the defined level of significant digits.
12.2
Repeated or Unscheduled Assessments of Safety Parameters 
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end of study assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics.  If 
there are repeated assessments at other post-baseline timepoints, the assessment from scheduled 
visit will be considered for summarizing data. However, all post-baseline assessments will be 
used for PCS value determination and all assessments will be presented in the data listings.


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12.3
Handling of Missing, Unused, and Spurious Data 
12.3.1
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)
For prior or concomitant medications (and/or therapies/procedures), incomplete (ie, 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.
12.3.1.1
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.
12.3.1.2
Missing Day and Month

If the year of the incomplete start date is;
o The same as the year of the date of the first dose of IP, then the day and month of the date 
of the first dose of IP will be assigned to the missing fields.
o Before the year of the date of the first dose of IP, then December 31 will be assigned to the 
missing fields.
o After the year of the date of the first dose of IP, then 01 January will be assigned to the 
missing fields.
12.3.1.2.1
Missing Month Only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
12.3.1.2.2
Missing Day Only

If only day is missing and 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 IP, then the day of the date of the first 
dose of IP will be assigned to the missing day.

If either the year is before the year of the date of the first dose of IP or if both years are the 
same but the month is before the month of the date of the first dose of IP, 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 IP or if both years are the 
same but the month is after the month of the date of the first dose of IP, then the first day 
of the month will be assigned to the missing day.
12.3.1.3
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of IP 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.


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12.3.1.3.1
Missing Day and Month

If the year of the incomplete stop date is;
o The same as the year as of the date of the last dose of IP, then the day and month of the 
date of the last dose of IP will be assigned to the missing fields.
o Before the year of the date of the last dose of IP, then 31 December will be assigned to the 
missing fields.
o After the year of the date of the last dose of IP, then 01 January will be assigned to the 
missing fields.
12.3.1.3.2
Missing Month Only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
12.3.1.3.3
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 IP, then the day of the date of the last dose of IP will be assigned to 
the missing day.

If either the year is before the year of the date of the last dose of IP or if both years are the
same but the month is before the month of the date of the last dose of IP, 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 IP or if both years are the same but the 
month is after the month of the date of the last dose of IP, then the first day of the month 
will be assigned to the missing day.
12.3.2
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 a 
TEAE or not. If a determination cannot be made using the non-missing date parts as to when the 
AE occurred relative to study drug administration, eg AE start year and month are the same as 
the year and month of the first dose of IP, then the AE will be classified as a TEAE.
To facilitate categorization of AEs as TEAEs, imputation of dates can be used. For AEs, the 
default is to only impute incomplete (ie, 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.
12.3.2.1
Incomplete Start Date 
Follow the same rules as in Section 12.3.1.1.
12.3.2.2
Incomplete Stop Date 
Follow the same rules as in Section 12.3.1.3.


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12.3.3
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of IP, 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 IP, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while both the actual and the imputed values 
will be used in data listings.
12.3.4
Missing Relationship to Investigational Product for Adverse Events 
If the relationship to IP is missing for an AE starting on or after the date of the first dose of IP, a 
causality of “Related” will be assigned. The imputed values for relationship to IP will be used for 
incidence summaries, while both the actual and the imputed values will be presented in data 
listings.
12.3.5
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, a character string being reported for a numerical variable, then the appropriately 
determined coded value will be used in the statistical analysis. However, the actual values as
reported in the database will be presented in data listings.


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13.
ANALYSIS SOFTWARE 
Phoenix WinNonlin version 8.0 or higher will be used to perform the PK analysis. Statistical 
analyses will be performed using Version 9.4 (or newer) of SAS(version to be delineated in the 
CSR) on a suitably qualified environment.


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14.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
The following change is made to this statistical analysis:

More clarification is added for the Safety Analysis Set.


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15.
REFERENCES
Not applicable


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16.
APPENDICES
16.1
Schedule of Assessments
Table 4
Schedule of Assessments for Subjects of Japanese Descent
Visit
Screening
Pre-dose 
Assessments
Treatment 
Period 1
Washout 
Periodi
Treatment 
Period 2
Washout 
Periodi
Treatment 
Period 3
Early 
Termination
Follow-
upj
Study Day
-28 to 
-02
-1
1
2
3-5
1
2
3-5
1
2
7 (±4)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographya
X
Medical/medication history
X
X
Physical examination
X
Xb
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
temperature, and respiratory rate)c
X
X
X
X
X
X
X
X
X
Height and weightd
X
X
X
X
X
X
X
Electrocardiogram (12-lead)
X
X
X
X
X
X
X
X
X
Biochemistry, hematology, and 
urinalysis
X
X
X
X
X
X
X
X
X
HIV, HBsAg, and HCV 
antibodies
X
Serum β-HCG pregnancy test 
(females only)e
X
X
Urine pregnancy test (females 
only)e
X
X
X
X
Urine drug, alcohol, and cotinine 
screeningf
X
X
IP administrationg
X
X
X


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Table 4
Schedule of Assessments for Subjects of Japanese Descent
Visit
Screening
Pre-dose 
Assessments
Treatment 
Period 1
Washout 
Periodi
Treatment 
Period 2
Washout 
Periodi
Treatment 
Period 3
Early 
Termination
Follow-
upj
Study Day
-28 to 
-02
-1
1
2
3-5
1
2
3-5
1
2
7 (±4)
PK blood samplingh
X
X
X
X
X
X
Check-in to the CRC
X
Discharge from the CRC
X
Adverse events/serious adverse 
eventsi
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
β-hCG=β-human chorionic gonadotropin; BP=blood pressure; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; IP=investigational product; PK=pharmacokinetic
a Subjects must have been born in Japan and must not have lived outside of Japan for >10 years; both parents and all 4 grandparents of must be of Japanese origin. 
b If more than 2 days have passed since screening, a physical examination should be repeated on Day -1.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the higher 
blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d Height will be recorded at the screening visit only.
e Serum β-hCG testing is required at screening and on Day -1 for all female subjects. 
f Tests for drugs of abuse, alcohol, and cotinine will be performed at screening and on Day -1. Testing for alcohol on Day -1 will be performed using an on-site 
breathalyzer test.
g All maribavir doses will be administered with a glass (240 ml) of room temperature water after a 10 hour overnight fasting with water restricted 1 hour before and 1 hour after 
dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 
hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours 
after dosing will be recorded.
h PK samples will be collected pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours post dosing with the IP on Day 1 of all 3 treatment periods.
i Washout period of a minimum of 72 hours and a maximum of 73 hours after administration of the IP on Day 1. Following the washout period, subjects will be asked regarding 
concomitant medications and any AEs.
jThere will be a post-treatment follow-up telephone call at 7 (±4) days after the last dose of IP. Subjects who experience AEs will be followed longer if needed, 
including an unscheduled clinic visit if appropriate, depending on the nature, severity, and seriousness of the AE.


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Table 5
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 1
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xe
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,c
Xe
X
X
Weightb
Xe
Electrocardiogram (12-lead)b,d
Xe
X
X
Biochemistry, hematology, and urinalysisb
Xe
X
IP administrationf
X
PK blood samplingg
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xe
X
X
X
Concomitant medicationb
Xe
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in Treatment Period 1 and 
Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the higher 
blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. The subject must be 
resting in the supine position for at least 5 minutes prior to collecting the ECG.
eBlood sampling assessments should be performed within 30 minutes prior to dose administration. All other predose assessments should be completed within 60 minutes of dose 
administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration.
f All maribavir doses will be administered with a glass (240 ml) of room temperature water after a 10 hour overnight fasting with water restricted 1 hour before and 1 hour after 
dosing.. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 
hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours 
after dosing will be recorded.
g The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-dose or by more than 15 minutes for 
samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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Table 6
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 2
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xf
Randomizationc
Xf
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,d
X f
X
X
Weightb
Xf
Electrocardiogram (12-lead)b,e
Xf
X
X
Biochemistry, hematology, and urinalysisb
Xf
X
IP administrationg
X
PK blood samplingh
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xf
X
X
X
Concomitant medicationb
Xf
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in Treatment Period 1 and 
Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Randomization will occur in Treatment Period 2, Day 1 or Day 1.
d Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the 
higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
e If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. The subject must be 
resting in the supine position for at least 5 minutes prior to collecting the ECG.
f Blood sampling assessments should be performed within 30 minutes prior to dose administration. All other predose assessments should be completed within 60 minutes of dose 
administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration.
g All maribavir doses will be administered with a glass (240 ml) of room temperature water after a 10 hour overnight fasting with water restricted 1 hour before and 1 hour after 
dosing. All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 
hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours 
after dosing will be recorded.
h The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-dose or by more than 15 minutes for 
samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


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Table 7
Detailed Schedule of Assessments for Subjects of Japanese Descent for Days 1 and 2 of Treatment Period 3
Study Day
Day 1a
Day 2
Hour (relative to dosing time)
Predose
0
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationb
Xe
Vital signs (BP, pulse, temperature, and 
respiratory rate)b,c
Xe
X
X
Weightb
Xe
X
Electrocardiogram (12-lead)b,d
Xe
X
X
Biochemistry, hematology, and urinalysisb
Xe
X
IP administrationf
X
PK blood samplingg
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
Xe
X
X
X
Concomitant medicationb
Xe
X
X
ECG=electrocardiogram; IP=Investigational Product; PK=pharmacokinetic; QTc=corrected QT interval
a There will be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in Treatment Period 1 and 
Treatment Period 2. There will also be a minimum of 72 hours and a maximum of 73 hours washout period between administration of the last dose of investigational product in 
Treatment Period 2 and Treatment Period 3. Following washout, subjects will be asked regarding concomitant medications and any AEs.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
c Vital signs will be obtained while subject is in the supine position on study days noted. BP at screening visit is compared on both arms. The same (right or left) arm with the 
higher blood pressure will be used throughout the study. Temperature will be taken at screening, at predose on Day 1, and on each study day.
d If QTc exceeds 450 msec, the ECG should be repeated 2 more times and the average of the 3 QTc values should be used to determine the subject’s eligibility. The subject must be 
resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Blood sampling assessments should be performed within 30 minutes prior to dose administration. All other predose assessments should be completed within 60 minutes of dose 
administration, with the exception of the physical examination which should be completed within 90 minutes of dose administration.
f All maribavir doses will be administered with a glass (240 ml) of room temperature water after a 10 hour overnight fasting with water restricted 1 hour before and 1 hour after 
dosing.All subjects (Japanese and Caucasian) can have their typical diet prior to the study; all subjects (Japanese and Caucasian) will receive identical meals on Day 1 (up to 24 
hours post dose) in all treatment periods to maintain control. Food will be provided to subjects approximately 4 hours after IP administration. Vomiting occurring within 4 hours 
after dosing will be recorded.
g The sponsor's expectation is that the investigator will ensure that every effort is made to collect all PK blood samples at the precise protocol scheduled time. PK blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than 5 minutes from samples drawn within 4 hours post-dose or by more than 15 minutes for 
samples drawn beyond 4 hours post-dose. Samples drawn outside these parameters will be considered a protocol deviation.


 
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Clinical Pharmacology Analysis Plan (CPAP) 
Version Number: 
1.0 
 
CONFIDENTIAL INFORMATION 
Do not distribute outside of Takeda without a confidentiality agreement. 
 
CLINICAL PHARMACOLOGY ANALYSIS PLAN (CPAP) 
 
STUDY NUMBER:  TAK-620-1020 
 
 
STUDY TITLE:  A PHASE 1, OPEN-LABEL, RANDOMIZED, CROSS-OVER STUDY 
TO EVALUATE THE PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF A 
SINGLE ORAL DOSE OF MARIBAVIR ADMINISTERED IN HEALTHY JAPANESE 
SUBJECTS COMPARED WITH MATCHED, HEALTHY, NON-HISPANIC, 
CAUCASIAN SUBJECTS AND TO ASSESS DOSE-PROPORTIONALITY OF 3 DOSES 
OF MARIBAVIR IN THE JAPANESE SUBJECTS 
 
 
 
 
 
 
 
TAKEDA CLINICAL PHARMACOLOGY 
 
 
 
 
Date: 24 July 2020 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda. 
 
 
 
 




 
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2.0 
TABLE OF CONTENTS 
 
1.0 
APPROVAL SIGNATURES ............................................................................................................ 2 
3.0 
INTRODUCTION .............................................................................................................................. 3 
4.0 
PK/PD METHODS OF ANALYSIS AND DATA PRESENTATION................................................. 4 
4.1 
PK/PD PARAMETER CALCULATIONS ......................................................................................... 4 
4.2 
EVALUABILITY OF PK/PD PARAMETER ESTIMATES .................................................................... 5 
4.3 
PK/PD PARAMETER SPECIFICATIONS ....................................................................................... 6 
4.4 
DATA TRANSFER FILES ............................................................................................................ 8 
4.5 
DATA DISPLAYS ....................................................................................................................... 9 
5.0 
MODIFICATION OF A CPAP ........................................................................................................ 10 
6.0 
REFERENCE ................................................................................................................................. 11 
 
3.0 
INTRODUCTION 
Maribavir is a potent and selective, orally bioavailable antiviral drug with a novel mechanism of 
action against CMV (Chulay et al. 1999) and a favorable nonclinical and clinical safety profile. It 
is a potent member of a new class of drugs, the benzimidazole ribosides (Williams et al. 2003). 
Maribavir is currently in Phase 3 clinical development for the treatment of CMV infection or 
disease, including those resistant or refractory to ganciclovir, valganciclovir, foscarnet, or 
cidofovir, in transplant recipients. 
Study TAK-620-1020 is being conducted to compare the PK, safety, and tolerability of maribavir 
administered as a single oral dose in healthy adult subjects of Japanese descent and matched, 
healthy, adult, non-Hispanic, Caucasian subjects. In accordance with the ICH-E5, this study is 
designed to evaluate whether there is any ethnic difference in PK and safety of maribavir 
between Japanese and non-Japanese subjects.  The results from this study will be utilized to 
guide dose selection for a future Phase 3 study in Japanese transplant patients with CMV 
infection. 
This document describes the methods used in the final analysis of pharmacokinetic and/or 
pharmacodynamic (PK/PD) parameters and the reporting of the results from these analyses.  
 
 
 


 
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4.0  
PK/PD METHODS OF ANALYSIS AND DATA PRESENTATION 
 
4.1  
PK/PD PARAMETER CALCULATIONS 
 
Details of the PK/PD methods to be used and the analytes for which PK/PD parameters are to 
be calculated are defined in Table 1 and Table 2.   
 
Table 1  Final Pharmacokinetic (PK) Parameter Calculations 
Table 1.  Final Pharmacokinetic (PK) Parameter Calculations 
 No PK calculations will be performed. 
or 
 PK calculations will be performed as follows (select one): 
 
 PK parameters will be determined using noncompartmental PK methods. 
 PK parameters will be determined using compartmental methods. 
 
 List the analytes for which PK parameters will be calculated:  Maribavir and 
 
 
 Actual sampling times will be used for PK parameter calculations.   
or 
  Other (describe):        
 
 An interim analysis (a protocol specified analysis which requires release of the interim analysis 
database) will be conducted (specify timing and extent of analysis):       
 
  Additional information:        
 
 
 
Table 2  Final Pharmacodynamic (PD) Parameter Calculations 
 No PD parameter calculations are under the purview of Clinical Pharmacology for this study.  
or 
 List the analytes for which PD parameters will be calculated:        
 
 
Actual sampling times will be used for PD parameter calculations.   
or 
 
Nominal sampling times will be used for PD parameter calculations. 
or 
 
Nominal sampling times will be used for PD parameter calculations unless the actual sampling 
time deviates by more than      minutes or more than       percent from the nominal time. 
 
 
Additional information:        
 
 
 
 
 
 
 
 
 


 
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4.2  
EVALUABILITY OF PK/PD PARAMETER ESTIMATES 
Details regarding the evaluability of the PK/PD parameter estimates are defined in Table 3.  
Parameter estimates that are considered unreliable (e.g., less than 3 data points were used 
to determine the terminal elimination slope by regression analysis, the regression line fitted 
to the terminal elimination phase data is of poor fit, etc.) will not be included in the clinical 
database, except for rare circumstances (e.g., a subject vomits after drug administration, in 
which case this subject’s PK parameters may be included in the clinical database, but are 
considered unreliable). 
 
Table 3  Evaluability of PK/PD Parameter Estimates 
 
Assay data: 
    A value of zero will be substituted for any assay result below the lower limit of quantification 
(BLQ) for that assay.   
    Individual assay concentrations deemed anomalous will be excluded from concentration 
summary statistics, concentration plots and PK/PD parameter calculations.a 
    Additional/other information:  Assay results of BLQ will be handled as follows for the non-
compartmental analysis: 
1. BLQ values that occur prior to the first quantifiable concentration of a profile will be set to 0 
2. A single BLQ value that occurs between 2 quantifiable concentrations in a profile will be set 
to missing. 
3. If 2 or more consecutive BLQ values occur after a quantifiable concentration, the 
concentration-time profile is considered to end at the time of the last prior quantifiable 
concentration and subsequent BLQ values will be set to missing. 
 
A subject’s PK parameter data is considered unreliable and will not be reported if the following criteria 
is met: 
   Insufficient data to determine a reliable t1/2 value (Therefore unable to determine AUC, CL, Vz 
and other terminal elimination rate constant dependent parameters). 
  Other (list):  Concentration results cannot be associated with a unique subject number. 
 
A subject’s PK/PD parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if the following criteria is met:  
 A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that period 
(e.g. single dose BE studies). 
 A subject drops out of the study prior to completing all arms of the study. 
 A subject did not meet inclusion/exclusion criteria that may have an effect on the PK.a 
 A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc.a 
 Additional information:  Terminal elimination rate constant dependent parameters (AUC0-inf, 
CL/F, Vz/F) will not be reported if there are insufficient data to determine a reliable t1/2 value 
and/or if the AUC0-inf%Extrap exceeds 20%.  Parameters such as Cmax, tmax, and AUClast may be 
reported on a case-by-case basis after discussion with the CPL. 
 
a  As determined by the CPL after consultation with the CPL’s manager (or designee). 
 
 
 
 


 
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4.3  
PK/PD PARAMETER SPECIFICATIONS 
The PK/PD parameter specifications are defined in Tables 4-5. Any selected parameters that 
are calculated using formulae other than the defined Phoenix WinNonlin calculation and 
interpolation formulae are considered “User Defined”, and the formulae used for the User 
Defined parameters must be included in Table 4 and/or Table 5.   
Table 4  PK/PD Parameter Specifications for Presentation of Data in In-text Tables 
Analyte(s): Maribavir, 
 
 
In-Text Table(s)  
 
 
Software 
User Defined 
 
 
 
# of Significant  
Figures  
 
Summary 
Used for Parameter 
Formula for 
Parameter 
Matrix 
Parametera 
Units 
 
Statistics 
Calculation 
Calculationb 
Plasma 
tmax 
h 
e 
c 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Cmax 
ȝg/mL 
3 
d 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
AUClast 
hȝg/mL 
3 
d 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
AUC0-inf 
hȝg/mL 
3 
d 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Dose-normalized 
Cmax 
ȝJP//400mg 
3 
d 
Phoenix WinNonlin 8.0 
x  Yes    Ƒ  No 
Plasma 
Dose-normalized 
AUClast 
hȝJP//400mg 
3 
d 
Phoenix WinNonlin 8.0 
x  Yes    Ƒ  No 
Plasma 
Dose-normalized 
AUC0-inf 
hȝJP//400mg 
3 
d 
Phoenix WinNonlin 8.0 
x  Yes    Ƒ  No 
Plasma 
t1/2 
h 
3 
f 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
CL/Fg 
L/h 
3 
f 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
a 
AUC values are calculated using the linear-up and log-down trapezoidal method unless otherwise noted below. 
b 
If yes, list below the parameter along with the equation that will be used for calculation of that parameter. 
c    Number of observations, median, range 
d 
Number of observations, geometric mean, minimum, maximum, geometric mean coefficient of variation 
e 
tmax will be reported up to 2 decimal places 
f 
Mean, SD, and CV% 
g 
Maribavir only 
 
User defined equations (list parameter and equation): 
Dose-normalized parameters will be calculated for Japanese subjects and normalized to 400 mg dose of 
maribavir as: 
Dose-normalized Cmax = Cmax / maribavir dose [mg] *400 
Dose-normalized AUClast = AUClast / maribavir dose [mg] * 400 
Dose-normalized AUC0-inf = AUC0-inf /maribavir dose [mg] *400 
 
 
 
 
 


 
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Table 5  PK/PD Parameter Specifications for Presentation of Data in Listings  
 
Analytes: Maribavir, 
 
 
Listings (end of text tables) 
 
 
Software 
User Defined 
 
 
 
# of Significant  
Figures 
 
Summary 
Used for Parameter 
Formula for 
Parameter 
Matrix 
Parametera 
Units 
Statistics 
Calculation 
Calculationb 
Plasma 
Concentration 
ȝJ /mL 
3 
d 
na 
na 
Plasma 
tmax 
h 
f 
c 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Cmax 
ȝg/mL 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
AUClast 
hȝg/mL 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
AUC0-inf 
hȝg/mL 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
AUC0-inf%Extrap. 
% 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Vz/Fg 
L 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Dose-normalized 
Cmax 
ȝJP/400mg 
3 
e 
Phoenix WinNonlin 8.0 
x  Yes   Ƒ  No 
Plasma 
Dose-normalized 
AUClast 
hȝJP/400mg 
3 
e 
Phoenix WinNonlin 8.0 
x  Yes    Ƒ  No 
Plasma 
Dose-normalized 
AUC0-inf 
hȝJP/400mg 
3 
e 
Phoenix WinNonlin 8.0 
x  Yes    Ƒ  No 
Plasma 
CL/Fg 
L/h 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
t1/2z 
hr 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Ȝz 
1/h 
3 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
Plasma 
Tlag 
h 
f 
e 
Phoenix WinNonlin 8.0 
Ƒ  Yes    x  No 
na   not applicable 
a 
AUC values are calculated using the linear-up and log-down trapezoidal method. 
b 
If yes, list below the parameter along with the equation that will be used for calculation of that parameter. 
c    Number of observations, median, range 
d 
Number of observations, mean, geometric mean, standard deviation, CV%, minimum, median, maximum 
e 
Number of observations, mean, standard deviation, CV%, minimum, median, maximum. In addition, geometric 
mean, geometric meancoefficient of variation, and 95% CI of the geometric mean are only reported for original 
and dose-normalized Cmax, AUClast, AUC0-inf. 
f 
tmax and Tlag will be reported up to 2 decimal places 
g 
Maribavir only 
 
User defined equations (list parameter and equation): 
Dose-normalized parameters will be calculated for Japanese subjects and normalized to 400 mg dose of 
maribavir as: 
Dose-normalized Cmax = Cmax / maribavir dose [mg] *400 
Dose-normalized AUClast = AUClast / maribavir dose [mg] * 400 
Dose-normalized AUC0-inf = AUC0-inf /maribavir dose [mg] *400 
 
 
 
 
 


 
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4.4  
DATA TRANSFER FILES 
Details concerning the electronic data transfer files that are to be prepared are defined in 
 Table 6 and Table 7: 
Table 6 Electronic Data Files from Clinical Database for PK/PD Parameter Analysis 
Files to be used for PK/PD parameter analysis which contain information from the clinical 
database: 
 
 No files containing information from the database will be transferred. 
 
 Database output file (DBO) containing final assay concentrations and actual sampling times (which 
may contain additional database information as described below) will be transferred as follows: 
 DBO data transferred from database will be at full precision as received from the BA vendor. 
or 
 DBO data transferred from database will be up to      decimal places. 
or 
 DBO data transferred from database will be      significant figures. 
 
DBO file type:  
  EXCEL  
 CSV  
SAS  
  Pipe Delimited 
Other (list):       
 
Additional subject information requested from the database (may be included in the DBO or may be in 
a separate file[s]): 
  Age (years)  
  Height (inches)       
  Height  (cm)   
  Baseline Weight  (lb.)     
  Baseline Weight (kg)     
  Body Mass Index (BMI) 
  Gender   
  Race   
  Nominal Sampling Time Post Dose    
  Actual Sampling Time Post Dose 
  Dosing Time Deviations     
  Sample Time Deviations 
  Dose Group     
  Dosing Period     
  Dosing Sequence   
  Baseline Creatinine Clearance 
  Concomitant Medications  
  Other(s) (list):       
 
Additional information (eg, descriptors needed to clarify any of the above selections): 
      
 
 Other file(s) to be transferred (list): Files from the bioanalytical vendor may be transferred in Excel 
or .csv format. 
 
 
 
 
 
 


 
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Table 7.  Electronic Data Files from PK/PD Parameter Analysis transferred to the Clinical 
Database 
 
PK/PD parameter data files to be transferred to the clinical database: 
 
 No files will be transferred to the clinical database. 
 
 PK parameter (PKP) file(s) will be transferred as follows. 
 PKP data transferred will be at full precision. 
or 
 PKP data transferred will be up to       decimal places. 
or 
 PKP data transferred will be 3 significant figures. 
 
PKP file type:  
  EXCEL  
 CSV  
  SAS export  
Other (list):      
 
 PD parameter (PDP) file(s) will be transferred as follows. 
 PDP data transferred will be at full precision. 
or 
 PDP data transferred will be up to       decimal places. 
or 
 PDP data transferred will be       significant figures. 
 
 
PDP file type:  
  EXCEL  
 CSV  
  SAS export 
Other (list):       
 
 File containing analyte concentrations and actual sampling times. 
 File transferred will be at full precision as received from the BA vendor. 
or 
 File transferred will be up to       decimal places. 
or 
 File transferred will be       significant figures. 
 
File type:  
  EXCEL  
  CSV  
  SAS export  
 Other (list):       
 
 Other File(s) (list):       
 
 
 
 
4.5  
DATA DISPLAYS 
Details concerning tables and figures related to PK/PD concentrations and/or parameters (those 
under the purview of Clinical Pharmacology) that are to be included in the clinical report are 
defined in Table 8. 
 


 
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Table 8.  Clinical Study Report (CSR) Data Displays  
Tables 
The following PK/PD tables are to be included in the final CSR: 
   Analyte concentration tables: 
 Mean concentration data (
  with or 
  without) descriptive statistics for (list matrix, analyte, 
and summary statistics to be included):        
 Individual concentration data (
  with or  
  without) descriptive statistics for plasma maribavir 
and 
; number of observations, geometric mean, arithmetic mean, standard deviation, 
minimum, median, maximum  
 
 PK/PD parameter tables: 
 Mean PK/PD parameters (
  with or    
  without descriptive statistics) for (list matrix and 
summary statistics to be included; parameters to be included also should be in Table 4 or 5): 
       
 Individual PK/PD parameters (
  with or    
  without) descriptive statistics for plasma maribavir 
and 
; number of observations, geometric mean, percent coefficient of variation for the 
geometric mean, 95% CI of the geometric mean, arithmetic mean, standard deviation, minimum, median, 
maximum 
 Other table(s) (describe table and the matrix and analyte/parameter(s) to be included in the table): 
      
 
Figures 
The following PK/PD figures are to be included in the final CSR: 
 
  Mean (
  linear    
  log-linear) concentration-time curves for: Plasma maribavir and 
 
 
 
  Individual (
  linear    
  log-linear) concentration-time curves for: Plasma maribavir and 
 
 
 
  Mean (
  Cmax    
  AUC) vs. dose for (list matrix and analyte for each): 
 
  Individual (
  Cmax    
  AUC) vs. dose for (list matrix and analyte for each): 
 
  Box plots (
  Cmax    
  AUC) vs. cohort (list matrix and analyte for each): 
 
  Scatter plots (
  Cmax    
  AUC) vs. regimen for (list matrix and analyte for each): 
 
  Other figure(s):  Forest plots of geometric mean ratios for maribavir Cmax, AUClast, and AUC0-inf 
between Japanese cohort vs the Non-Hispanic Caucasian cohort at 400 mg maribavir will be 
generated. Box-Whisker plots for dose-normalized maribavir Cmax, dose-normalized AUClast, and dose-
normalized AUC0-inf across doses will be generated with Japanese cohort and Non-Hispanic 
Caucasian side by side. 
 
 
 
5.0  
MODIFICATION OF A CPAP 
Modification/changes to an approved CPAP will be managed by amendment using FORM-
0002707 (Clinical Pharmacology Analysis Plan (CPAP) Amendment).   
 ______  
 


 
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6.0 
REFERENCE 
TOOL-0001296 Standard Pharmacokinetic Terminology 
Chulay, J., Biron, K., Wang, L., Underwood, M., Chamberlain, S., Frick, L., Good, S., Davis, 
M., Harvey, R., Townsend, L., Drach, J. & Koszalka, G. 1999. Development of novel 
benzimidazole riboside compounds for treatment of cytomegalovirus disease. Adv Exp Med Biol, 
458, 129-34. 
 
Williams, S. L., Hartline, C. B., Kushner, N. L., Harden, E. A., Bidanset, D. J., Drach, J. C., 
Townsend, L. B., Underwood, M. R., Biron, K. K. & Kern, E. R. 2003. In vitro activities of 
benzimidazole D- and L-ribonucleosides against herpesviruses. Antimicrob Agents Chemother, 
47, 2186-92.