Conditions: Healthy Volunteers
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: yes

Brief summary:
The Purpose of this study is to assess the relative bioavailability, dose proportionality, the impact of food on the rate and extent of absorption, palatability of the selected pediatric formulation of maribavir and the safety and tolerability of two candidate pediatric formulations and the adult tablet formulation of maribavir in healthy participants.

Detailed description:
The study will be conducted in two parts (Part 1 and Part 2). Part 1 consists of three treatment periods in six sequences and part 2 consists of four treatment periods in four sequences. In Part 1 two pediatric candidate powder formulations will be compared with maribavir 200mg tablet under fasted conditions in regards to their bioavailability and palatability. In Part 2 dose proportionality and impact of food (a high-fat meal) on the rate and extent of absorption of the selected pediatric formulation will be assessed. The pediatric formulation which will be evaluated in Part 2 will be chosen based on the results of planned analysis of Part 1 PK and palatability data from two candidate pediatric formulations and the doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation observed in Part 1.

Arms:
arm 1: Participants will receive 200 milligram (mg) of maribavir tablet orally (Sequence A) on Day 1 followed by 200 mg maribavir powder for oral suspension with 32.5 percent (%) drug loading (Sequence B) on Day 4 followed by maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 7 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 2: Participants will receive 200 mg maribavir powder for oral suspension with 32.5 % drug loading (Sequence B) on Day 1 followed by maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 4 and followed by 200 mg of maribavir tablet orally (Sequence A) on Day 7 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 3: Participants will receive maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 1 followed by 200 mg of maribavir tablet orally (Sequence A) on Day 4 and followed by 200 mg maribavir powder for oral suspension with 32.5 % drug loading (Sequence B) on Day 7 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 4: Participants will receive maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 1 followed by 200 mg maribavir powder for oral suspension with 32.5 percent (%) drug loading (Sequence B) on Day 4 and followed by 200 mg of maribavir tablet orally (Sequence A) on Day 7 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 5: Participants will receive 200 mg of maribavir tablet orally (Sequence A) on Day 1 followed by maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 4 and followed by 200 mg maribavir powder for oral suspension with 32.5 % drug loading (Sequence B) on Day 7 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 6: Participants will receive 200 mg maribavir powder for oral suspension with 32.5 % drug loading (Sequence B) on Day 1 followed by 200 mg of maribavir tablet orally (Sequence A) on Day 4 and followed by maribavir 200 mg powder for oral suspension with 36.1% drug loading (Sequence C) on Day 7 and with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4 and 7. arm 7: Participants under fast will receive 50 mg of maribavir powder for oral suspension (Sequence D) on Day 1 followed by 100 mg of maribavir powder for oral suspension (Sequence E) on Day 4 followed by participants feed with a high fat meal will receive 200 mg of maribavir powder for oral suspension (Sequence G) on Day 7 and then followed by participants under fast will receive 200 mg of maribavir powder for oral suspension (Sequence F) on Day 10 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4, 7 and 10. Doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation observed in Part 1. arm 8: Participants under fast will receive 100 mg of maribavir powder for oral suspension (Sequence E) on Day 1 followed by 200 mg of maribavir powder for oral suspension (Sequence F) on Day 4 followed by 50 mg of maribavir powder for oral suspension (Sequence D) on Day 7 and then followed by participants feed with a high fat meal will receive 200 mg of maribavir powder for oral suspension (Sequence G) on Day 10 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4, 7 and 10. Doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation observed in Part 1. arm 9: Participants under fast will receive 200 mg of maribavir powder for oral suspension (Sequence F) on Day 1 followed by participants feed with a high fat meal will receive 200 mg of maribavir powder for oral suspension (Sequence G) on Day 4 followed by participants under fast will receive 100 mg of maribavir powder for oral suspension (Sequence E) on Day 7 and then followed by 50 mg of maribavir powder for oral suspension (Sequence D) on Day 10 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4, 7 and 10. Doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation observed in Part 1. arm 10: Participants feed with a high fat meal will receive 200 mg of maribavir powder for oral suspension (Sequence G) on Day 1 followed by participants under fast will receive 50 mg of maribavir powder for oral suspension (Sequence D) on Day 4 followed by 200 mg of maribavir powder for oral suspension (Sequence F) on Day 7 and then followed by 100 mg of maribavir powder for oral suspension (Sequence E) on Day 10 with a washout period of minimum 72 hours and maximum of 73 hours between Day 1, 4, 7 and 10. Doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation observed in Part 1.

Interventions: intervention 1: Maribavir
Intervention descriptions: intervention 1: Participants in both part 1 and part 2 of the study will receive maribavir tablet or suspension orally depending upon the treatment sequence allocation for a total of 7 and 10 days respectively.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT04131556 
Study Title: 
A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose 
Proportionality, and Food Effect Study Comparing the Pharmacokinetics 
and Palatability of Two Candidate Pediatric Powder-for-Oral-Suspension 
Formulations of Maribavir to the Current Maribavir Tablet Formulation 
Administered in Healthy Adult Subjects 
Study Number: 
TAK-620-1019 
Protocol Version and Date: 
Original Protocol: 
28 Aug 2019 
Amendment 1:  
05 Nov 2019 


PROTOCOL:  TAK-620-1019 
TITLE: 
A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose 
Proportionality, and Food Effect Study Comparing the Pharmacokinetics 
and Palatability of Two Candidate Pediatric Powder-for-Oral-Suspension 
Formulations of Maribavir to the Current Maribavir Tablet Formulation 
Administered in Healthy Adult Subjects 
DRUG: 
TAK620 (SHP620), Maribavir
IND: 
051001 
EUDRACT NO.: 
2015-004725-13 
SPONSOR: 
Shire Human Genetic Therapies, Inc. (Shire, [and affiliates]); Shire is a 
wholly owned subsidiary of Takeda Pharmaceutical Company Limited 
300 Shire Way, Lexington, MA 02421 USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
, MD 
 
 USA 
Telephone: 
/ 
 
Fax: 
 
E-mail: 
 
PROTOCOL 
HISTORY: 
Original Protocol:  28-Aug-2019 
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. 
For non-commercial use only


Shire 
TAK-620-1019 
Maribavir 
Protocol Signature Page 
Sponsor's (Shire) Approval 
CONFIDENTIAL 
-
------ -
----.-----
Signature: 
Da
, MD, PhD, MPH 
Investigator's Acknowledgement 
I have read this protocol for Study TAK-620-1019. 
Page2 
28 Aug 2019 
Title: A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose Propmtionality, and 
Food Effect Study Comparing the Phannacokinetics and Palatability of Two Candidate Pediatric 
Powder-for-Oral-Suspension Formulations of Maribavir to the Current Maribavir Tablet 
Formulation Administered in Healthy Adult Subjects 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. 
It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines of Technical Requirements 
for Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice and 
with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
, MD 
(please hand print or type) 
 
 
 
Signature: 
Date: 
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EMERGENCY CONTACT INFORMATION 
In the event of an SAE, the investigator must fax or e-mail the "Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious 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)/Shire Medical Monitor  
using the details below. 
For protocol- or safety-related questions or concerns during normal business hours 8:00 
am-5:00pm (local time per region), the investigator must contact the Shire Medical 
Monitor: 
, MD, PhD, MPH 
Clinical Pharmacology Medical Leader/ Shire Study Medical Monitor 
Telephone: 
 (business hours) 
 (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 according to procedures. 
This includes any instances wherein the quality or performance of a Shire product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following: 
x A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty 
x Missing components 
x Damage to the product or unit carton 
x A mislabeled product (eg, potential counterfeiting/tampering) 
x A bacteriological, chemical, or physical change or deterioration of the product causing it 
to malfunction or to present a hazard or fail to meet label claims 
For instructions on reporting AEs related to product complaints, see Appendix 4.4.  
Please use the information below as applicable to report the Product Quality Complaint or Non-
Medical Complaint: 
Origin of Product Quality Complaint 
E-mail Address 
North and South America 
 
European Union and Rest of World 
 
 
Telephone number (provided for reference if needed): 
Shire, Lexington, MA (USA) 
 
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TABLE OF CONTENTS 
EMERGENCY CONTACT INFORMATION ................................................................................3 
PRODUCT QUALITY COMPLAINTS..........................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .........................................................................................................................9 
ABBREVIATIONS .......................................................................................................................10 
STUDY SYNOPSIS ......................................................................................................................12 
STUDY SCHEDULE(S) ...............................................................................................................19 
1. 
BACKGROUND INFORMATION .......................................................................................30 
1.1 
Indication and Current Treatment Options ...............................................................30 
1.2 
Product Background .................................................................................................31 
1.2.1 Preclinical Information ..........................................................................................31 
1.2.2 Clinical Information ...............................................................................................31 
1.2.3 Pharmacokinetics, metabolism and drug-drug interactions ...................................31 
1.3 
Risk/Benefit and Ethical Assessment .......................................................................33 
1.4 
Compliance Statement ..............................................................................................34 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................35 
2.1 
Rationale for the Study .............................................................................................35 
2.2 
Study Objectives ......................................................................................................35 
2.2.1 Primary Objectives.................................................................................................35 
2.2.2 Secondary Objectives.............................................................................................36 
3. 
STUDY DESIGN ...................................................................................................................37 
3.1 
Study Design and Flow Chart ..................................................................................37 
3.2 
Duration and Study Completion Definition .............................................................42 
3.3 
Sites and Regions .....................................................................................................42 
4. 
STUDY POPULATION .........................................................................................................43 
4.1 
Inclusion Criteria ......................................................................................................43 
4.2 
Exclusion Criteria .....................................................................................................43 
4.3 
Restrictions ...............................................................................................................45 
4.4 
Reproductive Potential .............................................................................................46 
4.4.1 Female Contraception ............................................................................................46 
4.4.2 Male Contraception ................................................................................................47 
4.5 
Discontinuation of Subjects .....................................................................................47 
4.5.1 Reasons for Discontinuation ..................................................................................47 
4.5.2 Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ..................................48 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................49 
5.1 
Prior Treatment ........................................................................................................49 
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5.2 
Concomitant Treatment ............................................................................................49 
5.2.1 Permitted Treatment...............................................................................................49 
5.2.2 Prohibited Treatment .............................................................................................49 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................50 
6.1 
Identity of Investigational Product ...........................................................................50 
6.1.1 Blinding the Treatment Assignment ......................................................................50 
6.2 
Administration of Investigational Product(s) ...........................................................50 
6.2.1 Allocation of Subjects to Treatment ......................................................................50 
6.2.2 Dosing ....................................................................................................................50 
 
Part 1, Treatment Period 1 ......................................................................50 
6.2.2.1
 
Washout Period ......................................................................................51 
6.2.2.2
 
Part 1, Treatment Period 2 ......................................................................51 
6.2.2.3
 
Washout Period ......................................................................................51 
6.2.2.4
 
Part 1, Treatment Period 3 ......................................................................51 
6.2.2.5
 
Part 2, Treatment Period 1 ......................................................................51 
6.2.2.6
 
Washout Period ......................................................................................51 
6.2.2.7
 
Part 2, Treatment Period 2 ......................................................................52 
6.2.2.8
 
Washout Period ......................................................................................52 
6.2.2.9
 
Part 2, Treatment Period 3 ......................................................................52 
6.2.2.10
 
Washout Period ......................................................................................52 
6.2.2.11
 
Part 2, Treatment Period 4 ......................................................................52 
6.2.2.12
6.3 
Labeling, Packaging, Storage, and Handling ...........................................................53 
6.3.1 Labeling .................................................................................................................53 
6.3.2 Packaging ...............................................................................................................53 
6.3.3 Storage ...................................................................................................................53 
6.4 
Drug Accountability .................................................................................................54 
6.5 
Subject Compliance ..................................................................................................55 
6.6 
Retention of Bioavailability Testing Samples ..........................................................55 
7. 
STUDY PROCEDURES ........................................................................................................56 
7.1 
Study Schedule .........................................................................................................56 
7.1.1 Screening Period ....................................................................................................56 
 
Screening Failure ....................................................................................56 
7.1.1.1
 
Rescreening of Subjects .........................................................................56 
7.1.1.2
7.1.2 Treatment Period Part 1 .........................................................................................57 
 
Admission to the Clinical Study Unit (CSU) (Day -1) ..........................57 
7.1.2.1
 
Day 1 to Day 3 (Part 1, Period 1) ...........................................................57 
7.1.2.2
 
Day 4 to Day 6 (Part 1, Period 2) ...........................................................57 
7.1.2.3
 
Day 7 to Day 8 (Part 1, Period 3) ...........................................................57 
7.1.2.4
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Final Visit ...............................................................................................57 
7.1.2.5
7.1.3 Treatment Period Part 2 .........................................................................................58 
 
Admission to the Clinical Pharmacology Unit (Day -1) ........................58 
7.1.3.1
 
Day 1 to Day 3 (Part 2, Period 1) ...........................................................58 
7.1.3.2
 
Day 4 to Day 6 (Part 2, Period 2) ...........................................................58 
7.1.3.3
 
Day 7 to Day 9 (Part 2, Period 3) ...........................................................58 
7.1.3.4
 
Day 10 to Day 11 (Part 2, Period 4) .......................................................58 
7.1.3.5
 
Final Visit ...............................................................................................59 
7.1.3.6
7.1.4 Follow-up Period ...................................................................................................59 
7.1.5 Additional Care of Subjects After the Study .........................................................59 
7.2 
Study Evaluations and Procedures ...........................................................................59 
7.2.1 Demographic and Other Baseline Characteristics .................................................59 
7.2.2 Safety .....................................................................................................................59 
 
Medical and Medication History ............................................................59 
7.2.2.1
 
Physical Examination (Including Height and Weight) ..........................60 
7.2.2.2
 
Adverse Event Collection .......................................................................60 
7.2.2.3
 
Vital Signs ..............................................................................................60 
7.2.2.4
 
Palatability Questionnaire ......................................................................62 
7.2.2.5
 
Clinical Laboratory Tests .......................................................................62 
7.2.2.6
 
Pregnancy Test .......................................................................................63 
7.2.2.7
 
Drug and Alcohol Screen .......................................................................63 
7.2.2.8
 
Serology Screen ......................................................................................64 
7.2.2.9
 
Electrocardiogram ..................................................................................64 
7.2.2.10
7.2.3 Pharmacokinetic Procedures ..................................................................................65 
 
Blood Sample Collection and Handling Procedures ..............................65 
7.2.3.1
 
Shipment of Plasma Pharmacokinetic Samples .....................................65 
7.2.3.2
 
Plasma Drug Assay Methodology ..........................................................65 
7.2.3.3
7.2.4 Volume of Blood to be Drawn from Each Subject in Part 1 .................................66 
7.2.5 Volume of Blood to be Drawn from Each Subject in Part 2 .................................66 
8. 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................68 
8.1 
Data Collection .........................................................................................................68 
8.2 
Clinical Data Management .......................................................................................68 
8.3 
Data Handling ..........................................................................................................68 
8.4 
Statistical Analysis Process ......................................................................................68 
8.5 
Planned  Analysis .....................................................................................................69 
8.6 
Sample Size Calculation and Power Considerations ................................................69 
8.7 
Study Population ......................................................................................................70 
8.7.1 Pharmacokinetic Analysis ......................................................................................70 
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8.7.2 Statistical Analysis of Pharmacokinetic Parameters ..............................................71 
 
Part 1 ......................................................................................................71 
8.7.2.1
 
Part 2 ......................................................................................................72 
8.7.2.2
8.8 
Safety Analyses ........................................................................................................72 
8.9 
Other Analyses .........................................................................................................73 
8.9.1 Palatability .............................................................................................................73 
9. 
REFERENCES .......................................................................................................................74 
10. APPENDICES ........................................................................................................................76 
Appendix 1 
Protocol History .....................................................................................76 
Appendix 2 
Palatability Questionnaire ......................................................................77 
Appendix 3 
Regulatory, Ethical, and Study Oversight Considerations .....................79 
Appendix 3.1 
Regulatory and Ethical Considerations ..................................................79 
Appendix 3.2 
Sponsor’s Responsibilities .....................................................................79 
Appendix 3.3 
Investigator’s Responsibilities ...............................................................80 
Appendix 3.4 
Ethical Considerations ............................................................................82 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ....................................................................86 
Appendix 4.1 
Adverse Event Definitions .....................................................................86 
Appendix 4.2 
Collection of Adverse Events .................................................................88 
Appendix 4.3 
Assessment of Adverse Events ..............................................................88 
Appendix 4.4 
Safety Reporting .....................................................................................90 
Appendix 4.5 
Serious Adverse Event Collection Time Frame .....................................90 
Appendix 4.6 
Serious Adverse Event Onset and Resolution Dates ..............................90 
Appendix 4.7 
Fatal Outcome ........................................................................................91 
Appendix 4.8 
Pregnancy ...............................................................................................91 
Appendix 4.9 
Abuse, Misuse, Overdose, and Medication Error ..................................91 
Appendix 4.10 Urgent Safety Measures .........................................................................92 
Appendix 4.11 Regulatory Agency, Institutional Review Board, Ethics 
Committee, and Site Reporting ..............................................................................93 
 
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LIST OF TABLES 
Table 1: Schedule of Assessments Part 1 ................................................................................19 
Table 2: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 1 ..............21 
Table 3: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 1 ..............22 
Table 4: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 1 ..............23 
Table 5: Schedule of Assessments Part 2 ................................................................................24 
Table 6: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 2 ..............26 
Table 7: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 2 ..............27 
Table 8: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 2 ..............28 
Table 9: Detailed Schedule of Assessments for Treatment Period 4 (Day 10), Part 2 ............29 
Table 10: Treatment Sequence Part 1: N=18 ...........................................................................37 
Table 11: Treatment Sequence Part 2: N=20 ...........................................................................40 
Table 12: Volume of Blood to be Drawn from Each Subject in Part 1 ...................................66 
Table 13: Volume of Blood to be Drawn from Each Subject in Part 2 ...................................66 
Table 14: Number of Subjects Required ..................................................................................69 
 
LIST OF FIGURES 
Figure 1: Study Design Flow Chart Part 1 ...............................................................................39 
Figure 2: Study Design Flow Chart Part 2 ...............................................................................42 
 
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ABBREVIATIONS 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the curve 
AUC0-last 
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 
E-HCG 
beta-human chorionic gonadotropin 
BCS 
Biopharmaceutics Classification System 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum concentration occurring at tmax 
CL/F 
oral clearance 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CSU 
clinical study unit 
CV% 
coefficient of variation 
EC 
ethics committee 
ECG 
electrocardiogram 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antibody 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HSA 
serum albumin 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
PK 
pharmacokinetics 
PCI 
potentially clinically important 
QTc 
corrected QT interval 
SAE 
serious adverse event 
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SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TID 
3 times daily 
Tlag 
delay between the time of dosing and time of appearance of concentration 
in the sampling 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
TSH 
thyroid-stimulating hormone 
t1/2 
terminal half-life 
US 
United States 
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STUDY SYNOPSIS 
Protocol number:  TAK-620-1019 
Drug: Maribavir 
Title of the study:  A Phase 1, Open-label, Randomized,  Crossover, Bioavailability, Dose Proportionality, and 
Food Effect Study Comparing the Pharmacokinetics and Palatability of Two Candidate Pediatric Powder-for-
Oral-Suspension Formulations of Maribavir to the Current Maribavir Tablet Formulation Administered in 
Healthy Adult Subjects  
Number of subjects (total and for each treatment arm): 38 subjects (18 in Part 1 and 20 in Part 2) 
Investigator:  
, MD 
Site(s) and Region(s):  
 
 
Study period (planned): 
2019-2020 
Clinical phase: 
1 
Objectives: 
Part 1:  
x 
To assess the relative bioavailability of 2 candidate pediatric formulations of maribavir given 
as a single oral dose at 200 mg as compared to the Phase 3 adult maribavir 200 mg tablet 
formulation in healthy adult subjects (Primary) 
x 
To assess the palatability of the candidate pediatric formulations measured by a questionnaire 
(Primary) 
x 
To assess the safety and tolerability of 2 candidate pediatric formulations and the adult tablet 
formulation of maribavir given as a single oral dose at 200 mg in healthy adult subjects 
(Secondary) 
Part 2:   
x 
To assess the dose proportionality of 50 mg, 100 mg, and 200 mg of the selected pediatric 
formulation (Primary) 
x 
To assess the impact of food on the rate and extent of absorption of the selected maribavir 
pediatric formulation given as 200 mg under fasted and fed conditions (Primary) 
x 
To assess the palatability of maribavir formulations at various doses and with food (Primary) 
x 
To assess the safety and tolerability of 2 candidate pediatric formulations and the adult tablet 
formulation of maribavir given as a single oral dose up to 200 mg in healthy adult subjects 
(Secondary) 
Rationale: 
In order to provide a palatable formulation for pediatric use, a taste-masking strategy that minimizes the 
availability of maribavir in the oral cavity is being explored. As the coating polymer has the potential to hinder 
drug release and absorption, 2 prototype formulations, each containing the same coating polymer but at different 
levels, are being evaluated in this study for their impact on palatability and rate and extent of absorption of 
maribavir. There were no significant effects of food on the rate and extent of absorption of maribavir from the 
adult tablet formulation, however, since maribavir is a Biopharmaceutics Classification System (BCS) II drug 
(ie, low solubility-high permeability drug) and the coating polymer may affect the rate and extent of absorption 
of maribavir, it is necessary to evaluate dose proportionality of the pediatric formulation and effects of food. 
Investigational product, dose, and mode of administration: 
Treatment A: maribavir 200 mg tablet- current Phase 3 formulation 
Treatment B: maribavir 200 mg powder for oral suspension, 32.5% drug loading 
Treatment C: maribavir 200 mg powder for oral suspension, 36.1% drug loading 
Treatment D: maribavir powder for oral suspension (50 mg fasted) 
Treatment E: maribavir powder for oral suspension (100 mg fasted) 
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Treatment F: maribavir powder for oral suspension (200 mg fasted) 
Treatment G: maribavir powder for oral suspension (200 mg fed with a high-fat meal) 
Methodology: 
This is a single-center (United States), open-label, randomized study. The study will be conducted sequentially 
in 2 parts. A total of 18 subjects will be enrolled in Part 1 of the study and a total of 20 subjects will be enrolled 
in Part 2. The study duration will comprise of a 28-day screening period for Part 1 and a 28-day screening 
period for Part 2. Part 1 will have 3 treatment periods with a 3-day washout period between each of the 3 
periods and a follow-up phone call. Part 2 will have 4 treatment periods with a 3-day washout period between 
each of the 4 treatment periods and a follow-up phone call. 
Subjects will be admitted to the clinical study unit (CSU) on Day -1. 
In  Part 1 2 pediatric candidate powder formulations will be compared with maribavir 200 mg tablet under 
fasted conditions in regards to their bioavailability and palatability to select 1 pediatric powder formulation for 
further evaluation in Part 2.   In Part 2 dose proportionality of  50, 100 and 200 mg  dose of the selected 
pediatric powder formulation of maribavir will be assessed, as well as the impact of food (a high-fat meal) on 
the rate and extent of absorption of the selected pediatric formulation. The pediatric formulation of maribavir 
which will be evaluated in Part 2 will be chosen based on the results of interim analysis of Part 1 
pharmacokinetic (PK) and palatability data from 2 candidate pediatric formulations.  
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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/and assent as applicable to participate in the study. 
3. Age 18-50 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. 
4.   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. Additional details 
will be outlined in the protocol.  
5.   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 electrocardiogram 
(ECG), hematology, blood chemistry (includes TSH and free T4 [FT4] at screening only), and 
urinalysis. 
6. Hemoglobin for males t135.0 g/L and females t120.0 g/L at screening and on Day -1. 
7. Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive with a body weight >50 kg (110 lbs). 
This inclusion criterion will only be assessed at the first screening visit. 
8.  Ability to swallow a dose of investigational product. 
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 investigational product, 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 investigational product or procedures. 
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), 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 investigational 
product. 
5. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first 
dose of investigational product. 
6. Within 30 days prior to the first dose of investigational product: 
a. 
Have used an IP (if elimination half-life is <6 days, otherwise 5 half-lives). 
b. Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study. 
c. 
Have had any substantial changes in eating habits, as assessed by the investigator. 
7. Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood pressure 
>89 mmHg or <49 mmHg. 
8. 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.  
9. Known history of alcohol or other substance abuse within the last year. 
10. 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). 
11. A positive screen for alcohol or drugs of abuse at screening or on Day -1 of Treatment Period 1. 
12. A positive human immunodeficiency virus (HIV), hepatitis B surface antibody (HBsAg), or hepatitis C 
virus (HCV) antibody screen. 
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13. 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 investigational product (maribavir). 
14. 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 tea, three 1 oz [85 g] chocolate bars. 
(Decaffeinated coffee, tea, or cola are not considered to contain caffeine). 
15. Prior screen failure randomization, participation, enrollment in this study or participation in Part 1 of 
this study. 
16. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) with 
the exception of hormonal replacement therapy. Current use of antacids and H2 antagonists. Current 
use is defined as use within 30 days of the first dose of investigational product.  
17. Ingestion of known CYP3A modulators within 7 days of Day 1, Period 1 (includes grapefruit or 
grapefruit juice, oranges, Seville oranges, apples or apple juice, vegetables from the mustard green 
family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard], charbroiled 
meats, and products containing these ingredients). 
18. Inability or unwillingness to consume 100 percent of high-fat meal in Part 2 (including subjects with 
lactose or gluten intolerance).. 
19. History of oral/nasal cavity infections, gastroesophageal reflux, asthma treatment with albuterol, zinc 
supplementation. 
20. Subjects with dry mouth syndrome or burning mouth syndrome or menopausal women suffering from 
dysgeusia. 
Maximum duration of subject involvement in the study: 
The maximum total duration of study participation for a subject in Part 1 is 46 days. The maximum total 
duration of study participation for a subject in Part 2 is 49 days. 
x 
Planned duration of screening period Part 1: 28 days 
x 
Planned duration of screening period Part 2: 28 days 
x 
Planned duration of treatment period Part 1: 7 days 
x 
Planned duration of treatment period Part 2: 10 days 
x 
Planned duration of follow-up Part 1: 7±2 days after the last dose of investigational product. 
x 
Planned duration of follow-up Part 2:  7±2 days after the last dose of investigational product. 
Endpoints and statistical analysis: 
Two analysis populations are defined for this study in Part 1 and in Part 2: pharmacokinetic and safety. 
For Part 1: 
x 
The pharmacokinetic population consists of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir  concentration value in Part 1. 
x 
The safety population includes subjects who have received at least 1 dose of maribavir in Part 
1. 
For Part 2:  
x 
The pharmacokinetic population consists of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir  concentration value in Part 2. 
x 
The safety population includes subjects who have received at least 1 dose of maribavir in Part 
2. 
Pharmacokinetic endpoint: 
The PK analysis will be based on the PK analysis dataset. Pharmacokinetic parameters will be calculated from 
maribavir concentration-time data using non-compartmental analysis (NCA) and all calculations will be based 
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on actual sampling times. Pharmacokinetic parameters will include, but not be limited to, the following: 
Part 1 (Day 1, Day 4, and Day 7) 
x 
Cmax: 
 
Maximum concentration occurring at tmax 
x 
tmax: 
 
Time of maximum observed concentration sampled during 
a dosing interval 
x 
AUC0-last: 
Area under the curve from the time of dosing to the last  
measurable concentration 
x 
AUC0-inf: 
Area under the curve extrapolated to infinity, calculated  
using the observed value of the last non-zero concentration 
x 
t1/2 
 
Terminal half-life 
x 
CL/F 
 
Apparent total body clearance following extravascular  
administration calculated as dose divided by AUC0-inf 
x 
Tlag 
 
Delay between the time of dosing and time of appearance  
of plasma concentration in the employed sampling scheme 
Part 2 (Day 1, Day 4, Day 7, and Day 10) 
x 
Cmax 
 
Maximum concentration occurring at tmax 
x 
tmax 
 
Time of maximum observed concentration sampled during 
a dosing interval 
x 
AUC0-last  
Area under the curve from the time of dosing to the last  
measurable concentration 
x 
AUC0-inf               Area under the curve extrapolated to infinity, calculated  
using the observed value of the last non-zero concentration 
x 
t1/2 
 
Terminal half-life  
x 
CL/F 
 
Apparent total body clearance following extravascular  
administration divided by the fraction of dose absorbed  
calculated as dose divided by AUC0-inf 
x 
Tlag 
 
Delay between the time of dosing and time of appearance  
of concentration in the sampling 
In addition, dose-normalized Cmax, AUC0-last, and AUC0-inf will be calculated for Treatments D, E, and F. 
Safety endpoint: 
Safety will be assessed for the following evaluations for both Part 1 and Part 2: 
x 
Number, severity, seriousness, and causality of treatment-emergent adverse events (TEAEs) 
x 
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. 
Palatability endpoint: 
The palatability will be evaluated to identify, characterize and quantify the sensory attributes of products, eg, 
basic tastes, texture and mouth feel and to assess the overall acceptability. 
 
Sample Size Justification: 
A sample size of 18 subjects in Part 1 and 20 subjects in Part 2 is calculated assuming a true mean ratio of 1.0 
with intra-subject coefficient of variation of 0.218, a total of 18 completers is required to have 80% power to 
show that the 90% confidence intervals of the ratios of the geometric means of the two formulations/treatment 
lie within the range of 0.80 to 1.25. 
The table below indicates the number of subjects required based on the following data: 
x 
The intra-subject coefficient of variation is assumed at 0.166 and 0.218 respectively for AUC0-inf and Cmax, 
which are estimated from the 90% confidence intervals (CIs) of the geometric mean ratio of AUC0-inf, and 
Cmax in Study 1263-104.   
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x 
Sample size estimation is performed using nQuery’s two one-sided test (TOST) of equivalence in ratio of 
mean for crossover design study. 
x 
True mean ratio: 1.00, 1.05 
x 
Power: 80%, 90% 
x 
One-sided Į-level: 0.05 (corresponding to 90% CI) 
x 
Bioequivalence range: 0.8-1.25 
 
  
Number of Subjects Required  
 
 
Intra-subject coefficient of variation 
True Ratio 
Power  
0.166 
0.218 
1.0 
80% 
12 
18 
 
90% 
14 
22 
1.05 
80% 
14 
22 
 
90% 
18 
28 
Note sample size estimation is performed using nQuery’s TOST of equivalence in ratio of mean for crossover 
design study. 
Statistical Methodology for Pharmacokinetic Endpoint(s): 
Part 1 
Individual concentrations and PK parameters of maribavir will be listed and summarized by 
treatment with descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient 
of variation [CV%], median, minimum, maximum, geometric mean, and %CV of geometric 
mean). Figures of individual and mean (+/-SD) concentration-time profiles of plasma maribavir by 
treatment will be generated on both linear and semi-log scales.  
Following the loge-transformation, the PK parameters including AUClast, AUC0-inf, and Cmax will be 
analyzed using a mixed effect model to include sequence, period, and treatment as fixed effects 
and subject within sequence as a random effect. Analysis of variance will be performed using SAS 
mixed linear models procedure. Point estimates and their associated 90% CIs will be constructed 
for the differences in the log-transformed parameters. The point estimates and their associated 90% 
CIs will be then back-transformed to provide point estimates for the ratio of geometric least  
squares means and associated 90% CIs  on the original scale.  Analysis of tmax and tlag will be 
performed by nonparametric t-test.  
Part 2 
Dose proportionality analysis 
The dose proportionality will be first assessed using the Power Model for 50-200 mg (fasted) dose 
range. The Power Model: log(Yijk)=Si + Pj + Exlog(Dk) + Hijk where D is the total number of doses, 
N are the total number of subjects and P the total number of periods and i=1,.….,N, j=1,.….,P and 
k=1,.…..,D. Yijk is the log-transformed response variable, AUC0-inf, AUC0-last, or Cmax on the kth 
dose, in the jth period, for the ith subject. Si is the random subject effect for the ith subject, Pj is the 
fixed period effect for the jth period, ȕ was the slope and Hijk is the error.  If the 90% confidence 
interval for the model estimated mean slope falls within 0.8 and 1.25 limits, then dose 
proportionality will be concluded. The estimate and 90% confidence interval for the slope and fold 
increase in PK exposure when doubling the dose will be presented. The corresponding graphical 
display from the powermodel (back transformed to raw linear scale) with the 90% CI overlaid on 
the observed data will be provided. 
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Additionally, a mixed effect analysis of variance (ANOVA) model will be performed with the log-
transformed dose normalized response variable, AUC0-inf, AUC0-last, or Cmax. The geometric mean 
ratios and 90% CI for each dose compared to the reference dose (50 mg dose) will be provided.  
Analysis of Effect of Food 
A mixed effect ANOVA model will be performed with log transformed AUC0-inf, AUC0-last, or 
Cmax. Point estimates and 90% CI for geometric mean ratios will be computed for treatments 
(maribavir 200 mg fed vs. 200 mg fasted). If the 90% CI for the geometric mean ratios of 
treatments (maribavir 200 mg fed vs. 200 mg fasted) falls within 0.8 and 1.25 limits, then 
equivalence will be concluded.  Analysis of tmax and tlag will be performed by nonparametric t-
test.  
Statistical Methodology for Palatability Endpoint: 
Data collected from the palatability questionnaire will be summarized descriptively. 
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STUDY SCHEDULE(S) 
Table 1: Schedule of Assessments Part 1 
Visita 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X  
X  
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
Medical/medication history 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X  
X 
 
 
X 
 
 
X 
X 
 
Randomization 
 
 
Xk 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, 
pulse)b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oral temperature 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Height and weightd 
X 
X  
X 
 
 
X 
 
 
X 
X 
 
Electrocardiogram (12-lead)b,e 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Biochemistry, hematology, and 
urinalysisb, f, m 
X 
X 
 
X 
 
 
X 
 
 
X 
 
HIV, HBsAg, and HCV 
antibodies 
X 
 
 
 
 
 
 
 
 
 
 
Beta HCG Pregnancy test 
(females only)b, g 
X 
X 
 
 
 
  
 
 
 
X 
 
FSHh test in perimenopausal 
women 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug and alcohol screeningi 
X 
X 
 
 
 
 
 
 
 
 
 
Investigational Drug 
Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetic blood samplingj, 
n 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
Palatability Assessment 
 
 
X 
 
 
X 
 
 
X 
 
 
Admit to the CSU (Day -1) 
 
X 
 
 
 
 
 
 
 
 
 
Discharge from the CSU (Day 8 
after last assessment) 
 
 
 
 
 
 
 
 
 
X 
 
Washout between treatment 
periods 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse events/serious adverse 
eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E-hCG=beta-human chorionic gonadotropin; CSU-clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating 
hormone 
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. Treatment Period 1 includes 
washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 7 through 8. 
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments. 
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c Vital signs will be obtained while subject is in the supine position on study days noted.  Subjects should be in the appropriate position for at least 
5 minutes prior to obtaining vital signs. 
d Height will be recorded at the screening visit only.  
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG. 
f Clinical laboratory assessments include serum biochemistry, TSH and FT4, at (screening only), hematology, and urinalysis.  
g Serum ȕ-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time points. 
h Females only, to confirm menopausal status. 
i Drugs of abuse and alcohol at screening and Day-1 
j See Table 2, Table 3, and Table 4 for detailed collection time points.  
k Randomization is for Treatment Period 1, Day 1 only. 
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 3 (Day 7). 
AEs/SAEs occurring up to the time of the follow-up telephone call will be captured. The follow-up telephone call should be completed for all 
subjects including those who withdraw or are removed from the study prior to Day 8 of Treatment Period 3. 
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1 
n 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 r5 
minutes from samples drawn within 4 hours post-dose or by more than r15 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 2: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 1 
Study Day 
Day 1 
Day 2 
Hour (relative to dosing time) 
Predose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
X 
 
 
Vital signs (blood pressure, pulse) a, 
c 
Xe 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (12-lead)a,d 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
X 
 
Pharmacokinetic blood samplingg 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only. 
c Vital signs will be obtained while subject is in the supine position on study days noted.  Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
f Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 Treatment Period 2 (Day 4), Part 1 
Study Day  
Day 4 
Day 5 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, pulse)a, b 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingf 
Xd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 4: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 1 
Study Day 
Day 7 
Day 8 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs (blood pressure, pulse)a, b 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy (females only)a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingf 
Xd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 Part 2 
Visita 
Screening 
Treatment Period 
1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment  
Period 4 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Randomization 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
High-fat meal prior to dose 
administration 
 
 
Xn 
 
 
Xn 
 
 
Xn 
 
 
Xn 
 
 
Vital signs (blood 
pressure, pulse)b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oral temperature 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Height and weightd 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Electrocardiogram (12-
lead)b,e 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Biochemistry, hematology, 
and urinalysisb, f, m 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
HIV, HBsAg, and HCV 
antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (females only)b, 
g 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
FSHh test in perimenopausal 
women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug and alcohol 
screeningi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Drug 
Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetic blood 
samplingj, o 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Palatability Assessment 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Admit to the CSU (Day -1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the CSU 
(Day 11 after last 
assessment) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Washout between 
treatment periods 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse events/serious 
adverse eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E-hCG=beta-human chorionic gonadotropin; CSU=clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating 
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Table 5: Schedule of Assessments Part 2 
Visita 
Screening 
Treatment Period 
1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment  
Period 4 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
hormone 
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 3-day washout period between administration of the last dose of 
investigational product in Treatment Period 2 and Treatment Period 3 and between administration of the last dose in Treatment 4. Treatment 
Period 1 includes washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 7 
through 9. 
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. Subjects should be in the appropriate position for at least 
5 minutes prior to obtaining vital signs. 
d Height will be recorded at the screening visit only.  
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG. 
f Clinical laboratory assessments include serum biochemistry, (TSH and FT4 at screening only), hematology, and urinalysis.  
g Serum ȕ-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time points 
h Females only, to confirm menopausal status 
i Drugs of abuse and alcohol at screening, and drugs of abuse and alcohol Day -1.  
j See Table 6, Table 7, Table 8, and Table 9 for detailed collection time points 
k Randomization is for Treatment Period 1, Day 1 only.  
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 43 (Day 
10). Adverse events/SAEs occurring up to the time of the follow-up telephone call will be captured. The follow-up telephone call should be 
completed for all subjects including those who withdraw or are removed from the study prior to Day 11 of Treatment Period 4. 
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1. 
n Subjects in Part 2 will receive maribavir depending on his/her randomized assignment to treatment sequence following an overnight fast of at 
least 10 hours. The study subjects should start the high-fat meal 30 minutes before administration of the drug product. Trial subjects should eat 
this meal in 30 minutes or less and consume 100 percent of the meal. 
o 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 r5 
minutes from samples drawn within 4 hours post-dose or by more than r15 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 Treatment Period 1 (Day 1), Part 2 
 
 
 
Study Day 
Day 1 
Day 2 
Hour (relative to dosing time) 
Predose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, 
pulse)a, c 
Xe 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (12-lead)a,d 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingg 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only. 
c Vital signs will be obtained while subject is in the supine position on study days noted.  Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
f Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must 
not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 Treatment Period 2 (Day 4), Part 2 
Study Day  
Day 4 
Day 5 
Hour (relative to dosing time) 
Pre-
dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Vital signs (blood pressure, pulse)a, 
b 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingf 
X d, e 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must 
not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 8: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 2 
Study Day 
Day 7 
Day 8 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examination a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, pulse)a, b 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingf 
Xd, e 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose. 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 9: Detailed Schedule of Assessments for Treatment Period 4 (Day 10), Part 2 
Study Day 
Day 10 
Day 11 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs (blood pressure, pulse)a, b 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy (females only)a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood sampling f 
Xd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 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 40-100% 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. Cytomegalovirus remains a significant problem 
for patients undergoing various types of transplants that are associated with the use of potent 
immunosuppressive chemotherapy, including hematopoietic stem cell transplants (HSCT) and 
solid organ transplants (SOT) (de la Hoz et al., 2002; Razonable and Emery, 2004). 
 
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 virus’s ability to modulate the immune system, either 
directly or secondary to the host antiviral response through regulation of cytokine, chemokine, 
and/or growth factor production. 
 
Cytomegalovirus prevention strategies (prophylaxis or preemptive therapy) for various high-risk 
transplant subjects exist, however, CMV infection or disease can still occur within the early 
(initial ~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 GVHD (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 
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with 3 months of oral ganciclovir. Ganciclovir-resistant disease accounted for 20% of CMV 
disease, 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 Investigator’s Brochure. 
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- 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, metabolism and drug-drug interactions 
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). Pharmacokinetic data obtained in Phase 
2 studies was 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 (HSA), lipoproteins, and 
alpha-1-acid-glycoprotein (AAG). 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 CYP3A4 pathway with the formation of the primary 
metabolite, VP44469. Renal clearance is a minor route of elimination of maribavir. 
 
Clinical studies conducted to evaluate the potential of drug-drug interactions demonstrated the 
following: 
x Concomitant administration of maribavir (400 mg BID) with tacrolimus, a substrate of 
CYP3A4 and P-gp, resulted in increased tacrolimus Cmax and AUC by 38% and 51%, 
respectively. 
x 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 pharmacokinetics of voriconazole (a CYP2C19 
substrate). 
x In vivo, maribavir 400 mg BID did not affect digoxin AUC; however, it increased Cmax 
by 24.8%. 
x 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. 
x Concomitant administration of antacid has no effect on maribavir exposure. 
x 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 
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maribavir besides showing that maribavir was well tolerated with no safety concerns at all doses 
evaluated. 
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 50-2400 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. A definitive QT 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 had a favorable safety and tolerability profile in both the Phase 2 and Phase 3 trials for 
CMV prophylaxis. Adverse events (AEs) were most commonly associated with gastrointestinal 
(GI) disorders (eg, diarrhea, dysgeusia, nausea, and vomiting). These events were generally of 
mild or moderate intensity. There were no signals of clinically significant effects of maribavir on 
vital signs, 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, treatment-emergent AEs (TEAEs) that occurred were events already 
observed in previous studies (ie, dysgeusia, GI events, elevated immunosuppressant drug levels, 
and rash) and there were no additional safety concerns raised from this study. In Study 
SHP620-203, TEAEs that occurred at a higher frequency in maribavir subjects compared with 
valganciclovir were events already observed in previous studies with maribavir (ie, dysgeusia, GI 
events, and elevated immunosuppressant drug levels). Analyses of clinical laboratory, vital signs, 
and ECG data did not identify any clinically meaningful differences across the maribavir 
treatment groups
 
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 investigator’s brochure for the most detailed and most 
current information regarding the drug metabolism, pharmacokinetics, 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 
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studies, and in studies that compared maribavir with other CMV therapies (ganciclovir, 
valganciclovir) for prophylaxis and for CMV treatment in SCT 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 investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, pharmacokinetics, 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 3. 
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2. STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
In the previous study SHP620-118, taste assessment study of maribavir, maribavir taste was 
characterized as a strong and lingering bitter taste at clinically-relevant doses, posing a taste-
masking challenge.   
In order to provide a palatable formulation for pediatric use, a taste-masking strategy that 
minimizes the availability of maribavir in the oral cavity is being explored.  The taste-masking 
relies on the use of a coating polymer that is insoluble at neutral pH (ie, of saliva) but soluble at 
acidic pH (ie, of gastric fluid).  By encapsulating maribavir inside the coating polymer, maribavir 
would be unavailable for taste perception in the mouth but, released in the stomach for 
absorption.  As the coating polymer has the potential to hinder drug release and absorption, 2 
prototype formulations, each containing the same coating polymer, but with different amounts, 
are being evaluated in this study for their impact on palatability and rate and extent of absorption 
of maribavir.   
There were no significant effects of food on the rate and extent of absorption of maribavir from 
the adult tablet formulation; however, since maribavir is a Biopharmaceutics Classification 
System (BCS) II drug and the coating polymer may affect the rate and extent of absorption of 
maribavir, it is necessary to evaluate the dose proportionality of the pediatric formulation and the 
effects of food. This study will be conducted in 2 parts and a planned analysis will be conducted 
after Part 1 to decide if 1 of the 2 candidate pediatric formulations can be selected based on 
palatability and relative bioavailability and will be further evaluated for dose proportionality and 
effects of food in Part 2. The results from this study may be used for further optimization of the 
pediatric formulation and will provide guidance on dose selection of the pediatric formulation in 
clinical development for pediatric patients. 
2.2 
Study Objectives 
2.2.1 
Primary Objectives 
The primary objectives of Part 1 of this study are to assess the relative bioavailability of 2 
candidate pediatric formulations of maribavir given as a single oral dose at 200 mg as compared 
to the Phase 3 adult maribavir 200 mg tablet formulation in healthy adult subjects. In addition, 
the palatability of the candidate pediatric formulations will be assessed by a questionnaire. 
The primary objectives of Part 2 of this study are to assess the dose proportionality of 50 mg, 
100 mg, and 200 mg of the selected pediatric formulation, to assess the impact of food on the 
rate and extent of absorption of the selected pediatric formulation given as 200 mg under fasted 
and fed conditions and to assess the palatability at various doses and with food. 
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2.2.2 
Secondary Objectives 
The secondary objective of Part 1 and Part 2 of this study is to assess the safety and tolerability 
of 2 candidate pediatric formulations and the adult tablet formulation of maribavir given as a 
single oral dose up to 200 mg in healthy adult subjects.  
 
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3. STUDY DESIGN 
3.1 
Study Design and Flow Chart 
The study will be conducted sequentially in 2 parts. In Part 1, two pediatric candidate powder 
formulations will be compared with maribavir 200 mg tablet under fasted conditions in regards 
to their bioavailability and palatability.  In Part 2 dose proportionality of  50, 100, and 200 mg  
dose of the selected pediatric powder formulation will be assessed, as well as the impact of food 
(a high-fat meal) on the rate and extent of absorption of the selected pediatric formulation. The 
pediatric formulation which will be evaluated in Part 2 will be chosen based on the results of 
interim analysis of Part 1 PK and palatability data from two candidate pediatric formulations. 
 
Part 1: Relative Bioavailability and Palatability 
A total of 18 healthy male and female subjects, 18-50 years of age, inclusive, will be enrolled 
and expected to complete Part 1 of this study. Subjects who withdraw early will be replaced; the 
replacement subjects will receive the same treatment sequence assigned to subject who withdraw 
early. The study will be comprised of the following periods:  a screening lasting up to 28 days, 3 
treatment periods in which subjects will receive a single dose of the study drug on the first day of 
each period after a 10-hour overnight fasting, a drug washout of  a minimum of 72 hours and 
maximum of 73 hours between dosing in periods 1 and 2 and periods 2 and 3, and a follow-up 
phone call (7±2 days) after the last dose of investigational drug (maribavir) is administered 
(Figure 1). The maximal total duration of study participation for a subject in Part 1 is 46 days, if 
the maximum screening, washout and follow-up durations are used. 
Screening will occur within 28 days prior to randomization to assess eligibility of subjects to 
participate in the study. Subjects will be admitted to the clinical study unit (CSU) on Day -1. On 
the morning of Day 1, subjects will be randomized to 1 of 6 sequences in a 1:1:1:1:1:1 treatment 
allocation. Subjects will receive assigned treatment under fasted conditions in each treatment 
period. The treatment sequences to be used in the study is shown in Table 10: 
Table 10: Treatment Sequence Part 1: N=18 
Sequence number (number of subjects per sequence)  Treatment Sequence 
1 (n=3) 
ABC 
2 (n=3) 
BCA 
3 (n=3) 
CAB 
4 (n=3) 
CBA 
5 (n=3) 
ACB 
6 (n=3) 
BAC 
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Treatment A: maribavir 200 mg tablet- current Phase 3 formulation 
Treatment B: maribavir 200 mg powder for oral suspension, 32.5% drug loading 
Treatment C: maribavir 200 mg powder for oral suspension, 36.1% drug loading 
Treatment Period 1 
x On Day 1, subjects in each cohort will receive 200 mg maribavir depending on 
his/her randomized assignment to the treatment sequence as presented in Table 
10.  
Washout Period 
x There will be a drug washout period of a minimum of 72 hours and maximum of 
73 hours between the administration of maribavir in Period 1 (Day 1) and the 
administration of maribavir in Period 2 (Day 4). 
Treatment Period 2 
x On Day 4, subjects in each cohort will receive 200 mg maribavir depending on 
his/her randomized assignment to treatment sequence (Table 10). 
Washout Period 
x There will be a drug washout period of a minimum of 72 hours and maximum of 
73 hours between the administration of maribavir in Period 2 (Day 4) and the 
administration of maribavir in Period 3 (Day 7). 
Treatment Period 3 
x On Day 7, subjects in each cohort will receive 200 mg maribavir depending on 
his/her randomized assignment to treatment sequence (Table 10).  
Assessments 
x Pharmacokinetic (PK) Assessment 
Serial blood samples for PK analysis of maribavir concentrations will be collected 
over 24 hours on Day 1, Day 4, and Day 7. These blood samples will be collected 
according to the Detailed Schedule of Assessments (Table 2, Table 3, and Table 
4).  
x Safety and Tolerability Assessment 
Safety and tolerability will be assessed based on treatment-emergent adverse 
events (TEAEs), vital signs, laboratory values, electrocardiogram (ECG) findings, 
and evaluation of clinical signs. 
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x Palatability Assessment 
Palatability will be assessed based on subjects’ responses to a questionnaire that 
will be completed following each dose administration on Day 1, Day 4 and Day 7. 
Follow-up 
x Subjects will remain in the CSU until completion of the last post dose 
assessment on Day 8. A post-treatment follow-up telephone call will be 
performed 7 (±2) days after the last dose of investigational product. 
Figure 1: Study Design Flow Chart Part 1 
Screening Period Days -28 through -2
Treatment 
A
Follow-up Phone Call (7±2 days after last dose of maribavir)
Day -1 – Admission to Clinical Study Unit
Treatment 
Period 1
(Day 1)
Treatment 
B
*Washout
 (Day 1 dose 
to Day 4 
dose)
Treatment A: Maribavir 200mg tablet
Treatment B: Maribavir powder for oral suspension, 32.5% drug loading
Treatment C: Maribavir powder for oral suspension, 36.1% drug loading
*NOTE: Treatment will be dependent on randomization sequence.
*NOTE: There will be a drug washout of a minimum of 72 hours and maximum of 73 hours between the administration of maribavir in 
Period 1 (Day 1) and the administration of maribavir in Period 2 (Day 4) and between the administration of maribavir in Period 2 (Day 
4) and the administration of maribavir in Period 3 (Day 7)
Treatment
C
Treatment 
B
Day 8 – Discharge from the Clinical Study Unit
Treatment 
Period 2
(Day 4)
Screening
Treatment 
C
*Washout
 (Day 4 dose 
to Day 7 
dose)
Treatment 
C
Treatment 
Period 3
(Day 7)
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
A
Treatment 
C
Treatment 
B
Treatment 
B
Treatment 
C
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
C
  
Part 2: Dose Proportionality and Food Effect 
A total of 20 healthy male and female subjects, 18-50 years of age, inclusive, will be enrolled 
and expected to complete Part 2 of this study. Subjects who withdraw early will be replaced and 
the replacement subjects will receive the same treatment sequence assigned to subject who 
withdraw early. The study will be comprised of the following periods:  a screening lasting up to 
28 days, 4 treatment periods in which subjects will receive a single dose of the study drug on the 
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first day of each period after a 10-hour overnight fasting, one treatment period in which subjects 
will receive a single dose of the study drug on the first day of the period after consuming a high-
fat meal,  a drug washout of a minimum of 72 hours and maximum of 73 hours between dosing 
in periods 1 and 2, periods 2 and 3, and periods 3 and 4, and a follow-up phone call (7±2 days) 
after the last dose of investigational drug (maribavir) is administered (Figure 2). The maximal 
total duration of study participation for a subject in Part 2 is 49 days, if the maximum screening, 
washout and follow-up durations are used. 
An interim analysis is planned after the completion of Part I to evaluate the PK and palatability 
data from the formulations investigated. Based on the results of the interim analysis of Part 1 
data, 1 pediatric formulation may be chosen to be assessed in Part 2.  
Screening will occur within 28 days prior to randomization to assess eligibility of subjects to 
participate in the study. Subjects will be admitted to the CSU on Day -1. On the morning of Day 
1, subjects will be randomized to 1 of 4 sequences in a 1:1:1:1 treatment allocation. The 
treatment sequences to be used in the study is shown in Table 11: 
Table 11: Treatment Sequence Part 2: N=20 
Sequence number (number of subjects per sequence)  Treatment Sequence 
1 (n=5) 
DEGF 
2 (n=5) 
EFDG 
3 (n=5) 
FGED 
4 (n=5) 
GDFE 
Treatment D: maribavir powder for oral suspension (50 mg fasted) 
Treatment E: maribavir powder for oral suspension (100 mg fasted) 
Treatment F: maribavir powder for oral suspension (200 mg fasted) 
Treatment G: maribavir powder for oral suspension (200 mg fed with a high-fat meal) 
Treatment Period 1 
x On Day 1, subjects in each cohort will receive maribavir depending on his/her 
randomized assignment to the treatment sequence as presented in Table 11.  
Washout Period 
x There will be a drug washout period of a minimum of 72 hours and maximum of 
73 hours between the administration of maribavir in Period 1 (Day 1) and the 
administration of maribavir in Period 2 (Day 4). 
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Treatment Period 2 
x On Day 4, subjects in each cohort will receive maribavir depending on his/her 
randomized assignment to treatment sequence (Table 11). 
Washout Period 
x There will be a drug washout period of a minimum of 72 hours and maximum of 
73 hours between the administration of maribavir in Period 2 (Day 4) and the 
administration of maribavir in Period 3 (Day 7). 
Treatment Period 3 
x On Day 7, subjects in each cohort will receive maribavir depending on his/her 
randomized assignment to treatment sequence (Table 11).  
Washout Period 
x There will be a drug washout period of a minimum of 72 hours and maximum of 
73 hours between the administration of maribavir in Period 3 (Day 7) and the 
administration of maribavir in Period 4 (Day 10). 
Treatment Period 4 
x On Day 10, subjects in each cohort will receive maribavir depending on his/her 
randomized assignment to treatment sequence (Table 11).  
Assessments 
x Pharmacokinetic (PK) Assessment 
Serial blood samples for PK analysis of maribavir concentrations will be collected 
over 24 hours on Day 1, Day 4, Day 7 and Day 10. These blood samples will be 
collected according to the Detailed Schedule of Assessments (Table 6, Table 7, 
Table 8, and Table 9).  
x Safety and Tolerability Assessment 
Safety and tolerability will be assessed based on treatment-emergent adverse 
events (TEAEs), vital signs, laboratory values, electrocardiogram (ECG) findings, 
and evaluation of clinical signs. 
x Palatability Assessment 
Palatability will be assessed based on subjects’ responses to a questionnaire that 
will be completed following each dose administration on Day 1, Day 4, Day 7, 
and Day 10. 
Follow-up 
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x Subjects will remain in the CSU until completion of the last post dose 
assessment on Day 11. A post-treatment follow-up telephone call will be 
performed 7 (±2) days after the last dose of investigational product. 
Figure 2: Study Design Flow Chart Part 2 
 
3.2 
Duration and Study Completion Definition 
The subject’s maximum duration of participation is expected to be approximately 46 days for 
Part 1 and 49 days for Part 2.  The study will be completed in approximately 12 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 
phone call, 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 1 clinical site in the 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 subject will not be considered eligible for the study without meeting all of the inclusion and 
exclusion criteria.  
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/and assent as applicable to participate in the 
study. 
3. Age 18-50 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. 
4. 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. 
Additional details will be outlined in the protocol.  
5. 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 TSH and free T4 (FT4) at screening only), and 
urinalysis. 
6. Hemoglobin for males t135.0 g/L and females t120.0 g/L at screening and on Day -1. 
7. Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive with a body weight >50 kg 
(110 lbs). This inclusion criterion will only be assessed at the first screening visit. 
8.  Ability to swallow a dose of investigational product. 
4.2 
Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met at 
the screening visit or Day -1 (if reassessed):  
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 investigational product, or clinical or laboratory 
assessments. 
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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 investigational product or procedures. 
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), 
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 
investigational product. 
5. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of investigational product. 
6. Within 30 days prior to the first dose of investigational product: 
-  
Have used an investigational product (if elimination half-life is <6 days, otherwise 5 
half-lives). 
-  
Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study. 
-   
Have had any substantial changes in eating habits, as assessed by the investigator. 
7. Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood pressure 
>89 mmHg or <49 mmHg. 
8. 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. 
9. Known history of alcohol or other substance abuse within the last year. 
10. 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). 
11. A positive screen for alcohol or drugs of abuse at screening or on Day -1 of Treatment 
Period 1. 
12. A positive HIV, hepatitis B surface antibody (HBsAg), or hepatitis C virus (HCV) antibody 
screen. 
13. 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 investigational product (maribavir). 
14. 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 tea, three 1 oz 
[85 g] chocolate bars. (Decaffeinated coffee, tea, or cola are not considered to contain 
caffeine). 
15. Prior screen failure, randomization, participation, or enrollment in this study or participation 
in Part 1 of this study. 
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16. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations) with the exception of hormonal replacement therapy. Current use of antacids 
and H2 antagonists.  Current use is defined as use within 30 days of the first dose of 
investigational product.  
17. Ingestion of known CYP3A modulators within 7 days of Day 1, Period 1 (includes grapefruit 
or grapefruit juice, oranges, Seville oranges, apples or apple juice, vegetables from the 
mustard green family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels 
sprouts, mustard], charbroiled meats, and products containing these ingredients).  
18. Inability or unwillingness to consume 100 percent of high-fat meal in Part 2 (including 
subjects with lactose or gluten intolerance). 
19. History of oral/nasal cavity infections, gastroesophageal reflux, asthma treatment with 
albuterol, zinc supplementation. 
20. Subjects with dry mouth syndrome or burning mouth syndrome or menopausal women 
suffering from dysgeusia. 
4.3 
Restrictions  
1. Subjects should refrain from strenuous physical exercise 48 hours prior to admission to the 
CRU and during the in-house stays at the CRU. 
2. Subjects should refrain from consuming grapefruit, Seville oranges, 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. Subjects should refrain from consuming pine nuts 7 days prior to Day 1 of the first treatment 
period through the completion of the last treatment period. 
4. Subjects should refrain from alcohol 48 hours prior to admission to the CRU and during the 
in-house stay at the CRU. 
5. Subjects should refrain from 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. Subjects should refrain from taking or regularly using any medication (including over-the 
counter multi-vitamin, herbal, or homeopathic preparations) with the exception of those 
listed in Section 5.2 from 14 days prior to receiving the first dose of the investigational 
product through the completion of the discharge assessments and procedures. Subjects should 
not use antacids or zinc supplementation.  
7. Subjects should refrain from foods or beverages containing caffeine/xanthine 48 hours prior 
to admission to the CRU and during the in-house stay at the CRU. 
8. Subjects will be required to follow standardized meal schedules and eat the meals provided 
by the site while housed in the CRU. No outside food or beverages (including gum, mints, 
etc) will be permitted. Menus will be identical for all subjects at the CRU. Copies of the 
menus will be provided to the sponsor for approval prior to the start of the study. While 
confined, the total daily nutritional composition should be approximately 50% carbohydrate, 
35% fat, and 15% protein. The daily caloric intake per subject should not exceed 
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approximately 3200 kcal. For Treatment G in Part 2, a high-fat (approximately 50 percent of 
total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal 
is to taken within 30 minutes prior to maribavir doses. This high-fat meal should derive 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively.   
(An example of a High Fat Breakfast: 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
toast with butter, 4 ounces of hash brown potatoes, 8 ounces of whole milk.  
*50 percent of calories are derived from fat. Substitutions can be made to this meal, if the 
content, volume, and viscosity are maintained.)  
4.4 
Reproductive Potential 
4.4.1 
Female Contraception 
There is no clinical experience with maribavir in pregnant subjects. Sexually active females of 
child-bearing potential should be using an acceptable form of contraception. Females of 
child-bearing potential must be advised to use acceptable contraceptives throughout the study 
period and for 30 days following the last dose of investigational product. If hormonal 
contraceptives are used they should be administered according to the package insert. 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 investigational product.  
Female subjects should be either: 
x Post-menopausal (12 consecutive months of spontaneous amenorrhea and t age 50 years) 
x 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 
x Females of child-bearing potential with a negative urine and/or serum beta-human chorionic 
gonadotropin (E-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: 
x Intrauterine devices plus condoms 
x Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 
x Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the first dose of investigational product, 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. 
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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 
investigational product. 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 investigational product. 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 investigational product. Male subjects must not donate sperm until 3 months after the last 
dose of investigational product. 
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 
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 investigational product is discontinued, regardless of the reason, the early withdrawal 
evaluations listed in Table 3 and Table 7 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 investigational 
product, and the total amount of investigational product administered must be recorded in the 
source documents and the case report form (CRF).  
Subjects who discontinue from the study may be replaced at the sponsor’s discretion to ensure 
that 18 subjects complete Part 1 of the study and 20 subjects complete Part 2 of the study. 
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:  
x Adverse event 
x Protocol deviation 
x Withdrawal by subject  
x Lost to follow-up 
x Other (The investigator must specify on the CRF) 
 
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4.5.2 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product. 
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5. PRIOR AND CONCOMITANT 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 pharmacokinetic equivalent of 5 half-lives, whichever is longer) of the date of first dose of 
investigational product.  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 
investigational product 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 investigational products) must be listed on the appropriate CRF page. 
Medications permitted during the study are listed below: 
x Hormonal contraceptives for females of child-bearing potential administered according to the 
package insert (see Section 4.4.1) 
x Hormone replacement therapy 
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 test product is maribavir, which will be provided in tablet and powder form.  
 
Maribavir tablet is a blue, film-coated tablet containing 200 mg of maribavir.  The tablets are 
packaged in a 60 cc, white, HDPE bottle containing 40 tablets.  
 
Maribavir powder for oral suspension is a white to off-white granular powder.  The 32.5% w/w 
powder contains 325 mg of maribavir for every 1 g of powder; the 36.1% w/w powder contains 
361 mg of maribavir for every 1 g of powder.  The powders are packaged in a 150 cc, white, 
HDPE bottle containing 40 g of powder.  The powders are to be compounded to form unit dose 
oral suspensions.  Additional information and detailed instructions are provided in the maribavir 
investigator’s brochure, and in a Pharmacy Manual that will be provided. 
The sponsor will provide the test product, maribavir. 
6.1.1 
Blinding 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. 
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.  
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study.  If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered. 
6.2.2 
Dosing 
 
Part 1, Treatment Period 1 
6.2.2.1
On Day 1, subjects will receive either a single 200 mg dose of maribavir, either in tablet form or 
as an oral suspension, depending on his/her randomized assignment to the treatment sequence. 
Subjects will fast for at least 10 hours prior to dosing and 4 hours after dosing on Day 1. The 
study subjects should take the drug product with 240 mL (8 fluid ounces) of water. Additional 
water is allowed ad lib except for 1 hour before and 1 hour after drug administration 
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Washout Period 
6.2.2.2
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4). 
 
Part 1, Treatment Period 2 
6.2.2.3
On Day 4, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence. Subjects will fast for at least 10 hours prior to 
dosing and 4 hours after dosing on Day 4. The study subjects should take the drug product with 
240 mL (8 fluid ounces) of water. Additional water is allowed ad lib except for 1 hour before and 
1 hour after drug administration 
 
Washout Period 
6.2.2.4
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7). 
 
Part 1, Treatment Period 3 
6.2.2.5
On Day 7, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence. Subjects will fast for at least 10 hours prior to 
dosing and 4 hours after dosing on Day 7. The study subjects should take the drug product with 
240 mL (8 fluid ounces) of water. Additional water is allowed ad lib except for 1 hour before and 
1 hour after drug administration. 
 
Part 2, Treatment Period 1 
6.2.2.6
On Day 1, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to the treatment sequence. For treatments D, E, and F, subjects will fast for at least 
10 hours prior to dosing and 4 hours after dosing on Day 1. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 1. Trial subjects 
should eat this meal in 30 minutes or less and consume 100 percent of the meal. Refer to Section 
4.3, Number 9 for specific information about the high-fat meal. The study subjects should take 
the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed ad lib 
except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours after 
dosing on Day 1. 
 
Washout Period 
6.2.2.7
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4). 
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Part 2, Treatment Period 2 
6.2.2.8
On Day 4, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 4. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 4. Refer to Section 
4.3, Number 9 for specific information about the high-fat meal. The study subjects should take 
the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed ad lib 
except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours after 
dosing on Day 4. 
 
Washout Period 
6.2.2.9
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7). 
 
Part 2, Treatment Period 3 
6.2.2.10
On Day 7, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 7. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 7. Refer to Section 
4.3, Number 9 for specific information about the high-fat meal. The study subjects should take 
the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed ad lib 
except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours after 
dosing on Day 7. 
 
Washout Period 
6.2.2.11
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 3 (Day 7) and the administration of maribavir 
in Period 4 (Day 10). 
 
Part 2, Treatment Period 4 
6.2.2.12
On Day 10, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 10. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 10. Refer to Section 
4.3, Number 9 for specific information about the high-fat meal. The study subjects should take 
the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed ad lib 
except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours after 
dosing on Day 10. 
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6.3 
Labeling, Packaging, Storage, and Handling 
6.3.1 
Labeling 
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product (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 investigational product in order to satisfy local or institutional 
requirements, but must not: 
x Contradict the clinical study label 
x Obscure the clinical study label 
x Identify the study subject by name 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.3.2 
Packaging 
Investigational product is packaged in the following labeled containers: 
x Maribavir tablet: 60 cc, white, square, HDPE bottle 
x Maribavir powder for oral suspension: 150 cc, white, round, 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 investigational product 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 
investigational product 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 investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
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records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room. 
6.4 
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing investigational product.  
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication 
will be documented in the subject's source and/or other investigational product record.  
No investigational product 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. 
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With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product 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 investigational products must be in 
accordance with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned.  All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 
Subject Compliance 
Compliance must be assessed by observation of dosing by the investigator or designee. In 
addition, the CRU personnel should perform a hand and mouth check (mouth check is only 
required for oral dosing) of the subject to assure the investigational product 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 Testing Samples 
In compliance with 21 CFR 320.38 (1999), and as recommended in the Center for Drug 
Evaluation and Research Guidance for Industry dated May 2004 regarding retention of relevant 
reserve (BA and BE test samples), CROs, site management organizations, or clinical 
investigators must retain samples when relevant BA/BE testing has been performed under 
contract by the sponsor.  Retained samples must meet 21 CFR 320.38 (1999) and 320.63 (1999) 
requirements for reserve samples of test article and reference standards according to the 
following: 
x Reserve samples must be representative of the test batches provided and therefore must be 
randomly selected from identical test article and/or reference standards provided to the site 
x The quantity should be sufficient optimally to permit the Food and Drug Administration 
(FDA) to perform all release testing identified in the application 5 times 
x Are adequately identified so that the reserve sample can be positively identified as having 
come from the same batches as used in the BA/BE studies 
x Be stored under conditions that maintain the samples identity, integrity, strength, quality, and 
purity 
x Be retained for at least 5 years following the date of New Drug Application or supplemental 
New Drug Application approval or, if the Investigational New Drug is discontinued, at least 
5 years following the date of completion of the BA/BE study 
x Samples must be annually inspected and documented to confirm integrity. 
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7. STUDY PROCEDURES 
Details regarding scheduled assessments and procedures to be conducted in this study are 
provided below and in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and 
Table 9. 
7.1 
Study Schedule 
The following “priority order” will be in effect when more than 1 procedure or assessment is 
required at a particular time point. 
x Spontaneous or solicited AE reporting 
x ECG 
x Vital signs  
x Pharmacokinetic blood sampling 
x Palatability Questionnaire 
x Clinical laboratory tests 
x Physical examination. 
NOTE:  Blood sampling for pharmacokinetic 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  
Screening procedures must be completed within 28 days of Day 1 as appropriate prior to 
receiving the first dose of investigational product. 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. 
 
Screening Failure 
7.1.1.1
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 enrolled or administered 
investigational product(s). 
 
Rescreening of Subjects 
7.1.1.2
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point. 
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. 
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7.1.2 
Treatment Period Part 1 
 
Admission to the Clinical Study Unit (CSU) (Day -1) 
7.1.2.1
Following the screening visit, eligible subjects will return to the CSU on Day -1 of the study. See 
Table 1 for a list of procedures to be completed upon admission to the CSU. 
Subjects who successfully complete the pre-admission assessments and procedures will be 
admitted to the CSU on Day -1 and assigned a subject number on Day 1 as described in Section 
6.2. Eligible subjects will be confined to the CSU from the morning of Day -1 until Day 8. 
 
Day 1 to Day 3 (Part 1, Period 1) 
7.1.2.2
Study Assessments for Day 1 to Day 3 are outlined in Table 1 and Table 2. Administration of 
maribavir will occur on Day 1. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 1. 
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4). 
 
Day 4 to Day 6 (Part 1, Period 2) 
7.1.2.3
Study Assessments for Day 4 to Day 6 are outlined in Table 1 and Table 3. Administration of 
maribavir will occur on Day 4. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 4. 
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7). 
 
Day 7 to Day 8 (Part 1, Period 3) 
7.1.2.4
Study Assessments for Day 7 to Day 8 are outlined in Table 1 and Table 4.  Administration of 
maribavir will occur on Day 7. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 7.  
 
Final Visit 
7.1.2.5
Subjects will remain in-house for the entire study. Final evaluation will be on Day 8. For any 
subject who discontinues prematurely, the final visit will be the day they discontinue. 
 
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7.1.3 
Treatment Period Part 2 
 
Admission to the Clinical Pharmacology Unit (Day -1) 
7.1.3.1
Following the screening visit, eligible subjects will return to the CSU on Day -1 of the study. See 
Table 5 for a list of procedures to be completed upon admission to the CSU. 
Subjects who successfully complete the pre-admission assessments and procedures will be 
admitted to the CSU on Day -1 and assigned a subject number on Day 1 as described in Section 
6.2. Eligible subjects will be confined to the CSU from the morning of Day -1 until Day 11. 
 
Day 1 to Day 3 (Part 2, Period 1) 
7.1.3.2
Study Assessments for Day 1 to Day 3 are outlined in Table 5 and Table 6. Administration of 
maribavir will occur on Day 1. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 1. 
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4). 
 
Day 4 to Day 6 (Part 2, Period 2) 
7.1.3.3
Study Assessments for Day 4 to Day 6 are outlined in Table 5 and Table 7. Administration of 
maribavir will occur on Day 4. Subjects will fast for at least 10 hours prior to dosing and 4 hours 
after dosing on Day 4. 
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7). 
 
Day 7 to Day 9 (Part 2, Period 3) 
7.1.3.4
Study Assessments for Day 7 to Day 9 are outlined in Table 5 and Table 8.  Administration of 
maribavir will occur on Day 7. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 7. 
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 3 (Day 7) and the administration of maribavir 
in Period 4 (Day 10). 
 
Day 10 to Day 11 (Part 2, Period 4) 
7.1.3.5
Study Assessments for Day 10 to Day 11 are outlined in Table 5 and Table 9. Administration of 
maribavir will occur on Day 10. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 10.  
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Final Visit 
7.1.3.6
Subjects will remain in-house for the entire study. Final evaluation will be on Day 11. For any 
subject who discontinues prematurely, the final visit will be the day they discontinue. 
7.1.4 
Follow-up Period 
The follow-up period for this protocol is 7±2 days for Part 1 and Part 2.   
At the end of this period there will be a telephone call initiated by staff to query for serious 
adverse events (SAEs), AEs, and concomitant treatments.  All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Appendix 4.2) 
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 
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 precise 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than r15 minutes will be considered a protocol deviation. 
Adverse events (defined as AEs occurring from the time of informed consent signature to first 
dose of investigational product), TEAEs (all AEs occurring 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 CSU, subject safety will also be 
closely monitored through blood pressure measurements, ECG measurement, clinical safety labs, 
and physician oversight. 
 
Medical and Medication History 
7.2.2.1
A complete medical and medication history, as well as demographic information, will be 
performed at the Screening Visit/time points described in Table 1 and Table 5 by a qualified 
licensed physician, physician’s assistant, or a nurse practitioner.  The medical history will be 
reviewed and recorded, including: 
x Date of birth 
x Sex 
x Race and ethnicity 
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x Recent ingestion of medication (30 days prior to entering the screening period) 
x History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases 
x Smoking habits  
 
Physical Examination (Including Height and Weight) 
7.2.2.2
A complete physical examination will be performed at the time points described in Table 1 and 
Table 5 by a qualified licensed physician, physician’s assistant, or a nurse practitioner. 
The physical examination will include a review of the following body systems: 
x General appearance 
x Skin 
x Head, eyes, ears, nose, and throat 
x Spine/neck/thyroid 
x Musculoskeletal 
x Respiratory 
x Cardiovascular 
x Neurological 
x Abdomen (including liver and kidneys) 
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 by the investigator. 
 
Adverse Event Collection 
7.2.2.3
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Refer to Appendix 4 for 
AE definitions, assessment, collection time frame, and reporting procedures.)  
 
Vital Signs 
7.2.2.4
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, Table 6, Table 7, Table 8, and Table 9 of this protocol. 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. 
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The same method for obtaining blood pressure measurement (auscultatory or oscillometric) 
should be used throughout the study for all subjects (and documented).  In addition, the 
conditions of vital sign measurements should be controlled and as consistent as possible during 
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 deflation rate 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 assumed 
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 caffeine, 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. If, after a single 
measurement is taken, there is a difference between arms in either systolic or diastolic blood 
pressure >10 mmHg, the site will perform triplicate BP measurements in each arm to determine 
the arm with the higher BP. The arm with the higher BP (based on the average of the 
3 BP measurements for each arm) should be used for inclusion at screening, and the last of the 
3 measurements recorded in the eCRF as the screening BP. The same (right or left) arm with the 
higher blood pressure will be used throughout the study.  
One reading (supine systolic blood pressure/diastolic blood pressure-heart rate) should be taken.   
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 
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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.  
 
Palatability Questionnaire 
7.2.2.5
A palatability questionnaire (Refer to Appendix 2) will be completed following each dose 
administration (within 5 minutes) on Day 1, Day 4, Day 7 in Part 1 and on Day 1, Day 4, Day 7 
and Day 10 in Part 2. 
 
Clinical Laboratory Tests 
7.2.2.6
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
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 (8.5 mL) for serum biochemistry will be collected into a gel separator tube at the 
time points described in Table 1 and Table 5.  The following parameters will be assessed:   
Sodium 
Phosphorus 
E-HCG 
(beta 
Human 
chorionic 
gonadotropin)a, b 
Potassium 
Protein 
 
Glucose  
Carbon dioxide 
 
Urea nitrogen 
Albumin 
 
Creatinine 
Aspartate transaminase  
 
Calcium 
Alanine transaminase  
 
Chloride 
Gamma glutamyl transferase  
 
Thyroid stimulating hormone (TSH)a 
Alkaline phosphatase  
 
Thyroxine (T4 total)a 
Total bilirubin  
 
FSHa, b 
Uric acid 
 
a See Table 1 and Table 5. 
b Females only. 
 
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Hematology 
Blood samples (4 mL) for hematology will be collected into an ethylenediaminetetraacetic acid 
(EDTA) tube at the time points described in Table 1 and Table 5.  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 and Table 
5.  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.  
 
Pregnancy Test  
7.2.2.7
A serum beta-HCG or urine  pregnancy test is performed on all females of child-bearing 
potential as outlined in Table 1 and Table 5, or if pregnancy is suspected, or on withdrawal of the 
subject from the study. 
 
Drug and Alcohol Screen  
7.2.2.8
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. 
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Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study. 
 
Serology Screen  
7.2.2.9
At the screening visit, a blood sample of approximately 8 mL 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. 
 
Electrocardiogram  
7.2.2.10
Twelve-lead ECGs will be performed at the times specified in Table 1 and Table 5.  All ECGs 
will be performed using the equipment supplied by the CRU.   
The following parameters will be recorded on the appropriate CRF page: heart rate, PR, RR, 
QRS, and QT intervals. The QTcF will be derived.  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 caffeine, 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.   
One complete recording, including a 10 second rhythm strip, should be taken at each time point.  
It should be immediately assessed as a valid recording and if not valid, it should be repeated.  
Invalid recordings will not be entered in the CRF. 
When a single ECG recording is performed at each time point, the ECG collected pre-dose on 
Day 1 will serve as the subject’s baseline ECG. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements. 
If the QTcF interval (calculated on line 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 2-4 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.   
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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). 
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. 
7.2.3 
Pharmacokinetic Procedures 
The name and address of the bioanalytical laboratory 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 pharmacokinetic (PK) blood sample collection times versus time of dosing will be 
monitored.  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 r5 minutes from samples drawn within 4 hours post-dose or by more than r15 
minutes for samples drawn beyond 4 hours post-dose.  Samples drawn outside these parameters 
will be considered a protocol deviation.  
 
Blood Sample Collection and Handling Procedures 
7.2.3.1
Blood samples will be collected at the time specified in Table 2, Table 3, Table 4, Table 6, Table 
7, Table 8, and Table 9 to measure plasma concentrations of maribavir.  Potential metabolites 
may also be determined as appropriate. 
Blood sample collection, processing and handling instructions are provided in the Laboratory 
Manual. 
 
Shipment of Plasma Pharmacokinetic Samples 
7.2.3.2
Plasma sample shipment handling instructions and contact information are provided in the 
Laboratory Manual. 
 
Plasma Drug Assay Methodology 
7.2.3.3
Plasma concentrations 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.  
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7.2.4 
Volume of Blood to be Drawn from Each Subject in Part 1 
Table 12: Volume of Blood to be Drawn from Each Subject in Part 1 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Pharmacokinetic samplesa 
3 
45 
135 
HBsAg, HIV, HCV 
8 
1 
8 
Safety 
Biochemistry and 
E-HCGb 
8.5 
5 
42.5 
 
Hematology 
4 
5 
20 
Total mL 
 
 
205.5 
E-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 3 mL of blood drawn has been used in determination of sample volume. 
b E-HCG testing for females only. 
 
 
During this study, it is expected that approximately 205.5 mL of blood will be drawn from all 
subjects, regardless of sex, in Part 1. 
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; however, the total volume drawn over the course of the study 
should be approximately 205.5 mL. When more than one blood assessment is to be done at the 
time point/period, if they require the same type of tube, the assessments may be combined. 
 
7.2.5 
Volume of Blood to be Drawn from Each Subject in Part 2 
Table 13: Volume of Blood to be Drawn from Each Subject in Part 2 
Assessment 
Sample Volume (mL) 
Number of 
Samples 
Total Volume (mL) 
Pharmacokinetic samplesa 
3 
60 
180 
HBsAg, HIV, HCV 
8 
1 
8 
Safety 
Biochemistry and 
E-HCGb 
8.5 
6 
51 
 
Hematology 
4 
6 
24 
Total mL 
 
 
263 
E-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 1 mL is to be discarded; then take 2 mL into appropriate tube for pharmacokinetic sample.  A 
total of 3 mL of blood drawn has been used in determination of sample volume. 
b E-HCG testing for females only. 
 
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During this study, it is expected that approximately 263 mL of blood will be drawn from all 
subjects, regardless of sex, in Part 2. 
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; however, the total volume drawn over the course of the study 
should be approximately 263 mL. When more than one 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.  Once a subject is randomized, it is expected that site personnel will complete the CRF 
entry within approximately 3 business days of the subject’s visit. 
8.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the sponsor’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 pharmacokinetic, pharmacodynamic, and safety data, as well as describe the 
approaches to be taken for summarizing other study information such as subject disposition, 
demographics and baseline characteristics, investigational product exposure, and prior and 
concomitant medications.  The SAP will also include a description of how missing, unused and 
spurious data will be addressed.  
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to conducting the planned analysis. 
All statistical analyses will be performed using SAS (SAS Institute, Cary, NC 27513).  
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8.5 
Planned  Analysis  
After the completion of Part 1, a selected set of analyses planned for Part 1 to evaluate the PK 
and palatability data from the formulations investigated will be conducted.  Based on the results 
of the analyses of Part 1 data, one pediatric formulation may be chosen to be assessed in Part 2.   
All analyses will be conducted after the completion of Part 2. 
8.6 
Sample Size Calculation and Power Considerations 
Sample size calculations were based on the following data: 
x The intra-subject coefficient of variation is assumed at 0.166 and 0.218 respectively for 
AUC0-inf and Cmax, which are estimated from the 90% confidence intervals (CIs) of the 
geometric mean ratio of AUC0-inf, and Cmax in Study 1263-104.   
x Sample size estimation is performed using nQuery’s two one sided test (TOST) of 
equivalence in ratio of mean for crossover design study. 
x True mean ratio: 1.00, 1.05 
x Power: 80%, 90% 
x One-sided Į-level: 0.05 (corresponding to 90% CI) 
x Bioequivalence range: 0.8-1.25 
Table 14: Number of Subjects Required 
 
 
Intra-subject coefficient of variation 
True Ratio Power  
0.166 
0.218 
1.0 
80% 
12 
18 
 
90% 
14 
22 
1.05 
80% 
14 
22 
 
90% 
18 
28 
Note: sample size estimation is performed using nQuery’s TOST of equivalence in ratio of mean 
for crossover design study. 
Assuming a true mean ratio of 1.0 with intra-subject coefficient of variation of 0.218, a total of 
18 completers is required to have 80% power to show that the 90% confidence intervals of the 
ratios of the geometric means of the two formulations/treatment lie within the range of 0.80 to 
1.25. 
Therefore, for Part 1, three subjects in each sequence with a total of 18 subjects is required to 
randomize subjects to 1 of 6 sequences in a 1:1:1:1:1:1 treatment allocation.  For Part 2, five 
subjects in each sequence with a total of 20 subjects is required to randomize subjects to 1 of 4 
sequences in 1:1:1:1 treatment allocation. 
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8.7 
Study Population   
The screened set will consist of all subjects who have signed informed consent. 
Enrolled set will consist of all subjects who have signed informed consent and also fulfilled the 
inclusion/exclusion criteria. 
The following subject populations are defined to analyze the data in Part 1 and Part 2:  
Part 1: 
x The pharmacokinetic set 1 will consist of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable 
post-dose maribavir  concentration value in Part 1. 
x The safety set 1 will consist of subjects who have received at least 1 dose of 
maribavir in Part 1. 
Part 2: 
x The pharmacokinetic set 2 will consist of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable 
post-dose maribavir  concentration value in Part 2. 
x The safety set 2 will consist of subjects who have received at least 1 dose of 
maribavir in Part 2.  
Part 1 and 2 (combined): 
x The total safety set will include subjects who have received at least 1 dose of 
maribavir in either Part 1 or Part 2. 
Subjects who do not provide reliable concentration-time profile (in 1 or more periods) may be 
excluded from pharmacokinetic analysis (for the corresponding period).  
8.7.1 
Pharmacokinetic Analysis 
All the pharmacokinetic analyses will be based on the PK analysis dataset.  
Pharmacokinetic parameters will be calculated from maribavir concentration-time data using 
non-compartmental analysis (NCA) and all calculations will be based on actual sampling times. 
Pharmacokinetic parameters will include, but not be limited to, the following: 
Part 1 (Day 1, Day 4, and Day 7) 
x Cmax 
Maximum concentration occurring at tmax 
x tmax 
Time of maximum observed concentration sampled during  a dosing 
interval 
x AUC0-last 
Area under the curve from the time of dosing to the last measurable 
concentration 
x AUC0-inf 
Area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration 
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x AUC0-inf%extrap 
The percent of AUC0-inf extrapolated, calculated by (1-AUC0-
last/AUC0-inf)*100 
x t1/2 
Terminal half-life 
x CL/F 
Apparent total body clearance following extravascular administration 
calculated as dose divided by AUC0-inf 
x Tlag 
Delay between the time of dosing and time of appearance of plasma 
concentration in the employed sampling scheme 
Part 2 (Day 1, Day 4, Day 7, and Day 10) 
x Cmax 
Maximum concentration occurring at tmax 
x tmax 
Time of maximum observed concentration sampled during a dosing 
interval 
x AUC0-last 
Area under the curve from the time of dosing to the last measurable 
concentration 
x AUC0-inf 
Area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration 
x AUC0-inf%extrap 
The percent of AUC0-inf extrapolated, calculated by (1-AUC0-
last/AUC0-inf)*100 
x t1/2 
Terminal half-life  
x CL/F 
Apparent total body clearance following extravascular  
administration divided by the fraction of dose absorbed  calculated as 
dose divided by AUC0-inf 
x Tlag 
Delay between the time of dosing and time of appearance of 
concentration in the sampling 
 
In addition, dose-normalized Cmax, AUC0-last, and AUC0-inf will be calculated for 
Treatments D, E, and F.  
8.7.2 
Statistical Analysis of Pharmacokinetic Parameters 
 
 Part 1 
8.7.2.1
Individual concentrations and PK parameters of maribavir will be listed and summarized by 
treatment with descriptive statistics (number, arithmetic mean, standard deviation [SD], 
coefficient of variation [CV%], median, minimum, maximum, geometric mean, and %CV of 
geometric mean). Figures of individual and mean (+/-SD) concentration-time profiles of plasma 
maribavir by treatment will be generated on both linear and semi-log scales.  
Following the loge-transformation, the PK parameters including AUC0-last, AUC0-inf, and Cmax 
will be analyzed using a mixed effect model to include sequence, period, and treatment as fixed 
effects and subject within sequence as a random effect. Analysis of variance will be performed 
using SAS mixed linear models procedure. Point estimates and their associated 90% CIs will be 
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constructed for the differences in the log-transformed parameters. The point estimates and their 
associated 90% CIs will be then back-transformed to provide point estimates for the ratio of 
geometric least  squares means and associated 90% CIs  on the original scale.  Analysis of tmax 
and Tlag will be performed by nonparametric t-test.  
 
Part 2 
8.7.2.2
Dose proportionality analysis: 
The dose proportionality will be first assessed using the Power Model for 50-200 mg (fasted) 
dose range. The Power Model: log(Yijk)=Si + Pj + Exlog(Dk) + Hijk where D is the total number of 
doses, N are the total number of subjects and P the total number of periods and i=1,.….,N, 
j=1,.….,P and k=1,.…..,D. Yijk is the log-transformed response variable, AUC0-inf, AUC0-last, or 
Cmax on the kth dose, in the jth period, for the ith subject. Si is the random subject effect for the 
ith subject, Pj is the fixed period effect for the jth period, ȕ was the slope and Hijk is the error.  If 
the 90% confidence interval for the model estimated mean slope falls within 0.8 and 1.25 limits, 
then dose proportionality will be concluded. The estimate and 90% confidence interval for the 
slope and fold increase in PK exposure when doubling the dose will be presented. The 
corresponding graphical display from the power model (back transformed to raw linear scale) 
with the 90% CI overlaid on the observed data will be provided. 
Additionally, a mixed effect analysis of variance (ANOVA) model will be performed with the 
log-transformed dose normalized response variable, AUC0-inf , AUC0-last, or Cmax. The geometric 
mean ratios and 90% CI for each dose compared to the reference dose (50 mg dose) will be 
provided.  
Analysis of Effect of Food: 
A mixed effect ANOVA model will be performed with log transformed AUC0-inf, AUC0-last or 
Cmax. Point estimates and 90% CI for geometric mean ratios will be computed for treatments 
(maribavir 200 mg fed vs. 200 mg fasted) . If the 90% CI for the geometric mean ratios of 
treatments (maribavir 200 mg fed vs. 200 mg fasted) falls within 0.8 and 1.25 limits, then 
equivalence will be concluded. Analysis of tmax and Tlag will be performed by nonparametric t-
test.  
8.8 
Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number and percentage of subjects experiencing TEAEs and the number of events will be 
calculated and summarized by SOC, by preferred term and by study treatment for Part 1 and Part 
2 separately, using the respective safety population.  Treatment-emergent adverse events will be 
further summarized by severity and relationship to study treatment. Adverse events related to 
study treatment, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed. 
Additionally, TEAEs will be summarized for Part 1 and 2 combined for all subjects enrolled on 
study who take at least one dose of maribavir by dose level regardless of formulation.  
Clinical laboratory tests, vital signs, and ECG findings will be summarized by study treatment 
and visit for Part 1 and Part 2 separately, using the respective safety population. 
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Potentially clinically important findings will be summarized by study treatment for Part 1 and 
Part 2 separately.  
Additionally, potentially clinically important (PCI) findings will be summarized for Part 1 and 
Part 2 combined for all subjects enrolled on study who take at least one dose of maribavir by 
dose level regardless of formulation. 
8.9 
Other Analyses 
8.9.1 
Palatability  
The palatability will be evaluated to identify and characterize basic tastes, texture and mouth feel 
and to assess the overall acceptability.  Palatability data will be summarized for Part 1 and Part 2 
separately using the respective safety population. 
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Townsend, L. B. and Koszalka, G. W. 2002. Potent and selective inhibition of human 
cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique 
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Boeckh, M., Nichols, W. G., Papanicolaou, G., Rubin, R., Wingard, J. R. and Zaia, J. 2003. 
Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known 
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Chulay, J., Biron, K., Wang, L., Underwood, M., Chamberlain, S., Frick, L., Good, S., Davis, 
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de la Hoz, R. E., Stephens, G. and 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. and Chou, S. 2006. Maribavir sensitivity of 
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Farrugia, E. and Schwab, T. R. 1992. Management and prevention of cytomegalovirus infection 
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Bidanset, D. J. 2004. Activities of benzimidazole D- and L-ribonucleosides in animal 
models of cytomegalovirus infections. Antimicrob Agents Chemother, 48, 1749-55. 
Krosky, P., Baek, M. and Coen, D. 2003. The human cytomegalovirus UL97 protein kinase, an 
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Legendre, C. and 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. and Boeckh, M. 2000. Emergence of 
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disease 
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Ullmann, J., Musso, M., Trenschel, R., Ribaud, P., Bornhauser, M., Cesaro, S., Crooks, 
B., Dekker, A., Gratecos, N., Klingebiel, T., Tagliaferri, E., Ullmann, A. J., Wacker, P. 
and Cordonnier, C. 2001. Cidofovir for cytomegalovirus infection and disease in 
allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the 
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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. and Ringden, O. 2006. Risk factors for the 
development of cytomegalovirus disease after allogeneic stem cell transplantation. 
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orthotopic liver transplantations. J Infect Dis, 160, 752-8. 
Pouria, S., State, O. I., Wong, W. and Hendry, B. M. 1998. CMV infection is associated with 
transplant renal artery stenosis. Qjm, 91, 185-9. 
Razonable, R. R. and Emery, V. C. 2004. Management of CMV infection and disease in 
transplant patients. 27-29 February 2004. Herpes, 11, 77-86. 
Reusser, P., Einsele, H., Lee, J., Volin, L., Rovira, M., Engelhard, D., Finke, J., Cordonnier, C., 
Link, H., Ljungman, P. and 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 
stem cell transplantation. Blood, 99, 1159-64. 
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. and 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 
transplantation. Jama, 261, 3607-9. 
Salzberger, B., Bowden, R. A., Hackman, R. C., Davis, C. and 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. and 
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. and 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. and Busuttil, R. W. 1995. Randomised comparison of 
ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-
transplant recipients. Lancet, 346, 69-74. 
Wolf, D., Courcelle, C., Prichard, M. and Mocarski, E. 2001. Distinct and separate roles for 
herpesvirus-conserved 
UL97 
kinase 
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DNA 
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encapsidation. Proc Natl Acad Sci U S A, 98, 1895-900. 
  
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10. APPENDICES 
APPENDIX 1 
PROTOCOL HISTORY 
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
28 Aug 2019 
USA 
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APPENDIX 2 
PALATABILITY QUESTIONNAIRE 
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APPENDIX 3 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
APPENDIX 3.1 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 3.2 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 
investigational product 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. 
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees 
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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 3.3 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.  Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
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). 
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. 
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation.  The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor.  Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
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. 
The CRA/study monitor will verify the contents of the completed CRF pages against the source 
data.  If the data are unclear or contradictory, queries are sent for corrections or verification of 
data. 
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. 
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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 US FDA, 
EMA, UK Medicines and Healthcare Products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
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 investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
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 3.4 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 
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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. 
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. 
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Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the 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; however, their initials and date of birth may 
also be collected, if permitted under local laws governing privacy. 
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. 
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, 
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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 4 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
APPENDIX 4.1 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 
investigational product 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 treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product.  
Serious Adverse Event  
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose: 
x Results in death 
x 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. 
x 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). 
x Results in persistent or significant disability/incapacity 
x Results in a congenital abnormality/birth defect 
x 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 
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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. 
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 Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the 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 RSI. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated form 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: 
x Suspected adverse reaction 
x Serious 
x Unexpected 
x Assessed as related to study treatment 
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 
investigational product, 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 investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered. 
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 
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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 4.2 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 investigational product 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 4.3 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 investigational 
product, must be recorded as new AEs. 
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, 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 investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source. 
The following additional guidance may be helpful: 
Term 
Relationship Definition 
Related 
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident. 
 
 
Not Related 
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event. 
Outcome Categorization 
The outcome of AEs must be recorded in the source during the course of the study. Outcomes are 
as follows: 
x Fatal 
x Not Recovered/Not Resolved 
x Recovered/Resolved 
x Recovered/Resolved With Sequelae 
x Recovering/Resolving 
x 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.  
 
 
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APPENDIX 4.4 SAFETY REPORTING 
Reference Safety Information 
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators. 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/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 (see Appendix 4.9) unless they result in an 
SAE. 
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
for Serious Adverse Events (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 Serious Adverse Events (SAEs) and Non-serious AEs as Required by 
Protocol (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
APPENDIX 4.5 SERIOUS ADVERSE EVENT COLLECTION TIME FRAME 
All SAEs (regardless of relationship to investigational product) 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/Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first becoming aware of the event. 
APPENDIX 4.6 SERIOUS ADVERSE EVENT ONSET AND RESOLUTION DATES 
The onset date of the SAE is defined as the date the event meets serious criteria.  The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
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. 
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APPENDIX 4.7 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. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product or it is a 
single dose study). The investigational product action of withdrawn should not be selected solely 
as a result of the subject’s death. 
APPENDIX 4.8 PREGNANCY 
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in 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/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. 
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. 
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.   
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 E-HCG test or 
ultrasound result will determine the pregnancy onset date. 
APPENDIX 4.9 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 4.1.  
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Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication error s unless these result in an SAE.  
The categories below are not mutually exclusive; the event can meet more than 1 category. 
x Abuse – Persistent or sporadic intentional intake of investigational product 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 
x Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol) 
x Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose 
x Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product.  For studies, medication errors are reportable to the sponsor only 
as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. Medication errors should be collected/reported for all products under 
investigation. The administration and/or use of the unassigned treatment is/are always reportable 
as a medication error. The administration and/or use of an expired investigational product should 
be considered as a reportable medication error. 
APPENDIX 4.10 
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: 
x Immediate change in study design or study procedures 
x Temporary or permanent halt of a given clinical trial or trials 
x 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 EC(s) and relevant 
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competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.  
APPENDIX 4.11 
REGULATORY AGENCY, INSTITUTIONAL REVIEW BOARD, 
ETHICS COMMITTEE, AND SITE REPORTING 
The sponsor is responsible for notifying the relevant regulatory authorities, institutional review 
boards (IRBs) and ethics committees (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 TAK620 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. 
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PROTOCOL: TAK-620-1019
TITLE:
A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose 
Proportionality, and Food Effect Study Comparing the Pharmacokinetics 
and Palatability of Two Candidate Pediatric Powder-for-Oral-Suspension 
Formulations of Maribavir to the Current Maribavir Tablet Formulation 
Administered in Healthy Adult Subjects
DRUG:
TAK620 (SHP620), Maribavir
IND:
051001
EUDRACT NO.:
2015-004725-13
SPONSOR:
Shire Human Genetic Therapies, Inc. (Shire, [and affiliates]); Shire is a 
wholly owned subsidiary of Takeda Pharmaceutical Company Limited
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD
 USA
Telephone: 
/ 
Fax: 
E-mail: 
PROTOCOL 
HISTORY:
Amendment 1: 05-Nov-2019
Original Protocol: 28-Aug-2019
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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Protocol Signature Page 
Sponsor's (Shire) Approval 
Signature: 
, MD, PhD, MPH 
Investigator's Acknowledgement 
I have read this protocol for Study TAK-620-1019. 
Title: A Phase 1, Open-label, Randomized, Crossover Bioavailability, Dose Prop01tionality, and 
Food Effect Study Comparing the Pharmacokinetics and Palatability of Two Candidate Pediatric 
Powder-for-Oral-Suspension Formulations of Maribavir to the Cunent Mm:ibavir Tablet 
Formulation Administered in Healthy Adult Subjects 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the inf01mation in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. 
It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to paiticipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation guidelines of Technical Requirements 
for Registration of Phaimaceuticals for Hun1an Use guidelines on Good Clinical Practice and 
with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
te1mination of my paiticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Naine and Address: 
, MD 
(please hand print or type) 
 
 
 
Si nature: 
Date: 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
05 Nov 2019
Global/Country/Site Specific
Country
Description of Change
Section(s) Affected by Change
Wording was added to allow for the doses to be evaluated in Part 2 of the 
study to be adjusted from the planned doses of 50mg, 100mg and 200mg. 
Dose adjustment will be based on relative bioavailability of the selected 
pediatric formulation (powder for oral suspension) to the Phase 3 tablet 
formulation observed in Part 1.
All statistical analyses will then be conducted based on the adjusted 
treatment groups.
Study Synopsis
Section 3.1
Table 11
Figure 2
Section 8.4
Section 8.7.2.2
Clarification was added to describe the exclusion requirements for over-
the counter and prescription medications.
Current use of any prescription medication with the exception of 
hormonal replacement therapy. Current use is defined as use within 30 
days of the first dose of investigational product. Current use of any over 
the counter medication (including herbal, or homeopathic preparations) 
within 14 days of the first dose of investigational product.
Study Synopsis
Section 4.2
Added as a separate line item exclusion criteria “Current use of antacids 
and H2 antagonists
Study Synopsis
Section 4.2
Clarified definition of ‘participation’ as it relates to exclusion criteria. 
The exclusion criteria was revised to read, “Prior screen failure, 
randomization, enrollment, participation in this study or participation in 
Part 1 of this study.”
Study Synopsis
Section 4.2
Clarification was added for consistency and to confirm that a serum beta-
HCG or urine pregnancy test is to be performed on all females as 
outlined in Table 1 and Table 5
Section 7.2.2.7
Clarified that FT4 not Thyroxine (T4 Total), is required with 
biochemistry at screening
Section 7.2.2.6
Changed “phosphorus” to “phosphate” in the list of biochemistry 
laboratory tests required
Section 7.2.2.6
Added ECG to schedule of assessments at the 3 hour timepoint on Days 
1, 4 and 7 in Part 1 and on Days 1, 4, 7 and 10 in Part 2.
Table 2
Table 3
Table 4
Table 6
Table 7
Table 8
Table 9
Removed biochemistry, hematology, and urinalysis from Day 1 Pre-dose 
in the detailed schedules of assessments.
Table 2
Table 6
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Changed pre-dose window for all treatment periods in Part 2 to reflect 
that the assessments should be performed within 60 minutes prior to dose 
administration.
Table 6
Table 7
Table 8
Table 9
Added clarification that the pre-dose PK sample for subjects on 
Treatment G in Part 2 should be collected after the high-fat breakfast and 
before dose administration.
Table 6
Table 7
Table 8
Table 9
Removed section referencing respiratory rate instructions as respiratory 
rate is not part of the required study assessments.
Section 7.2.2.4
Changed “interim” to “planned” for consistency and to clarify the Part 1 
to Part 2 analysis.
Study Synopsis
Section 3.1
Added the definition of Randomized Set for Part 1 and Part 2 of the 
study
Section 8.7
See Appendix 1 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the "Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious 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)/Shire Medical Monitor
using the details below.
For protocol- or safety-related questions or concerns during normal business hours 8:00 
am-5:00pm (local time per region), the investigator must contact the Shire Medical 
Monitor:
, MD, PhD, MPH
Clinical Pharmacology Medical Leader/ Shire Study Medical Monitor
Telephone: 
(business hours)
 (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 according to procedures.
This includes any instances wherein the quality or performance of a Shire product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following:
•
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty
•
Missing components
•
Damage to the product or unit carton
•
A mislabeled product (eg, potential counterfeiting/tampering)
•
A bacteriological, chemical, or physical change or deterioration of the product causing it 
to malfunction or to present a hazard or fail to meet label claims
For instructions on reporting AEs related to product complaints, see Appendix 4.4. 
Please use the information below as applicable to report the Product Quality Complaint or Non-
Medical Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................21
1.
BACKGROUND INFORMATION.......................................................................................32
1.1
Indication and Current Treatment Options...............................................................32
1.2
Product Background.................................................................................................33
1.2.1
Preclinical Information ..........................................................................................33
1.2.2
Clinical Information...............................................................................................33
1.2.3
Pharmacokinetics, metabolism and drug-drug interactions...................................33
1.2.4
Efficacy..................................................................................................................34
1.2.5
Safety .....................................................................................................................35
1.3
Risk/Benefit and Ethical Assessment.......................................................................35
1.4
Compliance Statement..............................................................................................36
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................37
2.1
Rationale for the Study.............................................................................................37
2.2
Study Objectives ......................................................................................................37
2.2.1
Primary Objectives.................................................................................................37
2.2.2
Secondary Objectives.............................................................................................38
3.
STUDY DESIGN ...................................................................................................................39
3.1
Study Design and Flow Chart ..................................................................................39
3.2
Duration and Study Completion Definition .............................................................44
3.3
Sites and Regions .....................................................................................................45
4.
STUDY POPULATION.........................................................................................................46
4.1
Inclusion Criteria......................................................................................................46
4.2
Exclusion Criteria.....................................................................................................46
4.3
Restrictions...............................................................................................................48
4.4
Reproductive Potential .............................................................................................49
4.4.1
Female Contraception............................................................................................49
4.4.2
Male Contraception................................................................................................50
4.5
Discontinuation of Subjects .....................................................................................50
4.5.1
Reasons for Discontinuation..................................................................................50
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4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................51
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................52
5.1
Prior Treatment ........................................................................................................52
5.2
Concomitant Treatment............................................................................................52
5.2.1
Permitted Treatment...............................................................................................52
5.2.2
Prohibited Treatment .............................................................................................52
6.
INVESTIGATIONAL PRODUCT ........................................................................................53
6.1
Identity of Investigational Product...........................................................................53
6.1.1
Blinding the Treatment Assignment ......................................................................53
6.2
Administration of Investigational Product(s) ...........................................................53
6.2.1
Allocation of Subjects to Treatment ......................................................................53
6.2.2
Dosing....................................................................................................................53
Part 1, Treatment Period 1......................................................................53
6.2.2.1
Washout Period ......................................................................................54
6.2.2.2
Part 1, Treatment Period 2......................................................................54
6.2.2.3
Washout Period ......................................................................................54
6.2.2.4
Part 1, Treatment Period 3......................................................................54
6.2.2.5
Part 2, Treatment Period 1......................................................................54
6.2.2.6
Washout Period ......................................................................................54
6.2.2.7
Part 2, Treatment Period 2......................................................................55
6.2.2.8
Washout Period ......................................................................................55
6.2.2.9
Part 2, Treatment Period 3......................................................................55
6.2.2.10
Washout Period ......................................................................................55
6.2.2.11
Part 2, Treatment Period 4......................................................................55
6.2.2.12
6.3
Labeling, Packaging, Storage, and Handling ...........................................................56
6.3.1
Labeling .................................................................................................................56
6.3.2
Packaging...............................................................................................................56
6.3.3
Storage ...................................................................................................................56
6.4
Drug Accountability.................................................................................................57
6.5
Subject Compliance..................................................................................................58
6.6
Retention of Bioavailability Testing Samples..........................................................58
7.
STUDY PROCEDURES........................................................................................................59
7.1
Study Schedule.........................................................................................................59
7.1.1
Screening Period ....................................................................................................59
Screening Failure....................................................................................59
7.1.1.1
Rescreening of Subjects .........................................................................59
7.1.1.2
7.1.2
Treatment Period Part 1 .........................................................................................60
Admission to the Clinical Study Unit (CSU) (Day -1) ..........................60
7.1.2.1
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Day 1 to Day 3 (Part 1, Period 1)...........................................................60
7.1.2.2
Day 4 to Day 6 (Part 1, Period 2)...........................................................60
7.1.2.3
Day 7 to Day 8 (Part 1, Period 3)...........................................................60
7.1.2.4
Final Visit...............................................................................................60
7.1.2.5
7.1.3
Treatment Period Part 2 .........................................................................................61
Admission to the Clinical Pharmacology Unit (Day -1)........................61
7.1.3.1
Day 1 to Day 3 (Part 2, Period 1)...........................................................61
7.1.3.2
Day 4 to Day 6 (Part 2, Period 2)...........................................................61
7.1.3.3
Day 7 to Day 9 (Part 2, Period 3)...........................................................61
7.1.3.4
Day 10 to Day 11 (Part 2, Period 4) .......................................................61
7.1.3.5
Final Visit...............................................................................................62
7.1.3.6
7.1.4
Follow-up Period ...................................................................................................62
7.1.5
Additional Care of Subjects After the Study .........................................................62
7.2
Study Evaluations and Procedures ...........................................................................62
7.2.1
Demographic and Other Baseline Characteristics .................................................62
7.2.2
Safety .....................................................................................................................62
Medical and Medication History............................................................62
7.2.2.1
Physical Examination (Including Height and Weight) ..........................63
7.2.2.2
Adverse Event Collection.......................................................................63
7.2.2.3
Vital Signs..............................................................................................63
7.2.2.4
Palatability Questionnaire ......................................................................65
7.2.2.5
Clinical Laboratory Tests .......................................................................65
7.2.2.6
Pregnancy Test .......................................................................................66
7.2.2.7
Drug and Alcohol Screen .......................................................................66
7.2.2.8
Serology Screen......................................................................................67
7.2.2.9
Electrocardiogram ..................................................................................67
7.2.2.10
7.2.3
Pharmacokinetic Procedures..................................................................................68
Blood Sample Collection and Handling Procedures ..............................68
7.2.3.1
Shipment of Plasma Pharmacokinetic Samples .....................................68
7.2.3.2
Plasma Drug Assay Methodology..........................................................68
7.2.3.3
7.2.4
Volume of Blood to be Drawn from Each Subject in Part 1 .................................69
7.2.5
Volume of Blood to be Drawn from Each Subject in Part 2 .................................69
8.
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................71
8.1
Data Collection.........................................................................................................71
8.2
Clinical Data Management.......................................................................................71
8.3
Data Handling ..........................................................................................................71
8.4
Statistical Analysis Process......................................................................................71
8.5
Planned Analysis ......................................................................................................72
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8.6
Sample Size Calculation and Power Considerations................................................72
8.7
Study Population ......................................................................................................73
8.7.1
Pharmacokinetic Analysis......................................................................................73
8.7.2
Statistical Analysis of Pharmacokinetic Parameters..............................................74
Part 1 ......................................................................................................74
8.7.2.1
Part 2 ......................................................................................................75
8.7.2.2
8.8
Safety Analyses ........................................................................................................75
8.9
Other Analyses .........................................................................................................76
8.9.1
Palatability .............................................................................................................76
9.
REFERENCES .......................................................................................................................77
10. APPENDICES ........................................................................................................................79
Appendix 1
Protocol History .....................................................................................79
Appendix 2
Palatability Questionnaire ......................................................................80
Appendix 3
Regulatory, Ethical, and Study Oversight Considerations .....................81
Appendix 3.1
Regulatory and Ethical Considerations ..................................................81
Appendix 3.2
Sponsor’s Responsibilities .....................................................................81
Appendix 3.3
Investigator’s Responsibilities ...............................................................82
Appendix 3.4
Ethical Considerations............................................................................84
Appendix 4
Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-Up, and Reporting ....................................................................88
Appendix 4.1
Adverse Event Definitions .....................................................................88
Appendix 4.2
Collection of Adverse Events.................................................................90
Appendix 4.3
Assessment of Adverse Events ..............................................................90
Appendix 4.4
Safety Reporting.....................................................................................91
Appendix 4.5
Serious Adverse Event Collection Time Frame .....................................92
Appendix 4.6
Serious Adverse Event Onset and Resolution Dates..............................92
Appendix 4.7
Fatal Outcome ........................................................................................92
Appendix 4.8
Pregnancy...............................................................................................93
Appendix 4.9
Abuse, Misuse, Overdose, and Medication Error ..................................93
Appendix 4.10
Urgent Safety Measures .........................................................................94
Appendix 4.11
Regulatory Agency, Institutional Review Board, Ethics 
Committee, and Site Reporting..............................................................................94
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LIST OF TABLES
Table 1: Schedule of Assessments Part 1 ................................................................................21
Table 2: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 1..............23
Table 3: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 1..............24
Table 4: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 1..............25
Table 5: Schedule of Assessments Part 2 ................................................................................26
Table 6: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 2..............28
Table 7: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 2..............29
Table 8: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 2..............30
Table 9: Detailed Schedule of Assessments for Treatment Period 4 (Day 10), Part 2............31
Table 10: Treatment Sequence Part 1: N=18...........................................................................39
Table 11: Treatment Sequence Part 2: N=20...........................................................................42
Table 12: Volume of Blood to be Drawn from Each Subject in Part 1 ...................................69
Table 13: Volume of Blood to be Drawn from Each Subject in Part 2 ...................................69
Table 14: Number of Subjects Required..................................................................................72
LIST OF FIGURES
Figure 1: Study Design Flow Chart Part 1...............................................................................41
Figure 2: Study Design Flow Chart Part 2...............................................................................44
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ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
AUC
area under the curve
AUC0-last
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
β-HCG
beta-human chorionic gonadotropin
BCS
Biopharmaceutics Classification System
BMI
body mass index
CI
confidence interval
Cmax
maximum concentration occurring at tmax
CL/F
oral clearance
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSU
clinical study unit
CV%
coefficient of variation
EC
ethics committee
ECG
electrocardiogram
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antibody
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HSA
serum albumin
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
PK
pharmacokinetics
PCI
potentially clinically important
QTc
corrected QT interval
SAE
serious adverse event
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SAP
statistical analysis plan
SD
standard deviation
TEAE
treatment-emergent adverse event
TID
3 times daily
Tlag
delay between the time of dosing and time of appearance of concentration 
in the sampling
tmax
time of maximum observed concentration sampled during a dosing 
interval
TSH
thyroid-stimulating hormone
t1/2
terminal half-life
US
United States
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STUDY SYNOPSIS
Protocol number: TAK-620-1019
Drug: Maribavir
Title of the study: A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose Proportionality, and 
Food Effect Study Comparing the Pharmacokinetics and Palatability of Two Candidate Pediatric Powder-for-
Oral-Suspension Formulations of Maribavir to the Current Maribavir Tablet Formulation Administered in 
Healthy Adult Subjects 
Number of subjects (total and for each treatment arm): 38 subjects (18 in Part 1 and 20 in Part 2)
Investigator:
, MD
Site(s) and Region(s): 
Study period (planned):
2019-2020
Clinical phase:
1
Objectives:
Part 1: 
•
To assess the relative bioavailability of 2 candidate pediatric formulations of maribavir given 
as a single oral dose at 200 mg as compared to the Phase 3 adult maribavir 200 mg tablet 
formulation in healthy adult subjects (Primary)
•
To assess the palatability of the candidate pediatric formulations measured by a questionnaire 
(Primary)
•
To assess the safety and tolerability of 2 candidate pediatric formulations and the adult tablet 
formulation of maribavir given as a single oral dose at 200 mg in healthy adult subjects 
(Secondary)
Part 2:
•
To assess the dose proportionality of 50 mg, 100 mg, and 200 mg of the selected pediatric 
formulation (Primary)
•
To assess the impact of food on the rate and extent of absorption of the selected maribavir 
pediatric formulation given as 200 mg under fasted and fed conditions (Primary)
•
To assess the palatability of maribavir formulations at various doses and with food (Primary)
•
To assess the safety and tolerability of 2 candidate pediatric formulations and the adult tablet 
formulation of maribavir given as a single oral dose up to 200 mg in healthy adult subjects 
(Secondary)
Rationale:
In order to provide a palatable formulation for pediatric use, a taste-masking strategy that minimizes the 
availability of maribavir in the oral cavity is being explored. As the coating polymer has the potential to hinder 
drug release and absorption, 2 prototype formulations, each containing the same coating polymer but at different 
levels, are being evaluated in this study for their impact on palatability and rate and extent of absorption of 
maribavir. There were no significant effects of food on the rate and extent of absorption of maribavir from the 
adult tablet formulation, however, since maribavir is a Biopharmaceutics Classification System (BCS) II drug 
(ie, low solubility-high permeability drug) and the coating polymer may affect the rate and extent of absorption 
of maribavir, it is necessary to evaluate dose proportionality of the pediatric formulation and effects of food.
Investigational product, dose, and mode of administration:
Treatment A: maribavir 200 mg tablet- current Phase 3 formulation
Treatment B: maribavir 200 mg powder for oral suspension, 32.5% drug loading
Treatment C: maribavir 200 mg powder for oral suspension, 36.1% drug loading
Treatment D: maribavir powder for oral suspension (50 mg fasted)
Treatment E: maribavir powder for oral suspension (100 mg fasted)
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Treatment F: maribavir powder for oral suspension (200 mg fasted)
Treatment G: maribavir powder for oral suspension (200 mg fed with a high-fat meal)
Doses for Treatment D/E/F/G may be adjusted based on relative bioavailability of the selected pediatric 
formulation (powder for oral suspension) to the Phase 3 tablet formulation. 
Methodology:
This is a single-center (United States), open-label, randomized study. The study will be conducted sequentially 
in 2 parts. A total of 18 subjects will be enrolled in Part 1 of the study and a total of 20 subjects will be enrolled 
in Part 2. The study duration will comprise of a 28-day screening period for Part 1 and a 28-day screening 
period for Part 2. Part 1 will have 3 treatment periods with a 3-day washout period between each of the 3 
periods and a follow-up phone call. Part 2 will have 4 treatment periods with a 3-day washout period between 
each of the 4 treatment periods and a follow-up phone call.
Subjects will be admitted to the clinical study unit (CSU) on Day -1.
In Part 1, 2 pediatric candidate powder formulations will be compared with maribavir 200 mg tablet under 
fasted conditions in regards to their bioavailability and palatability to select 1 pediatric powder formulation for 
further evaluation in Part 2. In Part 2 dose proportionality of 50, 100 and 200 mg dose of the selected pediatric 
powder formulation of maribavir will be assessed, as well as the impact of food (a high-fat meal) on the rate and 
extent of absorption of the selected pediatric formulation. The pediatric formulation of maribavir which will be 
evaluated in Part 2 will be chosen based on the results of planned analysis of Part 1 pharmacokinetic (PK) and 
palatability data from 2 candidate pediatric formulations and the doses to be evaluated in Part 2 may be adjusted 
based on relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 
3 tablet formulation observed in Part 1. 
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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/and assent as applicable to participate in the study.
3.
Age 18-50 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.
4. 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. Additional details 
will be outlined in the protocol. 
5. 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 electrocardiogram (ECG), hematology, blood chemistry 
(includes TSH and free T4 [FT4] at screening only), and urinalysis.
6.
Hemoglobin for males ≥135.0 g/L and females ≥120.0 g/L at screening and on Day -1.
7.
Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive with a body weight >50 kg (110 lbs). 
This inclusion criterion will only be assessed at the first screening visit.
8. Ability to swallow a dose of investigational product.
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 investigational product, 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 investigational product or procedures.
3.
Known or suspected intolerance or hypersensitivity to the investigational product(s), 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 investigational 
product.
5.
Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first 
dose of investigational product.
6.
Within 30 days prior to the first dose of investigational product:
a.
Have used an IP (if elimination half-life is <6 days, otherwise 5 half-lives).
b.
Have been enrolled in a clinical study (including vaccine studies) that, in the investigator’s 
opinion, may impact this Shire-sponsored study.
c.
Have had any substantial changes in eating habits, as assessed by the investigator.
7.
Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood pressure 
>89 mmHg or <49 mmHg.
8.
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. 
9.
Known history of alcohol or other substance abuse within the last year.
10. 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).
11. A positive screen for alcohol or drugs of abuse at screening or on Day -1 of Treatment Period 1.
12. A positive human immunodeficiency virus (HIV), hepatitis B surface antibody (HBsAg), or hepatitis C 
virus (HCV) antibody screen.
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13. 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 investigational product (maribavir).
14. 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 tea, three 1 oz [85 g] chocolate bars. 
(Decaffeinated coffee, tea, or cola are not considered to contain caffeine).
15. Prior screen failure, randomization, enrollment, participation in this study or participation in Part 1 of 
this study.
16. Current use of any prescription medication with the exception of hormonal replacement therapy.
Current use is defined as use within 30 days of the first dose of investigational product. Current use of 
any over the counter medication (including herbal, or homeopathic preparations) within 14 days of the 
first dose of investigational product.
17. Current use of antacids and H2 antagonists.
18. Ingestion of known CYP3A modulators within 7 days of Day 1, Period 1 (includes grapefruit or 
grapefruit juice, oranges, Seville oranges, apples or apple juice, vegetables from the mustard green 
family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard], charbroiled 
meats, and products containing these ingredients).
19. Inability or unwillingness to consume 100 percent of high-fat meal in Part 2 (including subjects with 
lactose or gluten intolerance).
20. History of 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.
Maximum duration of subject involvement in the study:
The maximum total duration of study participation for a subject in Part 1 is 46 days. The maximum total 
duration of study participation for a subject in Part 2 is 49 days.
•
Planned duration of screening period Part 1: 28 days
•
Planned duration of screening period Part 2: 28 days
•
Planned duration of treatment period Part 1: 7 days
•
Planned duration of treatment period Part 2: 10 days
•
Planned duration of follow-up Part 1: 7±2 days after the last dose of investigational product.
•
Planned duration of follow-up Part 2: 7±2 days after the last dose of investigational product.
Endpoints and statistical analysis:
Two analysis populations are defined for this study in Part 1 and in Part 2: pharmacokinetic and safety.
For Part 1:
•
The pharmacokinetic population consists of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir concentration value in Part 1.
•
The safety population includes subjects who have received at least 1 dose of maribavir in Part 
1.
For Part 2: 
•
The pharmacokinetic population consists of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir concentration value in Part 2.
•
The safety population includes subjects who have received at least 1 dose of maribavir in Part 
2.
Pharmacokinetic endpoint:
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The PK analysis will be based on the PK analysis dataset. Pharmacokinetic parameters will be calculated from 
maribavir concentration-time data using non-compartmental analysis (NCA) and all calculations will be based 
on actual sampling times. Pharmacokinetic parameters will include, but not be limited to, the following:
Part 1 (Day 1, Day 4, and Day 7)
•
Cmax:
Maximum concentration occurring at tmax
•
tmax:
Time of maximum observed concentration sampled during
a dosing interval
•
AUC0-last:
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
•
t1/2
Terminal half-life
•
CL/F
Apparent total body clearance following extravascular 
administration calculated as dose divided by AUC0-inf
•
Tlag
Delay between the time of dosing and time of appearance 
of plasma concentration in the employed sampling scheme
Part 2 (Day 1, Day 4, Day 7, and Day 10)
•
Cmax
Maximum concentration occurring at tmax
•
tmax
Time of maximum observed concentration sampled during
a dosing interval
•
AUC0-last 
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
•
t1/2
Terminal half-life 
•
CL/F
Apparent total body clearance following extravascular 
administration divided by the fraction of dose absorbed 
calculated as dose divided by AUC0-inf
•
Tlag
Delay between the time of dosing and time of appearance 
of concentration in the sampling
In addition, dose-normalized Cmax, AUC0-last, and AUC0-inf will be calculated for Treatments D, E, and F.
Safety endpoint:
Safety will be assessed for the following evaluations for both Part 1 and Part 2:
•
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. Baseline is defined as the last non-missing 
assessment prior to the first dose.
Palatability endpoint:
The palatability will be evaluated to identify, characterize and quantify the sensory attributes of products, eg, 
basic tastes, texture and mouth feel and to assess the overall acceptability.
Sample Size Justification:
A sample size of 18 subjects in Part 1 and 20 subjects in Part 2 is calculated assuming a true mean ratio of 1.0 
with intra-subject coefficient of variation of 0.218, a total of 18 completers is required to have 80% power to 
show that the 90% confidence intervals of the ratios of the geometric means of the two formulations/treatment 
lie within the range of 0.80 to 1.25.
The table below indicates the number of subjects required based on the following data:
•
The intra-subject coefficient of variation is assumed at 0.166 and 0.218 respectively for AUC0-inf and Cmax, 
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which are estimated from the 90% confidence intervals (CIs) of the geometric mean ratio of AUC0-inf, and 
Cmax in Study 1263-104.
•
Sample size estimation is performed using nQuery’s two one-sided test (TOST) of equivalence in ratio of 
mean for crossover design study.
•
True mean ratio: 1.00, 1.05
•
Power: 80%, 90%
•
One-sided Į-level: 0.05 (corresponding to 90% CI)
•
Bioequivalence range: 0.8-1.25
Number of Subjects Required 
Intra-subject coefficient of variation
True Ratio
Power 
0.166
0.218
1.0
80%
12
18
90%
14
22
1.05
80%
14
22
90%
18
28
Note sample size estimation is performed using nQuery’s TOST of equivalence in ratio of mean for crossover 
design study.
Statistical Methodology for Pharmacokinetic Endpoint(s):
Part 1
Individual concentrations and PK parameters of maribavir will be listed and summarized by 
treatment with descriptive statistics (number, arithmetic mean, standard deviation [SD], coefficient 
of variation [CV%], median, minimum, maximum, geometric mean, and %CV of geometric 
mean). Figures of individual and mean (+/-SD) concentration-time profiles of plasma maribavir by 
treatment will be generated on both linear and semi-log scales. 
Following the loge-transformation, the PK parameters including AUClast, AUC0-inf, and Cmax will be 
analyzed using a mixed effect model to include sequence, period, and treatment as fixed effects 
and subject within sequence as a random effect. Analysis of variance will be performed using SAS 
mixed linear models procedure. Point estimates and their associated 90% CIs will be constructed 
for the differences in the log-transformed parameters. The point estimates and their associated 90% 
CIs will be then back-transformed to provide point estimates for the ratio of geometric least
squares means and associated 90% CIs on the original scale. Analysis of tmax and tlag will be 
performed by nonparametric t-test. 
Part 2
Dose proportionality analysis
The dose proportionality will be first assessed using the Power Model for (fasted) dose range 
tested in Part 2. The Power Model: log(Yijk)=Si + Pj + βxlog(Dk) + εijk where D is the total number 
of doses, N are the total number of subjects and P the total number of periods and i=1,.….,N, 
j=1,.….,P and k=1,.…..,D. Yijk is the log-transformed response variable, AUC0-inf, AUC0-last, or 
Cmax on the kth dose, in the jth period, for the ith subject. Si is the random subject effect for the ith 
subject, Pj is the fixed period effect for the jth period, ȕ was the slope and εijk is the error. If the 
90% confidence interval for the model estimated mean slope falls within 0.8 and 1.25 limits, then 
dose proportionality will be concluded. The estimate and 90% confidence interval for the slope 
and fold increase in PK exposure when doubling the dose will be presented. The corresponding 
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graphical display from the powermodel (back transformed to raw linear scale) with the 90% CI 
overlaid on the observed data will be provided.
Additionally, a mixed effect analysis of variance (ANOVA) model will be performed with the log-
transformed dose normalized response variable, AUC0-inf, AUC0-last, or Cmax. The geometric mean 
ratios and 90% CI for each dose compared to the reference dose (50 mg dose) will be provided. 
Analysis of Effect of Food
A mixed effect ANOVA model will be performed with log transformed AUC0-inf, AUC0-last, or 
Cmax. Point estimates and 90% CI for geometric mean ratios will be computed for treatments 
(selected dose of maribavir fed vs. fasted). If the 90% CI for the geometric mean ratios of 
treatments (selected dose of maribavir fed vs. fasted) falls within 0.8 and 1.25 limits, then 
equivalence will be concluded. Analysis of tmax and tlag will be performed by nonparametric t-test. 
Statistical Methodology for Palatability Endpoint:
Data collected from the palatability questionnaire will be summarized descriptively.
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STUDY SCHEDULE(S)
Table 1: Schedule of Assessments Part 1
Visita
Screening
Treatment Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-
upl
Study Day
-28 to -2
-1
1j
2
3
4
5
6
7
8
Informed consent
X
Inclusion/exclusion criteria
X
X
Demography 
X
Medical/medication history
X
X
Physical examinationb
X
X
X
X
X
X
Randomization
Xk
Vital signs (blood pressure, 
pulse)b,c
X
X
X
X
X
X
X
X
X
X
Oral temperature
X
X
X
X
X
X
Height and weightd
X
X
X
X
X
X
Electrocardiogram (12-lead)b,e
X
X
X
X
X
X
X
X
Biochemistry, hematology, and 
urinalysisb, f, m
X
X
X
X
X
HIV, HBsAg, and HCV 
antibodies
X
Beta HCG Pregnancy test 
(females only)b, g
X
X
X
FSHh test in perimenopausal 
women
X
Urine drug and alcohol screeningi
X
X
Investigational Drug 
Administration
X
X
X
Pharmacokinetic blood samplingj, 
n
X
X
X
X
X
X
Palatability Assessment
X
X
X
Admit to the CSU (Day -1)
X
Discharge from the CSU (Day 8 
after last assessment)
X
Washout between treatment 
periods
X
X
X
X
X
X
Adverse events/serious adverse 
eventsb
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationb
X
X
X
X
X
X
X
X
X
X
X
β-hCG=beta-human chorionic gonadotropin; CSU-clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating 
hormone
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. Treatment Period 1 includes 
washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 7 through 8.
b In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
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Table 1: Schedule of Assessments Part 1
Visita
Screening
Treatment Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-
upl
Study Day
-28 to -2
-1
1j
2
3
4
5
6
7
8
c Vital signs will be obtained while subject is in the supine position on study days noted. Subjects should be in the appropriate position for at least 5 
minutes prior to obtaining vital signs.
d Height will be recorded at the screening visit only. 
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG.
f Clinical laboratory assessments include serum biochemistry, TSH and FT4, at (screening only), hematology, and urinalysis. 
g Serum ȕ-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time points.
h Females only, to confirm menopausal status.
i Drugs of abuse and alcohol at screening and Day-1
j See Table 2, Table 3, and Table 4 for detailed collection time points. 
k Randomization is for Treatment Period 1, Day 1 only.
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 3 (Day 7). 
AEs/SAEs occurring up to the time of the follow-up telephone call will be captured. The follow-up telephone call should be completed for all 
subjects including those who withdraw or are removed from the study prior to Day 8 of Treatment Period 3.
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1
n 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.
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Table 2: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 1
Study Day
Day 1
Day 2
Hour (relative to dosing time)
Predose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
Randomizationb
X
Vital signs (blood pressure, pulse) a, 
c
Xe
X
X
Oral Temperaturea
Xe
Weight
Xe
Electrocardiogram (12-lead)a,d
Xe
X
X
Biochemistry, hematology, and 
urinalysisa
X
Investigational drug administration
X
Pharmacokinetic blood samplingg
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xf
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only.
c Vital signs will be obtained while subject is in the supine position on study days noted. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 30 minutes prior to dose administration.
f Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
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Table 3: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 1
Study Day
Day 4
Day 5
Hour (relative to dosing time)
Pre-dose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
Vital signs (blood pressure, pulse)a, b
Xd
X
X
Oral Temperaturea
Xd
Weight
Xd
Electrocardiogram (12-lead)a,c
Xd
X
X
Biochemistry, hematology, and 
urinalysisa
X
Investigational drug administration
X
Pharmacokinetic blood samplingf
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xe
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 30 minutes prior to dose administration.
e Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
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Table 4: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 1
Study Day
Day 7
Day 8
Hour (relative to dosing time)
Pre-dose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
X
Vital signs (blood pressure, pulse)a, b
Xd
X
X
Electrocardiogram (12-lead)a,c
Xd
X
X
Oral Temperaturea
Xd
X
Weight
Xd
X
Biochemistry, hematology, and 
urinalysisa
X
Pregnancy (females only)a
X
Investigational drug administration
X
Pharmacokinetic blood samplingf
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xe
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 30 minutes prior to dose administration.
e Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
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Table 5: Schedule of Assessments Part 2
Visita
Screening
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment 
Period 4
Follow-upl
Study Day
-28 to -2
-1
1j
2
3
4
5
6
7
8
9
10
11
Informed consent
X
Inclusion/ exclusion criteria
X
X
Demography 
X
Medical/medication history
X
X
Physical examinationb
X
X
X
X
X
X
X
Randomization
Xk
High-fat meal prior to dose administration
Xn
Xn
Xn
Xn
Vital signs (blood pressure, pulse)b,c
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral temperature
X
X
X
X
X
X
X
Height and weightd
X
X
X
X
X
X
X
Electrocardiogram (12-lead)b,e
X
X
X
X
X
X
X
X
X
X
Biochemistry, hematology, and urinalysisb, f, m
X
X
X
X
X
X
HIV, HBsAg, and HCV antibodies
X
Pregnancy (females only)b, g
X
X
X
FSHh test in perimenopausal women
X
Urine drug and alcohol screeningi
X
X
Investigational Drug Administration
X
X
X
X
Pharmacokinetic blood samplingj, o
X
X
X
X
X
X
X
X
Palatability Assessment
X
X
X
X
Admit to the CSU (Day -1)
X
Discharge from the CSU (Day 11 after last 
assessment)
X
Washout between treatment periods
X
X
X
X
X
X
X
X
X
Adverse events/serious adverse eventsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 5: Schedule of Assessments Part 2
Visita
Screening
Treatment Period 1
Treatment Period 2
Treatment Period 3
Treatment 
Period 4
Follow-upl
Study Day
-28 to -2
-1
1j
2
3
4
5
6
7
8
9
10
11
Concomitant medicationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
β-hCG=beta-human chorionic gonadotropin; CSU=clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating hormone
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 3-day washout period between administration of the last dose of investigational product in Treatment Period 2 and Treatment Period 3 and between administration of the last dose in 
Treatment 4. Treatment Period 1 includes washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 7 through 9.
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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
d Height will be recorded at the screening visit only. 
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
f Clinical laboratory assessments include serum biochemistry, (TSH and FT4 at screening only), hematology, and urinalysis. 
g Serum ȕ-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time points
h Females only, to confirm menopausal status
i Drugs of abuse and alcohol at screening, and drugs of abuse and alcohol Day -1. 
j See Table 6, Table 7, Table 8, and Table 9 for detailed collection time points
k Randomization is for Treatment Period 1, Day 1 only. 
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 43 (Day 10). Adverse events/SAEs occurring up to the time of 
the follow-up telephone call will be captured. The follow-up telephone call should be completed for all subjects including those who withdraw or are removed from the study prior to Day 11 of 
Treatment Period 4.
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1.
n Subjects in Part 2 will receive maribavir depending on his/her randomized assignment to treatment sequence following an overnight fast of at least 10 hours. The study subjects should start the high-fat 
meal 30 minutes before administration of the drug product. Trial subjects should eat this meal in 30 minutes or less and consume 100 percent of the meal.
o 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.
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Table 6: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 2
Study Day
Day 1
Day 2
Hour (relative to dosing time)
Predose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
Randomizationb
X
Vital signs (blood pressure, 
pulse)a, c
Xe
X
X
Oral Temperaturea
X
Weight
Xe
Electrocardiogram (12-lead)a,d
Xe
X
X
Biochemistry, hematology, and 
urinalysisa
X
Investigational drug administration
X
Pharmacokinetic blood samplingg,
Xe, h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xf
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only.
c Vital signs will be obtained while subject is in the supine position on study days noted. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 60 minutes prior to dose administration.
f Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
h The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration.
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Table 7: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 2
Study Day
Day 4
Day 5
Hour (relative to dosing time)
Pre-
dose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
Vital signs (blood pressure, pulse)a, 
b
Xd
X
X
Oral Temperaturea
Xd
Weight
Xd
Electrocardiogram (12-lead)a,c
Xd
X
X
Biochemistry, hematology, and 
urinalysisa
X
Investigational drug administration
X
Pharmacokinetic blood samplingf
X d, g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xe
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 60 minutes prior to dose administration.
e Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration.
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Table 8: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 2
Study Day
Day 7
Day 8
Hour (relative to dosing time)
Pre-dose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examination a
X
Vital signs (blood pressure, pulse)a, b
Xd
X
X
Electrocardiogram (12-lead)a,c
Xd
X
X
Oral Temperaturea
Xd
Weight
Xd
Biochemistry, hematology, and 
urinalysisa
X
Investigational drug administration
X
Pharmacokinetic blood samplingf
Xd, g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xe
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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 60 minutes prior to dose administration.
e Palatability questionnaire should be given within 5 minutes of receiving dose.
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. 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.
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration.
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Table 9: Detailed Schedule of Assessments for Treatment Period 4 (Day 10), Part 2
Study Day
Day 10
Day 11
Hour (relative to dosing time)
Pre-dose
0
0.08
0.25
0.5
1
1.5
2
3
4
5
6
8
12
16
20
24
Physical examinationa
X
X
Vital signs (blood pressure, pulse)a, b
Xd
X
X
Electrocardiogram (12-lead)a,c
Xd
X
X
Oral Temperaturea
Xd
X
Weight
Xd
X
Biochemistry, hematology, and urinalysisa
X
Pregnancy (females only)a
X
Investigational drug administration
X
Pharmacokinetic blood sampling f
Xd, g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Palatability Assessment
Xe
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs.
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 These assessments should be performed within 60 minutes prior to dose administration.
e Palatability questionnaire should be given within 5 minutes of receiving dose
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. 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.
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration.
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1. BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Cytomegalovirus (CMV) is a beta herpesvirus that commonly infects humans; serologic
evidence of prior infection can be found in 40-100% of various adult populations 
(de la Hoz et al., 2002). However, symptomatic CMV infection or CMV disease occurs almost 
exclusively in individuals with compromised immune systems. Cytomegalovirus remains a 
significant problem for patients undergoing various types of transplants that are associated with 
the use of potent immunosuppressive chemotherapy, including hematopoietic stem cell 
transplants (HSCT) and solid organ transplants (SOT) (de la Hoz et al., 2002; 
Razonable and Emery, 2004).
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 virus’s ability to 
modulate the immune system, either directly or secondary to the host antiviral response through 
regulation of cytokine, chemokine, and/or growth factor production.
Cytomegalovirus prevention strategies (prophylaxis or preemptive therapy) for various high-risk
transplant subjects exist, however, CMV infection or disease can still occur within the early
(initial ~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 GVHD (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
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with 3 months of oral ganciclovir. Ganciclovir-resistant disease accounted for 20% of CMV
disease, 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 Investigator’s Brochure.
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- 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, metabolism and drug-drug interactions
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). Pharmacokinetic data obtained in Phase 
2 studies was 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 (HSA), lipoproteins, and
alpha-1-acid-glycoprotein (AAG). 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 CYP3A4 pathway with the formation of the primary
metabolite, VP44469. Renal clearance is a minor route of elimination of maribavir.
Clinical studies conducted to evaluate the potential of drug-drug interactions demonstrated the 
following:
•
Concomitant administration of maribavir (400 mg BID) with tacrolimus, a substrate of 
CYP3A4 and P-gp, resulted in increased tacrolimus Cmax 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 pharmacokinetics 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 50-2400 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. A definitive QT 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 had a favorable safety and tolerability profile in both the Phase 2 and Phase 3 trials for
CMV prophylaxis. Adverse events (AEs) were most commonly associated with gastrointestinal
(GI) disorders (eg, diarrhea, dysgeusia, nausea, and vomiting). These events were generally of
mild or moderate intensity. There were no signals of clinically significant effects of maribavir on
vital signs, 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, treatment-emergent AEs (TEAEs) that occurred were events already
observed in previous studies (ie, dysgeusia, GI events, elevated immunosuppressant drug levels,
and rash) and there were no additional safety concerns raised from this study. In Study SHP620-
203, TEAEs that occurred at a higher frequency in maribavir subjects compared with
valganciclovir were events already observed in previous studies with maribavir (ie, dysgeusia, GI
events, and elevated immunosuppressant drug levels). Analyses of clinical laboratory, vital signs,
and ECG data did not identify any clinically meaningful differences across the maribavir 
treatment groups.
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 investigator’s brochure for the most detailed and most
current information regarding the drug metabolism, pharmacokinetics, 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 SCT 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 
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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 investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, pharmacokinetics, 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 3.
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2. STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
In the previous study SHP620-118, taste assessment study of maribavir, maribavir taste was 
characterized as a strong and lingering bitter taste at clinically-relevant doses, posing a taste-
masking challenge.
In order to provide a palatable formulation for pediatric use, a taste-masking strategy that 
minimizes the availability of maribavir in the oral cavity is being explored. The taste-masking 
relies on the use of a coating polymer that is insoluble at neutral pH (ie, of saliva) but soluble at 
acidic pH (ie, of gastric fluid). By encapsulating maribavir inside the coating polymer, maribavir 
would be unavailable for taste perception in the mouth but, released in the stomach for 
absorption. As the coating polymer has the potential to hinder drug release and absorption, 
2 prototype formulations, each containing the same coating polymer, but with different amounts, 
are being evaluated in this study for their impact on palatability and rate and extent of absorption 
of maribavir.
There were no significant effects of food on the rate and extent of absorption of maribavir from 
the adult tablet formulation; however, since maribavir is a Biopharmaceutics Classification 
System (BCS) II drug and the coating polymer may affect the rate and extent of absorption of 
maribavir, it is necessary to evaluate the dose proportionality of the pediatric formulation and the 
effects of food. This study will be conducted in 2 parts and a planned analysis will be conducted 
after Part 1 to decide if 1 of the 2 candidate pediatric formulations can be selected based on 
palatability and relative bioavailability and will be further evaluated for dose proportionality and 
effects of food in Part 2. The results from this study may be used for further optimization of the 
pediatric formulation and will provide guidance on dose selection of the pediatric formulation in 
clinical development for pediatric patients.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objectives of Part 1 of this study are to assess the relative bioavailability of 
2 candidate pediatric formulations of maribavir given as a single oral dose at 200 mg as 
compared to the Phase 3 adult maribavir 200 mg tablet formulation in healthy adult subjects. In 
addition, the palatability of the candidate pediatric formulations will be assessed by a 
questionnaire.
The primary objectives of Part 2 of this study are to assess the dose proportionality of 50 mg, 
100 mg, and 200 mg of the selected pediatric formulation, to assess the impact of food on the 
rate and extent of absorption of the selected pediatric formulation given as 200 mg under fasted 
and fed conditions and to assess the palatability at various doses and with food. 
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2.2.2
Secondary Objectives
The secondary objective of Part 1 and Part 2 of this study is to assess the safety and tolerability 
of 2 candidate pediatric formulations and the adult tablet formulation of maribavir given as a 
single oral dose up to 200 mg in healthy adult subjects. 
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3. STUDY DESIGN
3.1
Study Design and Flow Chart
The study will be conducted sequentially in 2 parts. In Part 1, two pediatric candidate powder 
formulations will be compared with maribavir 200 mg tablet under fasted conditions in regards 
to their bioavailability and palatability. In Part 2 dose proportionality of 50, 100, and 200 mg
dose of the selected pediatric powder formulation will be assessed, as well as the impact of food 
(a high-fat meal) on the rate and extent of absorption of the selected pediatric formulation. The 
pediatric formulation which will be evaluated in Part 2 will be chosen based on the results of 
planned analysis of Part 1 PK and palatability data from two candidate pediatric formulations 
and the doses to be evaluated in Part 2 may be adjusted based on relative bioavailability of the 
selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation 
observed in Part 1.
Part 1: Relative Bioavailability and Palatability
A total of 18 healthy male and female subjects, 18-50 years of age, inclusive, will be enrolled 
and expected to complete Part 1 of this study. Subjects who withdraw early will be replaced; the 
replacement subjects will receive the same treatment sequence assigned to subject who withdraw 
early. The study will be comprised of the following periods: a screening lasting up to 28 days, 3 
treatment periods in which subjects will receive a single dose of the study drug on the first day of 
each period after a 10-hour overnight fasting, a drug washout of a minimum of 72 hours and 
maximum of 73 hours between dosing in periods 1 and 2 and periods 2 and 3, and a follow-up 
phone call (7±2 days) after the last dose of investigational drug (maribavir) is administered 
(Figure 1). The maximal total duration of study participation for a subject in Part 1 is 46 days, if 
the maximum screening, washout and follow-up durations are used.
Screening will occur within 28 days prior to randomization to assess eligibility of subjects to 
participate in the study. Subjects will be admitted to the clinical study unit (CSU) on Day -1. On 
the morning of Day 1, subjects will be randomized to 1 of 6 sequences in a 1:1:1:1:1:1 treatment 
allocation. Subjects will receive assigned treatment under fasted conditions in each treatment 
period. The treatment sequences to be used in the study is shown in Table 10:
Table 10: Treatment Sequence Part 1: N=18
Sequence number (number of subjects per sequence) Treatment Sequence
1 (n=3)
ABC
2 (n=3)
BCA
3 (n=3)
CAB
4 (n=3)
CBA
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Table 10: Treatment Sequence Part 1: N=18
Sequence number (number of subjects per sequence) Treatment Sequence
5 (n=3)
ACB
6 (n=3)
BAC
Treatment A: maribavir 200 mg tablet- current Phase 3 formulation
Treatment B: maribavir 200 mg powder for oral suspension, 32.5% drug loading
Treatment C: maribavir 200 mg powder for oral suspension, 36.1% drug loading
Treatment Period 1
• On Day 1, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to the treatment sequence as presented in Table 10. 
Washout Period
• There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours
between the administration of maribavir in Period 1 (Day 1) and the administration of 
maribavir in Period 2 (Day 4).
Treatment Period 2
• On Day 4, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence (Table 10).
Washout Period
• There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of 
maribavir in Period 3 (Day 7).
Treatment Period 3
• On Day 7, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence (Table 10).
Assessments
Pharmacokinetic (PK) Assessment
Serial blood samples for PK analysis of maribavir concentrations will be collected over 24 hours 
on Day 1, Day 4, and Day 7. These blood samples will be collected according to the Detailed 
Schedule of Assessments (Table 2, Table 3, and Table 4). 
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• Safety and Tolerability Assessment
Safety and tolerability will be assessed based on treatment-emergent adverse events 
(TEAEs), vital signs, laboratory values, electrocardiogram (ECG) findings, and 
evaluation of clinical signs.
• Palatability Assessment
Palatability will be assessed based on subjects’ responses to a questionnaire that will be 
completed following each dose administration on Day 1, Day 4 and Day 7.
Follow-up
• Subjects will remain in the CSU until completion of the last post dose assessment on Day 
8. A post-treatment follow-up telephone call will be performed 7 (±2) days after the last 
dose of investigational product.
Figure 1: Study Design Flow Chart Part 1
Screening Period Days -28 through -2
Treatment 
A
Follow-up Phone Call (7±2 days after last dose of maribavir)
Day -1 – Admission to Clinical Study Unit
Treatment 
Period 1
(Day 1)
Treatment 
B
*Washout
(Day 1 dose 
to Day 4 
dose)
Treatment A: Maribavir 200mg tablet
Treatment B: Maribavir powder for oral suspension, 32.5% drug loading
Treatment C: Maribavir powder for oral suspension, 36.1% drug loading
*NOTE: Treatment will be dependent on randomization sequence.
*NOTE: There will be a drug washout of a minimum of 72 hours and maximum of 73 hours between the administration of maribavir in 
Period 1 (Day 1) and the administration of maribavir in Period 2 (Day 4) and between the administration of maribavir in Period 2 (Day 
4) and the administration of maribavir in Period 3 (Day 7)
Treatment
C
Treatment 
B
Day 8 – Discharge from the Clinical Study Unit
Treatment 
Period 2
(Day 4)
Screening
Treatment 
C
*Washout
(Day 4 dose 
to Day 7 
dose)
Treatment 
C
Treatment 
Period 3
(Day 7)
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
A
Treatment 
C
Treatment 
B
Treatment 
B
Treatment 
C
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
C
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Part 2: Dose Proportionality and Food Effect
A total of 20 healthy male and female subjects, 18-50 years of age, inclusive, will be enrolled 
and expected to complete Part 2 of this study. Subjects who withdraw early will be replaced and 
the replacement subjects will receive the same treatment sequence assigned to subject who 
withdraw early. The study will be comprised of the following periods: a screening lasting up to 
28 days, 4 treatment periods in which subjects will receive a single dose of the study drug on the 
first day of each period after a 10-hour overnight fasting, one treatment period in which subjects 
will receive a single dose of the study drug on the first day of the period after consuming a high-
fat meal, a drug washout of a minimum of 72 hours and maximum of 73 hours between dosing in 
periods 1 and 2, periods 2 and 3, and periods 3 and 4, and a follow-up phone call (7±2 days) after 
the last dose of investigational drug (maribavir) is administered (Figure 2). The maximal total 
duration of study participation for a subject in Part 2 is 49 days, if the maximum screening, 
washout and follow-up durations are used.
A planned analysis is planned after the completion of Part I to evaluate the PK and palatability 
data from the formulations investigated. Based on the results of the planned analysis of Part 1 
data, 1 pediatric formulation may be chosen to be assessed in Part 2. 
Screening will occur within 28 days prior to randomization to assess eligibility of subjects to 
participate in the study. Subjects will be admitted to the CSU on Day -1. On the morning of Day 
1, subjects will be randomized to 1 of 4 sequences in a 1:1:1:1 treatment allocation. The 
treatment sequences to be used in the study is shown in Table 11:
Table 11: Treatment Sequence Part 2: N=20
Sequence number (number of subjects per sequence) Treatment Sequence
1 (n=5)
DEGF
2 (n=5)
EFDG
3 (n=5)
FGED
4 (n=5)
GDFE
Treatment D: maribavir powder for oral suspension (50 mg fasted)
Treatment E: maribavir powder for oral suspension (100 mg fasted)
Treatment F: maribavir powder for oral suspension (200 mg fasted)
Treatment G: maribavir powder for oral suspension (200 mg fed with a high-fat meal)
The doses for Treatment D/E/F/G may be adjusted based on relative bioavailability of the 
selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation 
observed in Part 1.
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Treatment Period 1
• On Day 1, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to the treatment sequence as presented in Table 11. 
Washout Period
• There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of 
maribavir in Period 2 (Day 4).
Treatment Period 2
• On Day 4, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence (Table 11).
Washout Period
• There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of 
maribavir in Period 3 (Day 7).
Treatment Period 3
• On Day 7, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence (Table 11). 
Washout Period
• There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 3 (Day 7) and the administration of 
maribavir in Period 4 (Day 10).
Treatment Period 4
• On Day 10, subjects in each cohort will receive maribavir depending on his/her 
randomized assignment to treatment sequence (Table 11). 
Assessments
Pharmacokinetic (PK) Assessment
Serial blood samples for PK analysis of maribavir concentrations will be collected over 24 hours 
on Day 1, Day 4, Day 7 and Day 10. These blood samples will be collected according to the 
Detailed Schedule of Assessments (Table 6, Table 7, Table 8, and Table 9). 
• Safety and Tolerability Assessment
Safety and tolerability will be assessed based on treatment-emergent adverse events 
(TEAEs), vital signs, laboratory values, electrocardiogram (ECG) findings, and 
evaluation of clinical signs.
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• Palatability Assessment
Palatability will be assessed based on subjects’ responses to a questionnaire that will be 
completed following each dose administration on Day 1, Day 4, Day 7, and Day 10.
Follow-up
• Subjects will remain in the CSU until completion of the last post dose assessment on Day 
11. A post-treatment follow-up telephone call will be performed 7 (±2) days after the last 
dose of investigational product.
Figure 2: Study Design Flow Chart Part 2
Screening Period Days -28 through -2
Follow-up Phone Call (7±2 daysafter last dose of maribavir) 
Day -1 – Admission to Clinical Pharmacology Unit
Treatment 
Period 1
(Day 1)
Treatment 
E
*Washout
(Day 1 dose 
to Day 4 
dose)
Treatment D: Maribavir powder for oral suspension (50 mg fasted)*
Treatment E: Maribavir powder for oral suspension (100 mg fasted)*
Treatment F: Maribavir powder for oral suspension (200 mg fasted)*
Treatment G: Maribavir powder for oral suspension (200 mg fed with a high-fat meal)*
*NOTE: Treatment will be dependent on randomization sequence. The doses to be evaluated in Part 2 may be adjusted based on 
relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation 
observed in Part 1.
*NOTE: There will be a drug washout of a minimum of 72 hours and maximum of 73 hours between the administration of 
maribavir in Period 1 (Day 1) and the administration of maribavir in Period 2 (Day 4) between the administration of maribavir in 
Period 2 (Day 4) and the administration of maribavir in Period 3 (Day 7), and  between the administration of maribavir in Period 3 
(Day 7) and the administration of maribavir in Period 4 (Day 10)
Day 11 – Discharge from Clinical Study Unit
Treatment 
Period 2
(Day 4)
Screening
Treatment 
G
*Washout
(Day 4 dose 
to Day 7 
dose)
Treatment 
G
Treatment 
Period 3
(Day 7)
Treatment 
G
Treatment 
D
Treatment 
F
Treatment 
E
Treatment 
F
Treatment 
D
*Washout
(Day7 dose 
to Day 10 
dose)
Treatment 
Period 4
(Day 10)
Treatment 
F
Treatment 
E
Treatment 
D
Treatment 
E
Treatment 
G
Treatment 
F
Treatment 
D
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 46 days for 
Part 1 and 49 days for Part 2. The study will be completed in approximately 12 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 
phone call, whichever is later (refer to Section 7.1.4 for the defined follow-up period for this 
protocol).
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3.3
Sites and Regions
This study will be conducted at 1 clinical site in the 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 subject will not be considered eligible for the study without meeting all of the inclusion and 
exclusion criteria. 
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/and assent as applicable to participate in the 
study.
3. Age 18-50 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.
4. 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. 
Additional details will be outlined in the protocol. 
5. 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 TSH and free T4 (FT4) at screening only), and 
urinalysis.
6. Hemoglobin for males ≥135.0 g/L and females ≥120.0 g/L at screening and on Day -1.
7. Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive with a body weight >50 kg 
(110 lbs). This inclusion criterion will only be assessed at the first screening visit.
8.
Ability to swallow a dose of investigational product.
4.2
Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met at 
the screening visit or Day -1 (if reassessed): 
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 investigational product, or clinical or laboratory 
assessments.
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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 investigational product or procedures.
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), 
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 
investigational product.
5. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of investigational product.
6. Within 30 days prior to the first dose of investigational product:
-
Have used an investigational product (if elimination half-life is <6 days, otherwise 5 half-
lives).
-
Have been enrolled in a clinical study (including vaccine studies) that, in the 
investigator’s opinion, may impact this Shire-sponsored study.
-
Have had any substantial changes in eating habits, as assessed by the investigator.
7. Confirmed systolic blood pressure >139 mmHg or <89 mmHg, and diastolic blood pressure 
>89 mmHg or <49 mmHg.
8. 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.
9. Known history of alcohol or other substance abuse within the last year.
10. 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).
11. A positive screen for alcohol or drugs of abuse at screening or on Day -1 of Treatment 
Period 1.
12. A positive HIV, hepatitis B surface antibody (HBsAg), or hepatitis C virus (HCV) antibody 
screen.
13. 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 investigational product (maribavir).
14. 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 tea, three 1 oz 
[85 g] chocolate bars. (Decaffeinated coffee, tea, or cola are not considered to contain 
caffeine).
15. Prior screen failure, randomization, enrollment, participation in this study or participation in 
Part 1 of this study.
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16. Current use of any prescription medication with the exception of hormonal replacement 
therapy. Current use is defined as use within 30 days of the first dose of investigational 
product. Current use of any over the counter medication (including herbal, or homeopathic 
preparations) within 14 days of the first dose of investigational product.
17. Current use of antacids and H2 antagonists.
18. Ingestion of known CYP3A modulators within 7 days of Day 1, Period 1 (includes grapefruit 
or grapefruit juice, oranges, Seville oranges, apples or apple juice, vegetables from the 
mustard green family [eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels 
sprouts, mustard], charbroiled meats, and products containing these ingredients).
19. Inability or unwillingness to consume 100 percent of high-fat meal in Part 2 (including 
subjects with lactose or gluten intolerance).
20. History of 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.
4.3
Restrictions 
1. Subjects should refrain from strenuous physical exercise 48 hours prior to admission to the 
CRU and during the in-house stays at the CRU.
2. Subjects should refrain from consuming grapefruit, Seville oranges, 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. Subjects should refrain from consuming pine nuts 7 days prior to Day 1 of the first treatment 
period through the completion of the last treatment period.
4. Subjects should refrain from alcohol 48 hours prior to admission to the CRU and during the 
in-house stay at the CRU.
5. Subjects should refrain from 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. Subjects should refrain from taking or regularly using any prescription medication with the 
exception of those listed in Section 5.2 from 30 days prior to receiving the first dose of the 
investigational product 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 
investigational product through the completion of the discharge assessments and procedures. 
Subjects should not use antacids or zinc supplementation. 
7. Subjects should refrain from foods or beverages containing caffeine/xanthine 48 hours prior 
to admission to the CRU and during the in-house stay at the CRU.
8. Subjects will be required to follow standardized meal schedules and eat the meals provided 
by the site while housed in the CRU. No outside food or beverages (including gum, mints, 
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etc) will be permitted. Menus will be identical for all subjects at the CRU. Copies of the 
menus will be provided to the sponsor for approval prior to the start of the study. While 
confined, the total daily nutritional composition should be approximately 50% carbohydrate, 
35% fat, and 15% protein. The daily caloric intake per subject should not exceed 
approximately 3200 kcal. For Treatment G in Part 2, a high-fat (approximately 50 percent of 
total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal 
is to taken within 30 minutes prior to maribavir doses. This high-fat meal should derive 
approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, 
respectively.
(An example of a High Fat Breakfast: 2 eggs fried in butter, 2 strips of bacon, 2 slices of 
toast with butter, 4 ounces of hash brown potatoes, 8 ounces of whole milk. 
*50 percent of calories are derived from fat. Substitutions can be made to this meal, if the 
content, volume, and viscosity are maintained.) 
4.4
Reproductive Potential
4.4.1
Female Contraception
There is no clinical experience with maribavir in pregnant subjects. Sexually active females of 
child-bearing potential should be using an acceptable form of contraception. Females of 
child-bearing potential must be advised to use acceptable contraceptives throughout the study 
period and for 30 days following the last dose of investigational product. If hormonal 
contraceptives are used they should be administered according to the package insert. 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 investigational product. 
Female subjects should be either:
•
Post-menopausal (12 consecutive months of spontaneous amenorrhea and ≥age 50 years)
•
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
•
Females of child-bearing potential with a negative urine and/or serum beta-human chorionic 
gonadotropin (β-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 investigational product, 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 
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30 days.
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 
investigational product. 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 investigational product. 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 investigational product. Male subjects must not donate sperm until 3 months after the last 
dose of investigational product.
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 
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 investigational product is discontinued, regardless of the reason, the early withdrawal 
evaluations listed in Table 3 and Table 7 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 investigational 
product, and the total amount of investigational product administered must be recorded in the 
source documents and the case report form (CRF). 
Subjects who discontinue from the study may be replaced at the sponsor’s discretion to ensure 
that 18 subjects complete Part 1 of the study and 20 subjects complete Part 2 of the study.
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:
•
Adverse event
•
Protocol deviation
•
Withdrawal by subject 
•
Lost to follow-up
•
Other (The investigator must specify on the CRF)
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4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
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5. PRIOR AND CONCOMITANT 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 pharmacokinetic equivalent of 5 half-lives, whichever is longer) of the date of first dose of 
investigational product. 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 
investigational product 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 investigational products) 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 (see Section 4.4.1)
•
Hormone replacement therapy
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 test product is maribavir, which will be provided in tablet and powder form. 
Maribavir tablet is a blue, film-coated tablet containing 200 mg of maribavir. The tablets are 
packaged in a 60 cc, white, HDPE bottle containing 40 tablets. 
Maribavir powder for oral suspension is a white to off-white granular powder. The 32.5% w/w 
powder contains 325 mg of maribavir for every 1 g of powder; the 36.1% w/w powder contains 
361 mg of maribavir for every 1 g of powder. The powders are packaged in a 150 cc, white, 
HDPE bottle containing 40 g of powder. The powders are to be compounded to form unit dose 
oral suspensions. Additional information and detailed instructions are provided in the maribavir 
investigator’s brochure, and in a Pharmacy Manual that will be provided.
The sponsor will provide the test product, maribavir.
6.1.1
Blinding 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.
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. 
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered.
6.2.2
Dosing
Part 1, Treatment Period 1
6.2.2.1
On Day 1, subjects will receive either a single 200 mg dose of maribavir, either in tablet form or 
as an oral suspension, depending on his/her randomized assignment to the treatment sequence. 
Subjects will fast for at least 10 hours prior to dosing and 4 hours after dosing on Day 1. The 
study subjects should take the drug product with 240 mL (8 fluid ounces) of water. Additional 
water is allowed ad lib except for 1 hour before and 1 hour after drug administration
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Washout Period
6.2.2.2
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4).
Part 1, Treatment Period 2
6.2.2.3
On Day 4, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence. Subjects will fast for at least 10 hours prior to 
dosing and 4 hours after dosing on Day 4. The study subjects should take the drug product with 
240 mL (8 fluid ounces) of water. Additional water is allowed ad lib except for 1 hour before and 
1 hour after drug administration
Washout Period
6.2.2.4
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7).
Part 1, Treatment Period 3
6.2.2.5
On Day 7, subjects in each cohort will receive 200 mg maribavir depending on his/her 
randomized assignment to treatment sequence. Subjects will fast for at least 10 hours prior to 
dosing and 4 hours after dosing on Day 7. The study subjects should take the drug product with 
240 mL (8 fluid ounces) of water. Additional water is allowed ad lib except for 1 hour before and 
1 hour after drug administration.
Part 2, Treatment Period 1
6.2.2.6
On Day 1, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to the treatment sequence. For treatments D, E, and F, subjects will fast for at least 
10 hours prior to dosing and 4 hours after dosing on Day 1. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 1. Trial subjects 
should eat this meal in 30 minutes or less and consume 100 percent of the meal. Refer to 
Section 4.3, Number 9 for specific information about the high-fat meal. The study subjects 
should take the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed 
ad lib except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours 
after dosing on Day 1.
Washout Period
6.2.2.7
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4).
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Part 2, Treatment Period 2
6.2.2.8
On Day 4, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 4. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 4. Refer to Section 
4.3, Number 9 for specific information about the high-fat meal. The study subjects should take 
the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed ad lib 
except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours after 
dosing on Day 4.
Washout Period
6.2.2.9
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7).
Part 2, Treatment Period 3
6.2.2.10
On Day 7, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 7. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 7. Refer to 
Section 4.3, Number 9 for specific information about the high-fat meal. The study subjects 
should take the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed 
ad lib except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours 
after dosing on Day 7.
Washout Period
6.2.2.11
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 3 (Day 7) and the administration of maribavir 
in Period 4 (Day 10).
Part 2, Treatment Period 4
6.2.2.12
On Day 10, subjects in each cohort will receive maribavir depending on his/her randomized 
assignment to treatment sequence. For treatments D, E, and F, subjects will fast for at least 10 
hours prior to dosing and 4 hours after dosing on Day 10. For treatment G, subjects will go 
through an overnight fast of at least 10 hours, receive the high-fat meal 30 minutes before 
administration of the drug product, and fast for 4 hours after dosing on Day 10. Refer to 
Section 4.3, Number 9 for specific information about the high-fat meal. The study subjects 
should take the drug product with 240 mL (8 fluid ounces) of water. Additional water is allowed 
ad lib except for 1 hour before and 1 hour after drug administration. Subjects will fast for 4 hours 
after dosing on Day 10.
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6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product (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 investigational product 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.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
•
Maribavir tablet: 60 cc, white, square, HDPE bottle
•
Maribavir powder for oral suspension: 150 cc, white, round, 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 investigational product 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 
investigational product 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 investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
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records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product.
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication 
will be documented in the subject's source and/or other investigational product record. 
No investigational product 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.
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With the written agreement of the sponsor, at the end of the study all unused stock and 
empty/used investigational product 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 investigational products must be in 
accordance with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance must be assessed by observation of dosing by the investigator or designee. In 
addition, the CRU personnel should perform a hand and mouth check (mouth check is only 
required for oral dosing) of the subject to assure the investigational product 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 Testing Samples
In compliance with 21 CFR 320.38 (1999), and as recommended in the Center for Drug 
Evaluation and Research Guidance for Industry dated May 2004 regarding retention of relevant 
reserve (BA and BE test samples), CROs, site management organizations, or clinical 
investigators must retain samples when relevant BA/BE testing has been performed under 
contract by the sponsor. Retained samples must meet 21 CFR 320.38 (1999) and 320.63 (1999) 
requirements for reserve samples of test article and reference standards according to the 
following:
•
Reserve samples must be representative of the test batches provided and therefore must be 
randomly selected from identical test article and/or reference standards provided to the site
•
The quantity should be sufficient optimally to permit the Food and Drug Administration 
(FDA) to perform all release testing identified in the application 5 times
•
Are adequately identified so that the reserve sample can be positively identified as having 
come from the same batches as used in the BA/BE studies
•
Be stored under conditions that maintain the samples identity, integrity, strength, quality, and 
purity
•
Be retained for at least 5 years following the date of New Drug Application or supplemental 
New Drug Application approval or, if the Investigational New Drug is discontinued, at least 
5 years following the date of completion of the BA/BE study
•
Samples must be annually inspected and documented to confirm integrity.
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7. STUDY PROCEDURES
Details regarding scheduled assessments and procedures to be conducted in this study are 
provided below and in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and 
Table 9.
7.1
Study Schedule
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 
•
Pharmacokinetic blood sampling
•
Palatability Questionnaire
•
Clinical laboratory tests
•
Physical examination.
NOTE: Blood sampling for pharmacokinetic 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 
Screening procedures must be completed within 28 days of Day 1 as appropriate prior to 
receiving the first dose of investigational product. 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.
Screening Failure
7.1.1.1
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 enrolled or administered 
investigational product(s).
Rescreening of Subjects
7.1.1.2
Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point.
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. 
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7.1.2
Treatment Period Part 1
Admission to the Clinical Study Unit (CSU) (Day -1)
7.1.2.1
Following the screening visit, eligible subjects will return to the CSU on Day -1 of the study. See 
Table 1 for a list of procedures to be completed upon admission to the CSU.
Subjects who successfully complete the pre-admission assessments and procedures will be 
admitted to the CSU on Day -1 and assigned a subject number on Day 1 as described in 
Section 6.2. Eligible subjects will be confined to the CSU from the morning of Day -1 until 
Day 8.
Day 1 to Day 3 (Part 1, Period 1)
7.1.2.2
Study Assessments for Day 1 to Day 3 are outlined in Table 1 and Table 2. Administration of 
maribavir will occur on Day 1. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 1.
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4).
Day 4 to Day 6 (Part 1, Period 2)
7.1.2.3
Study Assessments for Day 4 to Day 6 are outlined in Table 1 and Table 3. Administration of 
maribavir will occur on Day 4. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 4.
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7).
Day 7 to Day 8 (Part 1, Period 3)
7.1.2.4
Study Assessments for Day 7 to Day 8 are outlined in Table 1 and Table 4. Administration of 
maribavir will occur on Day 7. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 7. 
Final Visit
7.1.2.5
Subjects will remain in-house for the entire study. Final evaluation will be on Day 8. For any 
subject who discontinues prematurely, the final visit will be the day they discontinue.
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7.1.3
Treatment Period Part 2
Admission to the Clinical Pharmacology Unit (Day -1)
7.1.3.1
Following the screening visit, eligible subjects will return to the CSU on Day -1 of the study. See 
Table 5 for a list of procedures to be completed upon admission to the CSU.
Subjects who successfully complete the pre-admission assessments and procedures will be 
admitted to the CSU on Day -1 and assigned a subject number on Day 1 as described in 
Section 6.2. Eligible subjects will be confined to the CSU from the morning of Day -1 until 
Day 11.
Day 1 to Day 3 (Part 2, Period 1)
7.1.3.2
Study Assessments for Day 1 to Day 3 are outlined in Table 5 and Table 6. Administration of 
maribavir will occur on Day 1. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 1.
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 1 (Day 1) and the administration of maribavir 
in Period 2 (Day 4).
Day 4 to Day 6 (Part 2, Period 2)
7.1.3.3
Study Assessments for Day 4 to Day 6 are outlined in Table 5 and Table 7. Administration of 
maribavir will occur on Day 4. Subjects will fast for at least 10 hours prior to dosing and 4 hours 
after dosing on Day 4.
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 2 (Day 4) and the administration of maribavir 
in Period 3 (Day 7).
Day 7 to Day 9 (Part 2, Period 3)
7.1.3.4
Study Assessments for Day 7 to Day 9 are outlined in Table 5 and Table 8. Administration of 
maribavir will occur on Day 7. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 4 
hours after dosing on Day 7.
There will be a drug washout period of a minimum of 72 hours and maximum of 73 hours 
between the administration of maribavir in Period 3 (Day 7) and the administration of maribavir 
in Period 4 (Day 10).
Day 10 to Day 11 (Part 2, Period 4)
7.1.3.5
Study Assessments for Day 10 to Day 11 are outlined in Table 5 and Table 9. Administration of 
maribavir will occur on Day 10. Subjects will be given a palatability questionnaire immediately 
following medication administration. Subjects will fast for at least 10 hours prior to dosing and 
4 hours after dosing on Day 10. 
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Final Visit
7.1.3.6
Subjects will remain in-house for the entire study. Final evaluation will be on Day 11. For any 
subject who discontinues prematurely, the final visit will be the day they discontinue.
7.1.4
Follow-up Period
The follow-up period for this protocol is 7±2 days for Part 1 and Part 2.
At the end of this period there will be a telephone call initiated by staff to query for serious 
adverse events (SAEs), AEs, and concomitant treatments. All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Appendix 4.2)
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
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 precise 
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 investigational product), TEAEs (all AEs occurring 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 CSU, subject safety will also be 
closely monitored through blood pressure measurements, ECG measurement, clinical safety labs, 
and physician oversight.
Medical and Medication History
7.2.2.1
A complete medical and medication history, as well as demographic information, will be 
performed at the Screening Visit/time points described in Table 1 and Table 5 by a qualified 
licensed physician, physician’s assistant, or a nurse practitioner. The medical history will be 
reviewed and recorded, including:
•
Date of birth
•
Sex
•
Race and ethnicity
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•
Recent ingestion of medication (30 days prior to entering the screening period)
•
History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases
•
Smoking habits 
Physical Examination (Including Height and Weight)
7.2.2.2
A complete physical examination will be performed at the time points described in Table 1 and
Table 5 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)
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 by the investigator.
Adverse Event Collection
7.2.2.3
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Refer to Appendix 4 for 
AE definitions, assessment, collection time frame, and reporting procedures.)
Vital Signs
7.2.2.4
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, Table 6, Table 7, Table 8, and Table 9 of this protocol. 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.
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The same method for obtaining blood pressure measurement (auscultatory or oscillometric) 
should be used throughout the study for all subjects (and documented). In addition, the 
conditions of vital sign measurements should be controlled and as consistent as possible during 
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 deflation rate 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 assumed 
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 caffeine, 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. If, after a single 
measurement is taken, there is a difference between arms in either systolic or diastolic blood 
pressure >10 mmHg, the site will perform triplicate BP measurements in each arm to determine 
the arm with the higher BP. The arm with the higher BP (based on the average of the 3 BP 
measurements for each arm) should be used for inclusion at screening, and the last of the
3 measurements recorded in the eCRF as the screening BP. The same (right or left) arm with the 
higher blood pressure will be used throughout the study. 
One reading (supine systolic blood pressure/diastolic blood pressure-heart rate) should be taken.
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.
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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Palatability Questionnaire
7.2.2.5
A palatability questionnaire (Refer to Appendix 2) will be completed following each dose 
administration (within 5 minutes) on Day 1, Day 4, Day 7 in Part 1 and on Day 1, Day 4, Day 7 
and Day 10 in Part 2.
Clinical Laboratory Tests
7.2.2.6
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
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 (8.5 mL) for serum biochemistry will be collected into a gel separator tube at the 
time points described in Table 1 and Table 5. The following parameters will be assessed:
Sodium
Phosphate
β-HCG 
(beta 
Human 
chorionic 
gonadotropin)a, b
Potassium
Protein
Glucose 
Carbon dioxide
Urea nitrogen
Albumin
Creatinine
Aspartate transaminase 
Calcium
Alanine transaminase 
Chloride
Gamma glutamyl transferase 
Thyroid stimulating hormone (TSH)a
Alkaline phosphatase 
FT4
a
Total bilirubin 
FSHa, b
Uric acid
a See Table 1 and Table 5.
b Females only.
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Hematology
Blood samples (4 mL) for hematology will be collected into an ethylenediaminetetraacetic acid 
(EDTA) tube at the time points described in Table 1 and Table 5. 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 and Table 
5. 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. 
Pregnancy Test 
7.2.2.7
A serum beta-HCG or urine 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.
Drug and Alcohol Screen 
7.2.2.8
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 or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study.
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Serology Screen 
7.2.2.9
At the screening visit, a blood sample of approximately 8 mL 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.
Electrocardiogram 
7.2.2.10
Twelve-lead ECGs will be performed at the times specified in Table 1 and Table 5. All ECGs 
will be performed using the equipment supplied by the CRU.
The following parameters will be recorded on the appropriate CRF page: heart rate, PR, RR, 
QRS, and QT intervals. The QTcF will be derived. 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 caffeine, 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.
One complete recording, including a 10 second rhythm strip, should be taken at each time point.
It should be immediately assessed as a valid recording and if not valid, it should be repeated.
Invalid recordings will not be entered in the CRF.
When a single ECG recording is performed at each time point, the ECG collected pre-dose on 
Day 1 will serve as the subject’s baseline ECG.
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.
If the QTcF interval (calculated on line 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 2-4 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.
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 
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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).
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.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory 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 pharmacokinetic (PK) blood sample collection times versus time of dosing will be 
monitored. 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. 
Blood Sample Collection and Handling Procedures
7.2.3.1
Blood samples will be collected at the time specified in Table 2, Table 3, Table 4, Table 6, Table 
7, Table 8, and Table 9 to measure plasma concentrations of maribavir. Potential metabolites 
may also be determined as appropriate.
Blood sample collection, processing and handling instructions are provided in the Laboratory 
Manual.
Shipment of Plasma Pharmacokinetic Samples
7.2.3.2
Plasma sample shipment handling instructions and contact information are provided in the 
Laboratory Manual.
Plasma Drug Assay Methodology
7.2.3.3
Plasma concentrations 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. 
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7.2.4
Volume of Blood to be Drawn from Each Subject in Part 1
Table 12: Volume of Blood to be Drawn from Each Subject in Part 1
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
3
45
135
HBsAg, HIV, HCV
8
1
8
Safety
Biochemistry and 
β-HCGb
8.5
5
42.5
Hematology
4
5
20
Total mL
205.5
β-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 3 mL of blood drawn has been used in determination of sample volume.
b β-HCG testing for females only.
During this study, it is expected that approximately 205.5 mL of blood will be drawn from all 
subjects, regardless of sex, in Part 1.
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; however, the total volume drawn over the course of the study 
should be approximately 205.5 mL. When more than one blood assessment is to be done at the 
time point/period, if they require the same type of tube, the assessments may be combined.
7.2.5
Volume of Blood to be Drawn from Each Subject in Part 2
Table 13: Volume of Blood to be Drawn from Each Subject in Part 2
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
3
60
180
HBsAg, HIV, HCV
8
1
8
Safety
Biochemistry and 
β-HCGb
8.5
6
51
Hematology
4
6
24
Total mL
263
β-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 1 mL is to be discarded; then take 2 mL into appropriate tube for pharmacokinetic sample. A 
total of 3 mL of blood drawn has been used in determination of sample volume.
b β-HCG testing for females only.
During this study, it is expected that approximately 263 mL of blood will be drawn from all 
subjects, regardless of sex, in Part 2.
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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; however, the total volume drawn over the course of the study 
should be approximately 263 mL. When more than one 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. Once a subject is randomized, it is expected that site personnel will complete the CRF 
entry within approximately 3 business days of the subject’s visit.
8.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the sponsor’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 pharmacokinetic, pharmacodynamic, and safety data, as well as describe the 
approaches to be taken for summarizing other study information such as subject disposition, 
demographics and baseline characteristics, investigational product exposure, and prior and 
concomitant medications. The SAP will also include a description of how missing, unused and 
spurious data will be addressed. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to conducting the planned analysis.
The doses for Treatment D/E/F/G in Part 2 may be adjusted based on relative bioavailability of 
the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation 
observed in Part 1. All statistical analyses will then be conducted based on the adjusted treatment 
groups.
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All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513). 
8.5
Planned Analysis 
After the completion of Part 1, a selected set of analyses planned for Part 1 to evaluate the PK 
and palatability data from the formulations investigated will be conducted. Based on the results 
of the analyses of Part 1 data, one pediatric formulation may be chosen to be assessed in Part 2.
All analyses will be conducted after the completion of Part 2.
8.6
Sample Size Calculation and Power Considerations
Sample size calculations were based on the following data:
•
The intra-subject coefficient of variation is assumed at 0.166 and 0.218 respectively for 
AUC0-inf and Cmax, which are estimated from the 90% confidence intervals (CIs) of the 
geometric mean ratio of AUC0-inf, and Cmax in Study 1263-104.
•
Sample size estimation is performed using nQuery’s two one sided test (TOST) of 
equivalence in ratio of mean for crossover design study.
•
True mean ratio: 1.00, 1.05
•
Power: 80%, 90%
•
One-sided Į-level: 0.05 (corresponding to 90% CI)
•
Bioequivalence range: 0.8-1.25
Table 14: Number of Subjects Required
Intra-subject coefficient of variation
True Ratio
Power 
0.166
0.218
1.0
80%
12
18
90%
14
22
1.05
80%
14
22
90%
18
28
Note: sample size estimation is performed using nQuery’s TOST of equivalence in ratio of mean for crossover design study.
Assuming a true mean ratio of 1.0 with intra-subject coefficient of variation of 0.218, a total of 
18 completers is required to have 80% power to show that the 90% confidence intervals of the 
ratios of the geometric means of the two formulations/treatment lie within the range of 0.80 to 
1.25.
Therefore, for Part 1, three subjects in each sequence with a total of 18 subjects is required to 
randomize subjects to 1 of 6 sequences in a 1:1:1:1:1:1 treatment allocation. For Part 2, 
five subjects in each sequence with a total of 20 subjects is required to randomize subjects to 1 of 
4 sequences in 1:1:1:1 treatment allocation.
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8.7
Study Population
The Screened Set will consist of all subjects who have signed informed consent.
The Enrolled Set will consist of all subjects who have signed informed consent and also 
fulfilled the inclusion/exclusion criteria.
The following subject populations are defined to analyze the data in Part 1 and Part 2: 
Part 1:
• The Randomized Set 1 will consist of all subjects who were randomized to a treatment 
sequence in Part 1.
• The Safety Set 1 will consist of subjects who have received at least 1 dose of maribavir in 
Part 1.
• The Pharmacokinetic Set 1 will consist of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir concentration value in Part 1.
Part 2:
• The Randomized Set 2 will consist of all subjects who were randomized to a treatment 
sequence in Part 2.
• The Safety Set 2 will consist of subjects who have received at least 1 dose of maribavir in 
Part 2. 
• The Pharmacokinetic Set 2 will consist of subjects who received at least 1 dose of 
maribavir, did not vomit within 4 hours of dosing, and have at least 1 evaluable post-dose 
maribavir concentration value in Part 1 and 2 (combined):
• The Total Safety Set will include subjects who have received at least 1 dose of maribavir 
in either Part 1 or Part 2.
Subjects who do not provide reliable concentration-time profile (in 1 or more periods) may be 
excluded from pharmacokinetic analysis (for the corresponding period). 
8.7.1
Pharmacokinetic Analysis
All the pharmacokinetic analyses will be based on the PK analysis dataset. 
Pharmacokinetic parameters will be calculated from maribavir concentration-time data using 
non-compartmental analysis (NCA) and all calculations will be based on actual sampling times. 
Pharmacokinetic parameters will include, but not be limited to, the following:
Part 1 (Day 1, Day 4, and Day 7)
• Cmax
Maximum concentration occurring at tmax
• tmax
Time of maximum observed concentration sampled during a dosing interval
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• AUC0-lastArea 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-AUC0-
last/AUC0-inf)*100
• t1/2
Terminal half-life
• CL/F
Apparent total body clearance following extravascular administration calculated 
as dose divided by AUC0-inf
• Tlag
Delay between the time of dosing and time of appearance of plasma concentration 
in the employed sampling scheme
Part 2 (Day 1, Day 4, Day 7, and Day 10)
• Cmax
Maximum concentration occurring at tmax
• tmax
Time of maximum observed concentration sampled during a dosing interval
• AUC0-lastArea 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-AUC0-
last/AUC0-inf)*100
• t1/2
Terminal half-life 
• CL/F
Apparent total body clearance following extravascular administration divided by 
the fraction of dose absorbed calculated as dose divided by AUC0-inf
• Tlag
Delay between the time of dosing and time of appearance of concentration in the 
sampling
In addition, dose-normalized Cmax, AUC0-last, and AUC0-inf will be calculated for Treatments D, 
E, and F. 
8.7.2
Statistical Analysis of Pharmacokinetic Parameters
Part 1
8.7.2.1
Individual concentrations and PK parameters of maribavir will be listed and summarized by 
treatment with descriptive statistics (number, arithmetic mean, standard deviation [SD], 
coefficient of variation [CV%], median, minimum, maximum, geometric mean, and %CV of 
geometric mean). Figures of individual and mean (+/-SD) concentration-time profiles of plasma 
maribavir by treatment will be generated on both linear and semi-log scales. 
Following the loge-transformation, the PK parameters including AUC0-last, AUC0-inf, and Cmax
will be analyzed using a mixed effect model to include sequence, period, and treatment as fixed 
effects and subject within sequence as a random effect. Analysis of variance will be performed 
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using SAS mixed linear models procedure. Point estimates and their associated 90% CIs will be 
constructed for the differences in the log-transformed parameters. The point estimates and their 
associated 90% CIs will be then back-transformed to provide point estimates for the ratio of 
geometric least squares means and associated 90% CIs on the original scale. Analysis of tmax and 
Tlag will be performed by nonparametric t-test. 
Part 2
8.7.2.2
Dose proportionality analysis:
The dose proportionality will be first assessed using the Power Model for (fasted) dose range 
tested in Part 2. The Power Model: log(Yijk)=Si + Pj + βxlog(Dk) + εijk where D is the total 
number of doses, N are the total number of subjects and P the total number of periods and 
i=1,.….,N, j=1,.….,P and k=1,.…..,D. Yijk is the log-transformed response variable, AUC0-inf, 
AUC0-last, or Cmax on the kth dose, in the jth period, for the ith subject. Si is the random subject 
effect for the ith subject, Pj is the fixed period effect for the jth period, ȕ was the slope and εijk is 
the error. If the 90% confidence interval for the model estimated mean slope falls within 0.8 and 
1.25 limits, then dose proportionality will be concluded. The estimate and 90% confidence 
interval for the slope and fold increase in PK exposure when doubling the dose will be presented. 
The corresponding graphical display from the power model (back transformed to raw linear 
scale) with the 90% CI overlaid on the observed data will be provided.
Additionally, a mixed effect analysis of variance (ANOVA) model will be performed with the 
log-transformed dose normalized response variable, AUC0-inf , AUC0-last, or Cmax. The geometric 
mean ratios and 90% CI for each dose compared to the reference dose (50 mg dose) will be 
provided. 
Analysis of Effect of Food:
A mixed effect ANOVA model will be performed with log transformed AUC0-inf, AUC0-last or 
Cmax. Point estimates and 90% CI for geometric mean ratios will be computed for treatments 
(selected dose of maribavir fed vs. fasted) . If the 90% CI for the geometric mean ratios of 
treatments (selected dose of maribavir fed vs. fasted) falls within 0.8 and 1.25 limits, then 
equivalence will be concluded. Analysis of tmax and Tlag will be performed by nonparametric t-
test. 
8.8
Safety Analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number and percentage of subjects experiencing TEAEs and the number of events will be 
calculated and summarized by SOC, by preferred term and by study treatment for Part 1 and Part 
2 separately, using the respective safety population. Treatment-emergent adverse events will be 
further summarized by severity and relationship to study treatment. Adverse events related to 
study treatment, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
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Additionally, TEAEs will be summarized for Part 1 and 2 combined for all subjects enrolled on 
study who take at least one dose of maribavir by dose level regardless of formulation.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by study treatment 
and visit for Part 1 and Part 2 separately, using the respective safety population.
Potentially clinically important findings will be summarized by study treatment for Part 1 and 
Part 2 separately. 
Additionally, potentially clinically important (PCI) findings will be summarized for Part 1 and 
Part 2 combined for all subjects enrolled on study who take at least one dose of maribavir by 
dose level regardless of formulation.
8.9
Other Analyses
8.9.1
Palatability 
The palatability will be evaluated to identify and characterize basic tastes, texture and mouth feel 
and to assess the overall acceptability. Palatability data will be summarized for Part 1 and Part 2 
separately using the respective safety population.
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9. REFERENCES
Avery, P. 2007. Management of late, recurrent, and resistant cytomegalovirus in transplant 
patients. 7UDQVSODQW5HY 21, 65-76.
Biron, K. K., Harvey, R. J., Chamberlain, S. C., Good, S. S., Smith, A. A., 3rd, Davis, M. G., 
Talarico, C. L., Miller, W. H., Ferris, R., Dornsife, R. E., Stanat, S. C., Drach, J. C., 
Townsend, L. B. and Koszalka, G. W. 2002. Potent and selective inhibition of human 
cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique 
mode of action. $QWLPLFURE$JHQWV&KHPRWKHU 46, 2365-72.
Boeckh, M., Nichols, W. G., Papanicolaou, G., Rubin, R., Wingard, J. R. and Zaia, J. 2003. 
Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known 
challenges, and future strategies. %LRO%ORRG0DUURZ7UDQVSODQW 9, 543-58.
Chulay, J., Biron, K., Wang, L., Underwood, M., Chamberlain, S., Frick, L., Good, S., Davis, 
M., Harvey, R., Townsend, L., Drach, J. and Koszalka, G. 1999. Development of novel 
benzimidazole riboside compounds for treatment of cytomegalovirus disease. $GY ([S
0HG%LRO 458, 129-34.
de la Hoz, R. E., Stephens, G. and Sherlock, C. 2002. Diagnosis and treatment approaches of 
CMV infections in adult patients. -&OLQ9LURO 25 Suppl 2, S1-12.
Drew, W. L., Miner, R. C., Marousek, G. I. and Chou, S. 2006. Maribavir sensitivity of 
cytomegalovirus isolates resistant to ganciclovir, cidofovir or foscarnet. - &OLQ9LURO 37, 
124-7.
Farrugia, E. and Schwab, T. R. 1992. Management and prevention of cytomegalovirus infection 
after renal transplantation. 0D\R&OLQ3URF 67, 879-90.
Hodson, E. M., Jones, C. A., Webster, A. C., Strippoli, G. F., Barclay, P. G., Kable, K., 
Vimalachandra, D. and Craig, J. C. 2005. Antiviral medications to prevent 
cytomegalovirus disease and early death in recipients of solid-organ transplants: a 
systematic review of randomised controlled trials. /DQFHW 365, 2105-15.
Kanj, S., Sharara, A., Clavien, P. and Hamilton, J. 1996. Cytomegalovirus infection following 
liver transplantation: review of the literature. &OLQ,QIHFW'LV 22, 537-49.
Kern, E. R., Hartline, C. B., Rybak, R. J., Drach, J. C., Townsend, L. B., Biron, K. K. and 
Bidanset, D. J. 2004. Activities of benzimidazole D- and L-ribonucleosides in animal 
models of cytomegalovirus infections. $QWLPLFURE$JHQWV&KHPRWKHU 48, 1749-55.
Krosky, P., Baek, M. and Coen, D. 2003. The human cytomegalovirus UL97 protein kinase, an 
antiviral drug target, is required at the stage of nuclear egress. -9LURO 77, 905-14.
Legendre, C. and Pascual, M. 2008. Improving outcomes for solid-organ transplant recipients at 
risk from cytomegalovirus infection: late-onset disease and indirect consequences. &OLQ
,QIHFW'LV 46, 732-40.
Limaye, A. P., Corey, L., Koelle, D. M., Davis, C. L. and Boeckh, M. 2000. Emergence of 
ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ 
transplants. /DQFHW 356, 645-9.
Ljungman, P., Deliliers, G. L., Platzbecker, U., Matthes-Martin, S., Bacigalupo, A., Einsele, H., 
Ullmann, J., Musso, M., Trenschel, R., Ribaud, P., Bornhauser, M., Cesaro, S., Crooks, 
B., Dekker, A., Gratecos, N., Klingebiel, T., Tagliaferri, E., Ullmann, A. J., Wacker, P. 
and Cordonnier, C. 2001. Cidofovir for cytomegalovirus infection and disease in 
allogeneic stem cell transplant recipients. The Infectious Diseases Working Party of the 
European Group for Blood and Marrow Transplantation. %ORRG 97, 388-92.
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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. and Ringden, O. 2006. Risk factors for the 
development of cytomegalovirus disease after allogeneic stem cell transplantation. 
+DHPDWRORJLFD 91, 78-83.
Paya, C., Hermans, P., Wiesner, R., Ludwig, J., Smith, T., Rakela, J. and Krom, R. 1989. 
Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive 
orthotopic liver transplantations. -,QIHFW'LV 160, 752-8.
Pouria, S., State, O. I., Wong, W. and Hendry, B. M. 1998. CMV infection is associated with 
transplant renal artery stenosis. 4MP 91, 185-9.
Razonable, R. R. and Emery, V. C. 2004. Management of CMV infection and disease in 
transplant patients. 27-29 February 2004. +HUSHV 11, 77-86.
Reusser, P., Einsele, H., Lee, J., Volin, L., Rovira, M., Engelhard, D., Finke, J., Cordonnier, C., 
Link, H., Ljungman, P. and 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 
stem cell transplantation. %ORRG 99, 1159-64.
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. and Rubin, R. H. 
1981. Glomerulopathy associated with cytomegalovirus viremia in renal allografts. 1
(QJO-0HG 305, 57-63.
Rubin, R. H. 1989. The indirect effects of cytomegalovirus infection on the outcome of organ 
transplantation. -DPD 261, 3607-9.
Salzberger, B., Bowden, R. A., Hackman, R. C., Davis, C. and Boeckh, M. 1997. Neutropenia in 
allogeneic marrow transplant recipients receiving ganciclovir for prevention of 
cytomegalovirus disease: risk factors and outcome. %ORRG 90, 2502-8.
Singh, N., Wannstedt, C., Keyes, L., Wagener, M. M., de Vera, M., Cacciarelli, T. V. and 
Gayowski, T. 2004. Impact of evolving trends in recipient and donor characteristics on 
cytomegalovirus infection in liver transplant recipients. 7UDQVSODQWDWLRQ 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. and Kern, E. R. 2003. In vitro 
activities of benzimidazole D- and L-ribonucleosides against herpesviruses. $QWLPLFURE
$JHQWV&KHPRWKHU 47, 2186-92.
Winston, D. J., Wirin, D., Shaked, A. and Busuttil, R. W. 1995. Randomised comparison of 
ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-
transplant recipients. /DQFHW 346, 69-74.
Wolf, D., Courcelle, C., Prichard, M. and Mocarski, E. 2001. Distinct and separate roles for 
herpesvirus-conserved 
UL97 
kinase 
in 
cytomegalovirus 
DNA 
synthesis 
and 
encapsidation. 3URF1DWO$FDG6FL86$ 98, 1895-900.
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10. APPENDICES
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
28 Aug 2019
USA
Amendment 1.0 
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USA
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APPENDIX 2
PALATABILITY QUESTIONNAIRE
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APPENDIX 3
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
APPENDIX 3.1 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 3.2 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 
investigational product 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.
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 
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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 3.3 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. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
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).
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 investigational product, containers, and other study materials to 
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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.
The CRA/study monitor will verify the contents of the completed CRF pages against the source 
data. If the data are unclear or contradictory, queries are sent for corrections or verification of
data.
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 
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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 US FDA, 
EMA, UK Medicines and Healthcare Products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
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 investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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 3.4 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, 
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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.
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
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All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the 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; however, their initials and date of birth may 
also be collected, if permitted under local laws governing privacy.
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.
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 
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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 4
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
APPENDIX 4.1 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 
investigational product 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 treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product. 
Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:
•
Results in death
•
Is life-threatening. Note: The term ‘life-threatening’ in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, 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 
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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.
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 Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the 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 RSI. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated form 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
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 
investigational product, 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 investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
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 
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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 4.2 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 investigational product 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 4.3 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 investigational 
product, must be recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, 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.
Relationship Categorization
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A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
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 4.4 SAFETY REPORTING
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
Reporting Procedures
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All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/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 (see Appendix 4.9) unless they result in an 
SAE.
The investigator must complete, sign, and date the Shire “Clinical Study Serious Adverse Event 
for Serious Adverse Events (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 Serious Adverse Events (SAEs) and Non-serious AEs as Required by 
Protocol (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol.
APPENDIX 4.5 SERIOUS ADVERSE EVENT COLLECTION TIME FRAME
All SAEs (regardless of relationship to investigational product) 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/Shire Medical 
Monitor within 24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first becoming aware of the event.
APPENDIX 4.6 SERIOUS ADVERSE EVENT ONSET AND RESOLUTION DATES
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
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 4.7 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.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
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changed” or “not applicable” (if the subject never received investigational product or it is a 
single dose study). The investigational product action of withdrawn should not be selected solely 
as a result of the subject’s death.
APPENDIX 4.8 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/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.
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.
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.
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.
APPENDIX 4.9 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 4.1. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication error s unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.
•
Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
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
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•
Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)
•
Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose
•
Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. Medication errors should be collected/reported for all products under 
investigation. The administration and/or use of the unassigned treatment is/are always reportable 
as a medication error. The administration and/or use of an expired investigational product should 
be considered as a reportable medication error.
APPENDIX 4.10
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 EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 
APPENDIX 4.11
REGULATORY AGENCY, INSTITUTIONAL REVIEW BOARD, 
ETHICS COMMITTEE, AND SITE REPORTING
The sponsor is responsible for notifying the relevant regulatory authorities, institutional review 
boards (IRBs) and ethics committees (ECs) of related, unexpected SAEs.
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In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the TAK620 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.
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT04131556 
Study Title: 
A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose 
Proportionality, and Food Effect Study Comparing the Pharmacokinetics 
and Palatability of Two Candidate Pediatric Powder-for-Oral-Suspension 
Formulations of Maribavir to the Current Maribavir Tablet Formulation 
Administered in Healthy Adult Subjects 
Study Number: 
TAK-620-1019 
SAP Version and Date: 
Version 1.0:  
 
18 Dec 2019 


STATISTICAL ANALYSIS PLAN
TAK620 (SHP620), Maribavir 
PHASE 1 
A Phase 1, Open-label, Randomized, Crossover, Bioavailability, Dose 
Proportionality, and Food Effect Study Comparing the Pharmacokinetics and 
Palatability of Two Candidate Pediatric Powder-for-Oral-Suspension Formulations 
of Maribavir to the Current Maribavir Tablet Formulation Administered in 
Healthy Adult Subjects 
PROTOCOL IDENTIFIER: TAK-620-1019 
Study Sponsor(s): 
Shire Human Genetic Therapies, Inc. (Shire, [and affiliates]); 
Shire is a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited 
300 Shire Way, Lexington, MA 02421 USA 
Author: 
, PPD Statistician 
, PPD Pharmacokineticist 
Protocol: 
Amendment 1 (05 Nov 2019) 
SAP Version #: 
1.0 
SAP Date: 
18 Dec 2019 
Status: 
Final 
For non-commercial use only


Shire  
                                                       CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
1.0 
18Dec2019 
Not applicable 
 
 
 
 
 
 
 
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                                                       CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
TABLE OF CONTENTS 
REVISION HISTORY ......................................................................................................2 
TABLE OF CONTENTS ..................................................................................................3 
ABBREVIATIONS ............................................................................................................6 
1. 
INTRODUCTION..................................................................................................7 
2. 
OBJECTIVES AND ENDPOINTS ......................................................................7 
2.1 
Objectives ............................................................................................................7 
2.1.1 Primary Objectives.......................................................................................7 
2.1.2 Secondary Objective ....................................................................................7 
2.2 
Endpoints ............................................................................................................8 
2.2.1 Pharmacokinetic Endpoints .........................................................................8 
2.2.2 Safety Endpoints ..........................................................................................8 
2.2.3 Palatability Endpoints ..................................................................................8 
3. 
STUDY DESIGN ....................................................................................................9 
3.1 
General Description ............................................................................................9 
3.2 
Randomization ..................................................................................................11 
3.3 
Blinding .............................................................................................................12 
3.4 
Sample Size and Power Considerations ............................................................12 
4. 
STATISTICAL ANALYSIS SETS .....................................................................13 
4.1 
Screened Set ......................................................................................................13 
4.2 
Enrolled Set .......................................................................................................14 
4.3 
Randomized Sets ...............................................................................................14 
4.4 
Safety Sets .........................................................................................................14 
4.5 
Pharmacokinetic Sets ........................................................................................15 
5. 
STUDY SUBJECTS .............................................................................................15 
5.1 
Disposition of Subjects .....................................................................................15 
5.2 
Demographic and Other Baseline Characteristics.............................................15 
5.3 
Medical History .................................................................................................16 
5.4 
Prior Therapies, Procedures, and Medication ...................................................16 
5.5 
Concomitant Therapies, Procedures, and Medications .....................................17 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
5.6 
Exposure to Investigational Product .................................................................17 
5.7 
Treatment Compliance ......................................................................................17 
5.8 
Protocol Deviations ...........................................................................................18 
6. 
EFFICACY ANALYSES ....................................................................................18 
7. 
SAFETY ANALYSIS...........................................................................................18 
7.1 
Adverse Events..................................................................................................18 
7.1.1 Selected Adverse Events ............................................................................20 
7.2 
Clinical Laboratory Data ...................................................................................20 
7.3 
Vital Signs .........................................................................................................23 
7.4 
Electrocardiogram (ECG) .................................................................................24 
7.5 
Palatability ........................................................................................................25 
8. 
PHARMACOKINETIC ANALYSIS .................................................................25 
8.1 
Plasma Pharmacokinetic Concentrations ..........................................................25 
8.2 
Pharmacokinetic Parameters .............................................................................27 
8.3 
Statistical Analysis of Pharmacokinetic Data ...................................................28 
8.3.1 Part 1 ..........................................................................................................28 
8.3.2 Part 2 ..........................................................................................................28 
9. 
PHARMACODYNAMIC ANALYSIS...............................................................29 
10. 
OTHER ANALYSES ...........................................................................................29 
11. 
PLANNED ANALYSIS (INTERIM) AFTER PART 1 ....................................30 
12. 
DATA HANDLING CONVENTIONS ..............................................................30 
12.1 
General Data Reporting Conventions ...............................................................30 
12.2 
Repeated or Unscheduled Assessments of Safety Parameters ..........................31 
12.3 
Handling of Missing, Unused, and Spurious Data ............................................31 
12.3.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..............................................................................31 
12.3.1.1 Incomplete Start Date ..................................................................31 
12.3.1.2 Incomplete Stop Date ..................................................................32 
12.3.2 Missing Date Information for Adverse Events ..........................................33 
12.3.2.1 Incomplete Start Date ..................................................................33 
12.3.2.2 Incomplete Stop Date ..................................................................33 
12.3.3 Missing Severity Assessment for Adverse Events.....................................33 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
12.3.4 Missing Relationship to Investigational Product for Adverse Events .......34 
12.3.5 Character Values of Clinical Laboratory Variables ...................................34 
13. 
ANALYSIS SOFTWARE ...................................................................................34 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................34 
15. 
REFERENCES .....................................................................................................35 
16. 
APPENDICES ......................................................................................................36 
16.1 
Schedule of Activities .......................................................................................36 
 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
ABBREVIATIONS 
AE 
adverse event 
AUC 
area under the curve 
AUC0-inf 
area under the curve from the time of dosing to the last measurable 
concentration 
AUC0-inf%extrap 
percent of AUC0-inf extrapolated 
AUC0-last 
area under the curve from the time of dosing to the last measurable 
concentration 
BLQ 
below limit of quantitation
BMI 
body mass index
CI 
confidence interval
CL/F 
apparent total body clearance following extravascular administration 
Cmax 
maximum concentration occurring at time of maximum observed 
concentration sampled during a dosing interval
CSR 
clinical study report
CV 
coefficient of variation
ECG 
electrocardiogram 
IP 
investigational product 
PCI 
potentially clinically important  
PK 
pharmacokinetic(s)
PT 
Preferred Term 
SD 
standard deviation 
SOC 
System Organ Class 
t1/2 
terminal half-life 
TEAE   
treatment-emergent adverse event 
Tlag 
delay between the time of dosing and time of appearance of plasma 
concentration in the employed sampling scheme
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
 
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                                                       CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
1. 
INTRODUCTION  
This statistical analysis plan provides a technical and detailed elaboration of the statistical 
analyses of pharmacokinetic (PK), palatability, safety, and tolerability data as described 
in the TAK-620-1019 protocol amendment 1 dated 05 Nov 2019. Specifications for 
tables, figures, and listings are contained in a separate document.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objectives 
The primary objectives of Part 1 are: 
x 
To assess the relative bioavailability of 2 candidate pediatric formulations of 
maribavir given as a single oral dose at 200 mg as compared to the Phase 3 adult 
maribavir 200 mg tablet formulation in healthy adult subjects.  
x 
To assess the palatability of two candidate pediatric formulations of maribavir by 
using a questionnaire. 
The primary objectives of Part 2 are: 
x 
To assess the dose proportionality of 50 mg, 100 mg, and 200 mg of the selected 
pediatric formulation of maribavir. 
x 
To assess the impact of food on the rate and extent of absorption of the selected 
pediatric formulation of maribavir given as 200 mg under fasted and fed conditions. 
x 
To assess the palatability of the selected pediatric formulation of maribavir at 
various doses and with food. 
2.1.2 Secondary Objective 
The secondary objective for both Part 1 and Part 2 is: 
x 
To assess the safety and tolerability of 2 candidate pediatric formulations and the 
adult tablet formulation of maribavir given as a single oral dose up to 200 mg in 
healthy adult subjects. 
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Protocol Number: TAK-620-1019 
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2.2 
Endpoints 
2.2.1 Pharmacokinetic Endpoints 
Part 1 (Day 1, Day 4, and Day 7) and Part 2 (Day 1, Day 4, Day 7, and Day 10) 
x 
Time of maximum observed concentration sampled during a dosing interval (tmax) 
x 
Maximum concentration occurring at tmax (Cmax) 
x 
Area under the curve (AUC) from the time of dosing to the last measurable 
concentration (AUC0-last) 
x 
AUC extrapolated to infinity, calculated using the observed value of the last 
non zero concentration (AUC0-inf) 
x 
The percent of AUC0-inf extrapolated, calculated by (1-AUC0-last/AUC0-inf)*100 
(AUC0-inf%extrap) 
x 
Terminal half-life (t1/2) 
x 
Apparent total body clearance following extravascular administration calculated as 
dose divided by AUC0-inf (CL/F) 
x 
Delay between the time of dosing and time of appearance of plasma concentration 
in the employed sampling scheme (Tlag) 
x 
Dose-normalized Cmax (for Part 2 Treatments D, E, and F only, refer to Section 3.1 
for treatment descriptions) 
x 
Dose-normalized AUC0-last (for Part 2 Treatments D, E, and F only, refer to 
Section 3.1 for treatment descriptions) 
x 
Dose-normalized AUC0-inf (for Part 2 Treatments D, E, and F only, refer to 
Section 3.1 for treatment descriptions) 
2.2.2 Safety Endpoints 
Part 1 and Part 2: 
x 
Number, severity, seriousness, and causality of treatment-emergent adverse events 
(TEAEs) 
x 
Changes in vital signs, electrocardiograms (ECGs), and clinical laboratory results 
(hematology, chemistry, and urinalysis) from baseline to post-baseline time points.  
2.2.3 Palatability Endpoints 
Part 1 and Part 2: 
x 
To identify and characterize the sensory attributes of products, eg, basic tastes, 
texture and mouth feel and to assess the overall acceptability. 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
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3. 
STUDY DESIGN   
3.1 
General Description 
The study will be conducted sequentially in 2 parts: 
x 
In Part 1, two pediatric candidate powder formulations will be compared with 
maribavir 200 mg tablet (current Phase 3 formulation) under fasted conditions with 
respect to their bioavailability and palatability, and one formulation will be selected 
for Part 2.  
x 
In Part 2, dose proportionality of 50, 100, and 200 mg dose of the selected pediatric 
powder formulation will be assessed, as well as the impact of food (a high-fat meal) 
on the rate and extent of absorption of the selected pediatric formulation.  
The pediatric formulation which will be assessed in Part 2 will be chosen based on the 
results of planned analysis (interim) of Part 1 PK and palatability data from two candidate 
pediatric formulations. The doses to be evaluated in Part 2 may be adjusted based on 
relative bioavailability of the selected pediatric formulation (powder for oral suspension) 
to the Phase 3 tablet formulation observed in Part 1. The planned analysis (interim) of 
Part 1 is described in Section 11. Final analysis will be performed after Part 2 is 
completed. 
Study design flow charts for Part 1 and Part 2 are presented in Figure 1 and Figure 2, 
respectively. 
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Figure 1: Study Design Flow Chart Part 1 
Screening Period Days -28 through -2
Treatment 
A
Follow-up Phone Call (7±2 days after last dose of maribavir)
Day -1 – Admission to Clinical Study Unit
Treatment 
Period 1
(Day 1)
Treatment 
B
*Washout
 (Day 1 dose 
to Day 4 
dose)
Treatment A: Maribavir 200mg tablet
Treatment B: Maribavir powder for oral suspension, 32.5% drug loading
Treatment C: Maribavir powder for oral suspension, 36.1% drug loading
*NOTE: Treatment will be dependent on randomization sequence.
*NOTE: There will be a drug washout of a minimum of 72 hours and maximum of 73 hours between the administration of maribavir in 
Period 1 (Day 1) and the administration of maribavir in Period 2 (Day 4) and between the administration of maribavir in Period 2 (Day 
4) and the administration of maribavir in Period 3 (Day 7)
Treatment
C
Treatment 
B
Day 8 – Discharge from the Clinical Study Unit
Treatment 
Period 2
(Day 4)
Screening
Treatment 
C
*Washout
 (Day 4 dose 
to Day 7 
dose)
Treatment 
C
Treatment 
Period 3
(Day 7)
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
A
Treatment 
C
Treatment 
B
Treatment 
B
Treatment 
C
Treatment 
A
Treatment 
B
Treatment 
A
Treatment 
C
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Figure 2: Study Design Flow Chart Part 2 
Screening Period Days -28 through -2
Follow-up Phone Call (7±2 daysafter last dose of maribavir) 
Day -1 – Admission to Clinical Pharmacology Unit
Treatment 
Period 1
(Day 1)
Treatment 
E
*Washout
 (Day 1 dose 
to Day 4 
dose)
Treatment D: Maribavir powder for oral suspension (50 mg fasted)*
Treatment E: Maribavir powder for oral suspension (100 mg fasted)*
Treatment F: Maribavir powder for oral suspension (200 mg fasted)*
Treatment G: Maribavir powder for oral suspension (200 mg fed with a high-fat meal)*
*NOTE: Treatment will be dependent on randomization sequence. The doses to be evaluated in Part 2 may be adjusted based on 
relative bioavailability of the selected pediatric formulation (powder for oral suspension) to the Phase 3 tablet formulation 
observed in Part 1.
*NOTE: There will be a drug washout of a minimum of 72 hours and maximum of 73 hours between the administration of 
maribavir in Period 1 (Day 1) and the administration of maribavir in Period 2 (Day 4) between the administration of maribavir in 
Period 2 (Day 4) and the administration of maribavir in Period 3 (Day 7), and  between the administration of maribavir in Period 3 
(Day 7) and the administration of maribavir in Period 4 (Day 10)
Day 11 – Discharge from Clinical Study Unit
Treatment 
Period 2
(Day 4)
Screening
Treatment 
G
*Washout
 (Day 4 dose 
to Day 7 
dose)
Treatment 
G
Treatment 
Period 3
(Day 7)
Treatment 
G
Treatment 
D
Treatment 
F
Treatment 
E
Treatment 
F
Treatment 
D
*Washout
 (Day7 dose 
to Day 10 
dose)
Treatment 
Period 4
(Day 10)
Treatment 
F
Treatment 
E
Treatment 
D
Treatment 
E
Treatment 
G
Treatment 
F
Treatment 
D
3.2
Randomization 
Part 1: 
Subjects who meet all the inclusion criteria and none of the exclusion criteria on the 
morning of Day 1 will be randomized (1:1:1:1:1:1 ratio) to 1 of 6 sequences as shown in 
Table 1. 
Table 1: Treatment Sequence Part 1: N=18 
Sequence number (number of subjects per sequence) 
Treatment Sequence 
1 (n=3) 
ABC 
2 (n=3) 
BCA 
3 (n=3) 
CAB 
4 (n=3) 
CBA 
5 (n=3) 
ACB 
6 (n=3) 
BAC 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
x 
Treatment A: maribavir 200 mg tablet- current Phase 3 formulation 
x 
Treatment B: maribavir 200 mg powder for oral suspension, 32.5% drug loading 
x 
Treatment C: maribavir 200 mg powder for oral suspension, 36.1% drug loading 
Part 2: 
Subjects who meet all the inclusion criteria and none of the exclusion criteria on the 
morning of Day 1 will be randomized (1:1:1:1 ratio) to 1 of 4 sequences as shown in 
Table 2.  
Table 2: Treatment Sequence Part 2: N=20 
Sequence number (number of subjects per sequence) 
Treatment Sequence 
1 (n=5) 
DEGF 
2 (n=5) 
EFDG 
3 (n=5) 
FGED 
4 (n=5) 
GDFE 
 
x 
Treatment D: maribavir powder for oral suspension (50 mg fasted) 
x 
Treatment E: maribavir powder for oral suspension (100 mg fasted) 
x 
Treatment F: maribavir powder for oral suspension (200 mg fasted) 
x 
Treatment G: maribavir powder for oral suspension (200 mg fed with a high-fat 
meal) 
The doses for Treatments D, E, F, and G may be adjusted based on relative 
bioavailability of the selected pediatric formulation (powder for oral suspension) to the 
Phase 3 tablet formulation observed in Part 1. 
There is no stratification for this study for either part. 
3.3 
Blinding  
This is an open-label study. Blinding is not applicable. 
3.4 
Sample Size and Power Considerations 
Sample size calculations were based on the following data: 
x 
The intra-subject coefficient of variation (CV) is assumed at 0.166 and 0.218 
respectively for AUC0-inf and Cmax, which are estimated from the 90% confidence 
intervals (CIs) of the geometric mean ratio of AUC0-inf, and Cmax in 
Study 1263-104. 
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Statistical Analysis Plan v1.0 
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18 Dec 2019 
x 
Sample size estimation is performed using nQuery’s two one sided test of 
equivalence in ratio of mean for crossover design study. 
x 
True mean ratio: 1.00, 1.05 
x 
Power: 80%, 90% 
x 
One-sided α-level: 0.05 (corresponding to 90% CI) 
x 
Bioequivalence range: 0.8-1.25 
Table 3: Number of Subjects Required 
 
 
Intra-subject coefficient of variation 
True Ratio 
Power  
0.166 
0.218 
1.0 
80% 
12 
18 
 
90% 
14 
22 
1.05 
80% 
14 
22 
 
90% 
18 
28 
Note: sample size estimation is performed using nQuery’s two one sided test of equivalence in ratio of 
mean for crossover design study. 
 
Assuming a true mean ratio of 1.0 with intra-subject CV of 0.218, a total of 18 
completers is required to achieve 80% study power to show that the 90% CIs for the 
geometric mean ratios of test formulation/reference formulation lie within the range of 
0.80 to 1.25. 
Therefore, for Part 1, three subjects in each sequence with a total of 18 subjects is 
required to randomize subjects to 1 of 6 sequences in a 1:1:1:1:1:1 treatment allocation. 
For Part 2, five subjects in each sequence with a total of 20 subjects is required to 
randomize subjects to 1 of 4 sequences in 1:1:1:1 treatment allocation. Subjects who 
withdraw early will be replaced and the replacement subject will receive the same 
treatment sequence as the subject being replaced. 
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Screened Set 
The Screened Set consists of all subjects who have signed informed consent form. 
Subjects who were rescreened will be counted once in the Screened Set. 
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18 Dec 2019 
4.2 
Enrolled Set 
The Enrolled Set consists of all subjects who have signed informed consent form and also 
fulfilled the inclusion/exclusion criteria. 
4.3 
Randomized Sets 
Part 1: The Randomized Set 1 consists of all subjects who were randomized to 
a treatment sequence in Part 1.  
Part 2: The Randomized Set 2 consists of all subjects who were randomized to 
a treatment sequence in Part 2. 
For analyses that will be performed using the randomized sets, the randomized treatment 
will be used regardless of the treatment actually received. 
4.4 
Safety Sets   
Part 1: The Safety Set 1 consists of all subjects who received at least 1 dose of maribavir 
in Part 1. 
Part 2: The Safety Set 2 consists of all subjects who received at least 1 dose of maribavir 
in Part 2. 
Part 1 and 2 (Combined): The Total Safety Set includes subjects who received at least 1 
dose of maribavir in either Part 1 or Part 2. 
For analyses that will be performed using the safety sets, the treatment actually received 
will be used. 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
4.5 
Pharmacokinetic Sets  
Part 1: The PK Set 1 consists of subjects who received at least 1 dose of maribavir, did 
not vomit within 4 hours of dosing, and had at least 1 evaluable post-dose maribavir 
concentration value in Part 1. 
Part 2: The PK Set 2 consists of subjects who received at least 1 dose of maribavir, did 
not vomit within 4 hours of dosing, and had at least 1 evaluable post-dose maribavir 
concentration value in Part 2. 
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects included in each statistical analysis set (ie, Randomized, Safety, 
and PK) will be summarized separately for Part 1 and Part 2.  
The reasons for exclusion from the PK sets will be presented in the listings. 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, will be summarized 
separately for Part 1 and Part 2. Discontinuation reason will be specified. All subjects 
who prematurely discontinued the study or discontinued the study drug will be listed 
separately for Part 1 and Part 2. 
Summaries and listing of subject disposition will be based on the randomized sets. 
5.2 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented in 
tables for Part 1 and Part 2 Safety Set as well as PK Set separately. In addition, 
descriptive summaries of demographic and baseline characteristics will be presented in a 
table for the Total Safety Set by dose level regardless of the formulation. Demographics 
and other baseline characteristics data will be listed for Part 1 and Part 2 separately, and 
the listings will be based on the Safety Set for the corresponding part of the study. 
The following demographic characteristics will be summarized in the following order in 
the tables: age (years), sex, race, ethnicity, weight (kg), height (cm), and body mass index 
(BMI, kg/m2).  
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Protocol Number: TAK-620-1019 
18 Dec 2019 
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 as: weight (kg) / (height [m])2. 
Height and weight at the last available measurement prior to first single dose of the 
investigational product (IP) will be used to calculate BMI. 
Age, sex, race, and ethnicity will be summarized based on data obtained at the Screening 
Visit. Weight and height will be summarized from the last available measurement prior to 
the first single dose of IP, and BMI will be calculated.  
5.3 
Medical History 
Medical history will be collected at the Screening Visit and will be coded using MedDRA 
Version 22.1 or newer (version to be delineated in the clinical study report [CSR]). 
Listings will be provided using the safety sets. 
Medical history will be summarized separately for Part 1 and Part 2 by system organ 
class (SOC) and preferred term (PT), based on the Safety Set for the corresponding part. 
The summary of medical history will include the number 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 for each part of the study. 
5.4 
Prior Therapies, Procedures, and Medication  
Prior medications will be coded using the World Health Organization Drug Dictionary 
Global B3 dated September 2019.  
Prior 
medications 
(therapies/procedures) 
are 
defined 
as 
the 
medications 
(therapies/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 classification) and PT will be summarized based on the number 
and proportion of subjects separately for Part 1 and Part 2, based on the Safety Set for the 
corresponding part of the study. Multiple medication usage by a subject in the same 
category will be counted only once. 
All prior therapies, procedures and medications will be listed separately for Part 1 and 
Part 2 based on the Safety Set for the corresponding part of the study. 
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
5.5 
Concomitant Therapies, Procedures, and Medications  
Concomitant medications will be coded using the World Health Organization Drug 
Dictionary Global B3 dated September 2019.  
Medications (therapies/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 date and time 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/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/procedure) and not be considered 
a concomitant medication (therapy/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 treatment and overall separately for Part 1 and Part 2, based 
on the Safety Set for the corresponding part of the study. Multiple medication usage by a 
subject in the same category will be counted only once. 
All concomitant therapies, procedures, and medications will be listed separately for Part 1 
and Part 2 based on the Safety Set for the corresponding part of the study. 
5.6 
Exposure to Investigational Product 
Exposure to IP 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 treatment separately for Part 1 and Part 2 
based on the Safety Set for the corresponding part of the study. 
Listings will be created by subject number and visit presenting the date and time of dose 
administration separately for Part 1 and Part 2 based on the Safety Set for the 
corresponding part of the study. 
5.7 
Treatment Compliance  
Treatment compliance will be summarized in terms of number of subjects who completed 
the drug administration, who fasted 10 hours before study drug administration, and who 
fasted 4 hours after the study drug administration, by treatment separately for Part 1 and 
Part 2 based on the Safety Set for the corresponding part of the study.  
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Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
For Treatment G in Part 2, a high-fat meal is to be consumed within 30 minutes prior to 
maribavir doses. A listing will be created by subject number and visit for meal 
consumption. 
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 
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 and site for each 
treatment and overall separately for Part 1 and Part 2 based on the Safety Set. 
Major/minor protocol deviations will be listed based on the Safety Set separately for 
Part 1 and Part 2. 
6. 
EFFICACY ANALYSES 
Not applicable.  
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the safety sets. Safety variables include AEs, 
clinical laboratory data, vital signs, and ECG data. For clinical laboratory tests, vital 
signs, and ECG data, baseline is defined as the last value collected before the first single 
dose of each treatment.  
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 22.1 or newer (version to be 
delineated in the CSR). 
An AE (classified by PT) that occurs after the first dose of IP, or that worsens in intensity 
or is reported with increased frequency following first dose of IP, will be considered 
a TEAE. If more than 1 AE with the same PT is reported before the date of the first dose 
of IP, then the AE with the greatest severity will be used as the benchmark for 
comparison to the AEs occurring after the first dose of IP under the PT.  
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Statistical Analysis Plan v1.0 
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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 single dose 
of IP 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 IP, and TEAEs leading to discontinuation of 
IP. 
 
The number and percentage of subjects reporting TEAEs, as well as the number of 
events, will be tabulated by SOC and PT; by SOC, PT, and maximum severity. 
Treatment-emergent AEs considered related to IP will also be summarized by SOC and 
PT. If more than 1 AE occurs with the same PT for the same subject, then the subject will 
be counted only once for that PT using the most severe and most related occurrence for 
the summarization by severity and by relationship to IP. Presentation by SOC and PT will 
present SOC sorted alphabetically and PT within SOC by descending order of incidence. 
Treatment-emergent AEs and related TEAEs will be summarized by PT by descending 
order of frequency. Non-serious TEAEs, serious TEAEs, TEAEs leading to 
discontinuation of IP, and TEAEs leading to death, will be summarized by SOC, PT, and 
treatment group.  
Summaries of TEAEs will be presented separately for Part 1 and Part 2 using the 
corresponding Safety Set; additionally, summary of TEAEs will be presented for the 
Total Safety Set by dose level regardless of formulation. 
Duration of an AE is calculated from the event start date time to the event stop date time. 
If both start and stop times are available, duration will be presented in hours with 
1 decimal. If any of the start or end times are unavailable, duration will be presented in 
days as an integer. Listings of AEs will be presented by subject separately for Part 1 and 
Part 2 based on the corresponding Safety Set. 
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Statistical Analysis Plan v1.0 
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18 Dec 2019 
7.1.1 
Selected Adverse Events   
The following AEs (per PT) will be summarized for Part 1 as part of the planned 
(interim) analysis: 
x 
Dysgeusia 
x 
Nausea 
x 
Vomiting 
x 
Diarrhea 
x 
Neutropenia 
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
at each assessment time point for quantitative variables as well as shift tables from 
baseline to each visit for both quantitative and qualitative variables will be presented by 
treatment group separately for Part 1 and Part 2 for the following clinical laboratory 
variables.  
Hematology 
Hemoglobin, hematocrit, red blood cells, platelet count, white blood 
cell count – total and differential, total neutrophils (absolute), 
eosinophils (absolute), monocytes (absolute), basophils (absolute), and 
lymphocytes (absolute). 
Biochemistry 
Sodium, potassium, glucose, urea nitrogen, creatinine, calcium, 
chloride, thyroid stimulating hormone, free T4, follicle-stimulating 
hormone, phosphate, protein, carbon dioxide, albumin, aspartate 
transaminase, alanine transaminase, gamma glutamyl transferase, 
alkaline phosphatase, total bilirubin, uric acid, and beta human 
chorionic gonadotropin. 
Urinalysis 
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte 
esterase, and 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. 
Clinical laboratory test values are potentially clinically important (PCI) if they meet 
either the low or high PCI criteria listed in Table 4. The number and percentage of 
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Statistical Analysis Plan v1.0 
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subjects with post-baseline PCI values will be tabulated by treatment group separately for 
Part 1 and Part 2 based on the corresponding Safety Set; and will be tabulated based on 
the Total Safety Set by dose level regardless of formulation. 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 PCI value. Supportive listings of subjects with post-baseline PCI values 
will be provided including the subject number, site, baseline, and post-baseline values 
separately for Part 1 and Part 2.  
Table 4: Criteria for Potentially Clinical Important Laboratory Tests 
Parameter 
Classification  
Criteria: SI Units (Conventional Units) 
Hematology 
Hemoglobin 
LOW and DECREASE 
<100 g/L (10g/dL) AND 
Decrease of ≥ 20 g/L (2.0 g/dL) from baseline value 
HIGH 
>200 g/L (20g/dL) 
Hematocrit 
LOW and DECREASE 
≤0.6 × LLN AND 
Decrease of ≥0.06 L/L (6.0%) from baseline value 
HIGH 
>1.3 × ULN 
RBC count 
LOW 
<3 × 1012/L 
HIGH 
>7.5 × 1012/L 
Platelets 
(thrombocytes) 
LOW 
<0.6 × LLN OR <100 × 109/L (100 × 103/μL) 
HIGH 
>1.5 × ULN OR >500 × 109/L (500 × 103/μL) 
WBC 
LOW 
<0.5 × LLN OR <3.0 × 109/L (3 × 103/μL) 
HIGH 
>2 × ULN OR >16.0 × 109/L (16 × 103/μL) 
Neutrophils  
LOW 
<1.5 × 109/L (1.5 × 103/μL) OR < 40% 
HIGH 
>6.2 × 109/L (6.2 × 103/μL) OR > 70 % 
Eosinophils  
HIGH 
>0.5 × 109/L (0.5 × 103/μL) OR > 10.0% 
Monocytes 
HIGH 
>1.1 × 109/L (1.1 × 103/μL) OR >11 % 
Basophils 
HIGH 
>0.2 × 109/L (0.2 × 103/μL) OR > 2% 
Lymphocytes 
LOW 
<0.8 × 109/L (0.8 × 103/μL) OR < 22 % 
HIGH 
> 4.0 × 109/L (4.0 × 103/μL) OR > 44 % 
Biochemistry 
Sodium 
LOW 
>5 mmol/L (5 mEq/L) below LLN 
HIGH 
>5 mmol/L (5 mEq/L) above ULN 
Potassium 
LOW and DECREASE 
Below LLN AND  
Decrease of >0.5 mmol/L (0.5 mEq/L) from 
baseline value 
HIGH and INCREASE 
Above ULN AND 
Increase of > 0.5 mmol/L (0.5 mEq/L) from 
baseline value 
Glucose (fasting) 
LOW 
≤4.2 mmol/L 
HIGH 
≥6.7 mmol/L 
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Statistical Analysis Plan v1.0 
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Parameter 
Classification  
Criteria: SI Units (Conventional Units) 
Blood urea nitrogen 
(BUN) 
HIGH 
>1.5 × ULN 
Creatinine 
HIGH and INCREASE 
>150 μmol/L AND 
Increase > 30% from baseline value 
Calcium 
LOW and DECREASE 
Below LLN AND 
Decrease of ≥0.25 mmol/L (1.0 mg/dL) from 
baseline value 
HIGH and INCREASE 
Above ULN AND 
Increase of ≥ 0.25 mmol/L (1.0 mg/dL) from 
baseline value 
Phosphate 
LOW 
>0.162 mmol/L (0.5 mg/dL) below LLN 
HIGH 
>0.162 mmol/L (0.5 mg/dL) above ULN 
Protein 
LOW and DECREASE 
Below LLN AND 
Decrease of ≥20 g/L (2.0 g/dL) from baseline value 
HIGH and INCREASE 
Above ULN AND 
Increase of ≥20 g/L (2.0 g/dL) from baseline value 
Albumin 
LOW and DECREASE 
Below LLN AND 
Decrease of ≥10 g/L (1.0 g/dL) from baseline value 
HIGH and INCREASE 
Above ULN AND 
Increase 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 
>1.5 × ULN 
Uric acid (with normal 
diet) 
LOW and DECREASE 
Below LLN AND 
Decrease of >0.119 mmol/L (2.0 mg/dL) from 
baseline value 
HIGH and INCREASE 
Above ULN AND 
Increase of >0.119 mmol/L (2.0 mg/dL) from 
baseline value 
Thyroid stimulating 
hormone 
LOW 
<0.5 μU/L 
HIGH 
>5.0 μU/L 
Urinalysis 
Urine glucose 
HIGH 
≥1+ 
Urine protein 
HIGH 
≥2+ 
Urine blood 
HIGH 
≥2+ 
Urine ketones 
HIGH 
≥2+ 
Urine bilirubin 
HIGH 
Positive 
Urine nitrites 
HIGH 
Positive 
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Parameter 
Classification  
Criteria: SI Units (Conventional Units) 
Urine leukocyte 
esterase 
HIGH 
Positive 
Abbreviations: LLN=lower limit of normal value provided by the laboratory, RBC=Red Blood Cells, 
ULN=upper limit of normal value provided by the laboratory, WBC=White Blood Cells. 
 
All laboratory data will be listed separately for Part 1 and Part 2 based on the 
corresponding Safety Set. 
7.3 
Vital Signs 
Descriptive statistics for vital signs (eg, systolic and diastolic blood pressure, pulse rate, 
body temperature, and body weight) and their changes from baseline at each 
post-baseline visit and timepoint will be presented by treatment group separately for Part 
1 and Part 2 based on the corresponding Safety Set. 
Vital sign values will be considered PCI if they meet both the observed value criteria and 
the change from baseline criteria listed in Table 5. The number and percentage of 
subjects with PCI post-baseline values will be tabulated by treatment group separately for 
Part 1 and Part 2 based on the corresponding Safety Set; and will be tabulated based on 
the Total Safety Set by dose level regardless of formulation. The percentages will be 
calculated relative to the number of subjects with baseline and at least 1 post-baseline 
assessment. The numerator is the total number of subjects with at least 1 PCI 
post-baseline vital sign value. Supportive listings of subjects with post-baseline PCI 
values will be provided including the subject number, site, baseline, and post-baseline 
PCI values.  
Table 5: Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change 
from 
Baseline 
Value 
Systolic blood pressure 
(mmHg) 
High 
t140 
Increase of t20 
Low 
d90 
Decrease of t20 
Diastolic blood pressure 
(mmHg) 
High 
t90 
Increase of t15 
Low 
d50 
Decrease of t15 
Pulse rate 
(beats per minute) 
High 
t100 
Increase of >15 
Low 
d45 
Decrease of >15 
Temperature (regardless of 
method) 
High 
>38.3°C or >100.9°F 
 
Low 
<35°C or <95°F 
 
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Respiratory rate (breaths/min) 
Low 
<10 
 
High 
>25 
 
Weight (kg) 
High 
- 
Increase of t5% 
Low 
- 
Decrease of t5% 
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 separately for Part 1 and Part 2 based on the 
corresponding Safety Set. 
7.4 
Electrocardiogram (ECG) 
Descriptive statistics for ECG variables (heart rate, RR interval, PR interval, QRS 
interval, QT interval, and QTc intervals) and their changes from baseline at each 
assessment time point will be presented by treatment group. QTc interval will be 
calculated using both Fridericia (QTcF=QT/(RR)1/3) and Bazett (QTcB=QT/(RR)1/2) 
corrections; and if RR is not available, it will be replaced with 60/heart rate in the 
correction formula. Electrocardiogram interpretation will be summarized by visit. A shift 
table from baseline to each visit for qualitative ECG results will be presented. Summaries 
will be presented separately for Part 1 and Part 2 based on the corresponding Safety Set. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the 
upper limit values listed in Table 6. The number and percentage of subjects with 
post-baseline PCI values will be tabulated by treatment group separately for Part 1 and 
Part 2 based on the corresponding Safety Set; and by dose level based on the Total Safety 
Set. The percentages will be calculated relative to the number of subjects with available 
baseline and at least 1 post-baseline assessment. The numerator is the total number of 
subjects with at least 1 PCI post-baseline ECG value. Listings of all subjects with 
post-baseline PCI value will be provided separately for Part 1 and Part 2 including the 
subject number, site, baseline, and post-baseline PCI values. 
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Table 6: 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 separately for Part 1 and Part 2. 
7.5 
Palatability 
A palatability questionnaire will be completed following each dose administration to 
identify and characterize basic tastes, texture, and mouth feel and to assess the overall 
acceptability. 
Palatability data will be summarized by treatment separately for Part 1 and Part 2 based 
on the corresponding Safety Set. 
8. 
PHARMACOKINETIC ANALYSIS  
All summaries and analyses of the PK data will be based on the Pharmacokinetic Set 
defined in Section 4.5.  
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. 
8.1 
Plasma Pharmacokinetic Concentrations 
Blood samples will be drawn from each subject during this study for the determination of 
plasma concentration of maribavir. Serial blood samples will be collected at the 
following time points for each part of the study.  
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Collection of Blood Samples of Maribavir for Pharmacokinetic Analysis in Part 1 
Analyte 
Matrix 
Dosing Day 
Scheduled Time (hours) 
Maribavir 
Plasma 
1 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
 
Plasma 
4 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
 
Plasma 
7 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
 
Collection of Blood Samples of Maribavir for Pharmacokinetic Analysis in Part 2 
Analyte 
Matrix 
Dosing Day 
Scheduled Time (hours) 
Maribavir 
Plasma 
1 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
Plasma 
4 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
Plasma 
7 
Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, and 24 hours 
post dose
Plasma 
10 
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 will be measured using a validated analytical method. 
The following procedures will be used for plasma maribavir concentrations below the 
lower limit of quantification (LLOQ): 
x 
Samples that are below limit of quantification (BLQ) are reported as <LLOQ on the 
data listings, where LLOQ is replaced by the actual value for LLOQ for specific 
PK assay. 
x 
Samples that are BLQ are treated as zero in the calculation of summary statistics 
(eg, mean, SD, etc.) for the plasma concentrations at individual time points. 
Geometric mean will be set to missing where zero values exist. 
x 
Mean concentrations are reported as zero if all values are BLQ or zero, and no 
other descriptive statistics are reported. If the calculated mean (± SD) concentration 
is less than the LLOQ, the value will be reported as calculated. The mean values 
derived using these conventions will be used to create the mean plasma 
concentration versus time plots. 
x 
For calculation of PK parameters, BLQ values prior to the first measurable 
concentration will be set to zero All BLQ values following the first measurable 
concentration will be set to “missing”. 
x 
Missing values will not be imputed. 
For each part, the concentration of maribavir in plasma will be summarized by treatment 
and scheduled sampling time using descriptive statistics (n, arithmetic mean, SD, median, 
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minimum, and maximum). Individual plasma concentration data will be presented in data 
listings by Part and Treatment. 
For each part, individual concentrations of maribavir in plasma will be plotted by actual 
time on linear and semilogarithmic scales for each subject, displaying all treatments. 
Plots of mean maribavir plasma concentrations versus nominal time for all treatments 
will also be provided on linear and semilogarithmic scales for each part of the study.  
8.2 
Pharmacokinetic Parameters 
Pharmacokinetic parameters of plasma maribavir will be determined from the 
concentration-time profiles for all evaluable subjects. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times, 
except for interim PK analysis at the end of Part 1 where normal times will be used to 
allow for quick turnaround on PK data analysis and internal decision-making. The 
following PK parameters will be calculated using non-compartmental analysis using 
Phoenix WinNonlin version 8.0 or higher or SAS version 9.4 or higher (version to be 
delineated in the CSR). The PK parameters for maribavir will include, but may not be 
limited to: 
Part 1 and Part 2 PK Parameters  
Parameter 
Description 
Cmax 
Maximum observed drug concentration
tmax 
Time of maximum observed concentration sampled during a dosing interval
AUC0-last 
AUC from time zero to the last measurable concentration in plasma
AUC0-inf 
AUC from time zero 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-AUC0-last/AUC0-inf) 
*100 
t1/2 
Terminal half-life 
CL/F 
Apparent total body clearance following oral administration, calculated as 
dose divided by AUC0-inf
Tlag 
Delay between the time of dosing and time of appearance of plasma 
concentration in the employed sampling scheme
 
Additional Part 2 PK Parameters  
Parameter 
Description 
Cmax/D* 
Dose-normalized Cmax
AUC0-last/D* 
Dose-normalized AUC0-last
AUC0-inf/D* 
Dose-normalized AUC0-inf
*For Treatments D, E, and F only 
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Descriptive statistics (n, arithmetic mean, SD, median, minimum, maximum, and %CV) 
will be used to summarize the plasma PK parameters for maribavir by treatment for each 
part of the study. In addition, geometric mean, 95% CI of geometric mean and geometric 
CV% will be computed for Cmax, AUC0-last and AUC0-inf Individual plasma PK parameters 
will be presented in a data listing for each part of the study.  
For Part 2, scatter plots of individual plasma maribavir Cmax and AUCs (original and 
dose-normalized) versus dose will be provided.  
8.3 
Statistical Analysis of Pharmacokinetic Data 
8.3.1 Part 1 
Relative bioavailability  
To evaluate the relative bioavailability of test treatment (Treatment B or C) versus 
reference treatment (Treatment A, i.e. current Phase 3 maribavir 200 mg tablet 
formulation), following the natural log-transformation, the PK parameters AUC0-last, 
AUC0-inf, and Cmax will be analyzed using a linear mixed effect model with sequence, 
period, and treatment as fixed effects and subject within sequence as a random effect. 
Point estimates and their associated 90% CIs will be constructed for the differences in the 
log-transformed parameters. The point estimates and their associated 90% CIs will be 
back-transformed to provide point estimates for the ratio of geometric least squares 
means and associated 90% CIs on the original scale. If the 90% CIs of the geometric 
mean ratios for both Cmax and AUCs are within (0.8, 1.25), bioequivalence between the 
two formulations (test powder for oral suspension versus reference tablet) will be 
claimed. A forest plot will be generated to display the relative bioavailability results. 
Statistical analysis of tmax and Tlag will be performed using a nonparametric test. 
The median difference of tmax and Tlag between treatments and 90% CIs of the median 
difference will be calculated from Hodges-Lehman estimate, and p-value will be 
produced from Wilcoxon signed rank test.  
8.3.2 Part 2 
Dose proportionality 
Dose proportionality will be first assessed using the Power Model for (fasted) dose range 
tested in Part 2. The Power Model: log(Yijk)=Si + Pj + βxlog(Dk) + εijk, where D is the 
total number of doses, N are the total number of subjects and P the total number of 
periods and i=1,.….,N, j=1,.…., P and k=1,.….., D. Yijk is the log-transformed response 
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variable, AUC0-inf, AUC0-last, or Cmax on the kth dose, in the jth period, for the ith subject. Si 
is the random subject effect for the ith subject, Pj is the fixed period effect for the jth 
period, β was the slope and εijk is the error. 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 with associated 90% CI in PK parameters when doubling the dose will be 
calculated.  
Additionally, a linear mixed effect analysis of variance model with treatment, period, and 
sequence as fixed effects and subject within sequence as a random effect will be 
performed to fit log-transformed dose-normalized response variable, AUC0-inf/D, 
AUC0-last/D, or Cmax/D, and to estimate all treatment differences and corresponding 
two-sided 90% CIs. The geometric mean ratios and 90% CI for each dose compared to 
the reference dose (50 mg dose) will be provided.  
Food Effect 
In Part 2, food effect will be assessed by comparison of Treatment G (200 mg selected 
maribavir formulation under fed condition) to Treatment F (200 mg selected maribavir 
formulation under fasted condition). The effect of food on maribavir PK parameters will 
be evaluated using an analysis of variance model on the natural log-transformed Cmax, 
AUC0-last, and AUC0-inf with treatment, sequence, and period as fixed effects and subject 
within sequence as a random effect. Point estimates and 90% CIs for geometric mean 
ratios of Cmax, AUC0-last, and AUC0-inf will be computed. If the 90% CIs for the geometric 
mean ratios falls within 0.8 and 1.25 limits, ‘no food effect’ on the exposure will be 
claimed. A forest plot will be generated to display the food effect on maribavir PK 
parameters. 
Analysis of tmax and Tlag will be performed using nonparametric test. The median 
difference in tmax and Tlag between treatments and 90% CIs of the median difference will 
be calculated from Hodges-Lehman estimate, and p- value will be produced from 
Wilcoxon signed rank test. 
9. 
PHARMACODYNAMIC ANALYSIS 
Not applicable. 
10. 
OTHER ANALYSES 
No other analyses are planned for this study. 
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11. 
PLANNED ANALYSIS (INTERIM) AFTER PART 1 
The formulation to be evaluated in Part 2 will be chosen based on the results from the 
Part 1 PK and palatability data from two candidate pediatric formulations. Thus, a 
selected set of analyses will be conducted after Part 1. If the number of replaced 
subject(s) is <=2, then planned analysis (interim) will be conducted based on the 
available Part 1 data without waiting for the replaced subject(s) to complete Part 1. 
Evaluation of Part 1 PK will include performing noncompartmental analysis (NCA) by 
using nominal time to obtain PK parameters listed in Section 8.2. Statistical analysis of 
Part 1 PK parameters will be performed to compare the differences between test 
treatments (Treatment B or C) and reference treatment (Treatment A).  
The disposition, demographics, AEs, SAEs, and selected AEs data will also be reviewed.  
Palatability data from Part 1 will be reviewed. 
Based on the results of the planned analysis of Part 1 data, the specific pediatric 
formulation will be chosen to be assessed in Part 2 of the study.  
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. 
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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. Derived questionnaire scores, and other similar efficacy parameters recorded as 
integers, should be rounded to 1 decimal place for reporting. 
9. Averaged lab results (e.g. diastolic/systolic blood pressure and pulse [when taken in 
triplicate]) should be rounded to 1 decimal place for reporting. 
10. 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 or unscheduled assessments of safety parameters before the start 
of IP, then the results from the final safety assessment made prior to the start of IP will be 
used as baseline. If end of study assessments are repeated or unscheduled, the last post-
baseline assessment will be used as the end of study assessment for generating 
descriptive statistics. However, all post-baseline assessments will be used for PCS value 
determination, and all assessments will be presented in the data listings. 
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. 
12.3.1.1.1 
Missing Day and Month 
x 
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 
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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. 
12.3.1.1.2 
Missing Month Only 
x 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
12.3.1.1.3 
Missing Day Only 
x 
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. 
x 
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. 
x 
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. 
12.3.1.2 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. 
12.3.1.2.1 
Missing Day and Month 
x 
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. 
12.3.1.2.2 
Missing Month Only 
x 
The day will be treated as missing and both month and day will be replaced 
according to the above procedure. 
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12.3.1.2.3 
Missing Day Only 
x 
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. 
x 
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. 
x 
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 12.3.1.2. 
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. 
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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. 
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. 
14.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
The following change is made to this statistical analysis: 
x 
An additional summary for selected AEs (dysgeusia, nausea, vomiting, diarrhea, 
neutropenia) is added to support the planned (interim) analysis after Part 1. 
x 
Planned analysis (interim) is updated as follows: 
The formulation to be evaluated in Part 2 will be chosen based on the results from 
the Part 1 PK and palatability data from two candidate pediatric formulations. 
Thus, a selected set of analyses will be conducted after Part 1. If the number of 
replaced subject(s) is <=2, then planned analysis (interim) will be conducted based 
on the available Part 1 data without waiting for the replaced subjects to complete 
Part 1. 
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15.
REFERENCES
Not applicable 
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16.
APPENDICES
16.1 
Schedule of Activities 
Table 7: Schedule of Assessments Part 1 
Visita 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
Inclusion/exclusion criteria 
X  
X
Demography  
X 
Medical/medication history 
X 
X 
Physical examinationb
X 
X  
X 
X
X 
X 
Randomization
Xk 
Vital signs (blood pressure, 
pulse)b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral temperature 
X 
X 
X 
X 
X 
X 
Height and weightd 
X 
X  
X 
X 
X 
X 
Electrocardiogram (12-lead)b,e
X 
X 
X 
X 
 
X 
X
 
X 
X
Biochemistry, hematology, and 
urinalysisb, f, m 
X 
X 
 
X 
 
X
X 
HIV, HBsAg, and HCV 
antibodies 
X 
Beta HCG Pregnancy test 
(females only)b, g 
X 
X 
X 
FSHh test in perimenopausal 
women
X
Urine drug and alcohol 
screeningi 
X 
X 
Investigational Drug 
Administration 
X
 
X
 
X
Pharmacokinetic blood 
samplingj, n
X 
X 
 
X 
X
 
X 
X
Palatability Assessment 
X 
X 
X 
Admit to the CSU (Day -1) 
X 
Discharge from the CSU (Day 8 
after last assessment) 
 
X
Washout between treatment 
periods 
X 
X 
X 
X 
X 
X
Adverse events/serious adverse 
eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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   18 Dec 2019 
Visita 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Follow-
upl 
Concomitant medicationb
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
E-hCG=beta-human chorionic gonadotropin; CSU-clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating 
hormone 
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. Treatment Period 1 includes 
washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 7 through 8. 
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.  Subjects should be in the appropriate position for at 
least 5 minutes prior to obtaining vital signs. 
d Height will be recorded at the screening visit only. 
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG. 
f Clinical laboratory assessments include serum biochemistry, TSH and FT4, at (screening only), hematology, and urinalysis.  
g Serum β-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time 
points. 
h Females only, to confirm menopausal status. 
i Drugs of abuse and alcohol at screening and Day-1 
j See Table 8, Table 9, and Table 10 for detailed collection time points.  
k Randomization is for Treatment Period 1, Day 1 only. 
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 3 (Day 
7). AEs/SAEs occurring up to the time of the follow-up telephone call will be captured. The follow-up telephone call should be completed for 
all subjects including those who withdraw or are removed from the study prior to Day 8 of Treatment Period 3. 
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1 
n 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 r5 
minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn beyond 4 hours post-dose.  Samples 
drawn outside these parameters will be considered a protocol deviation. 
Page 37
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 8: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 1 
Study Day 
Day 1 
Day 2 
Hour (relative to dosing time) 
Predose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X
Randomizationb
X
Vital signs (blood pressure, pulse) a, c 
Xe 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Oral Temperaturea 
Xe
Weight
Xe
Electrocardiogram (12-lead)a,d 
Xe 
 
 
 
 
 
 
 
X 
X 
Biochemistry, hematology, and 
urinalysisa 
X 
Investigational drug administration 
X 
Pharmacokinetic blood samplingg 
Xe 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xf 
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only. 
c Vital signs will be obtained while subject is in the supine position on study days noted.  Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
f Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn 
beyond 4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
Page 38
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 9: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 1 
Study Day  
Day 4 
Day 5 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
Vital signs (blood pressure, pulse)a, b 
Xd 
X 
X 
Oral Temperaturea 
Xd 
Weight
Xd 
Electrocardiogram (12-lead)a,c
Xd 
X 
X 
Biochemistry, hematology, and 
urinalysisa 
X 
Investigational drug administration 
X 
Pharmacokinetic blood samplingf
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment
Xe 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn 
beyond 4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
Page 39
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 10: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 1 
Study Day 
Day 7 
Day 8 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa
X
X 
Vital signs (blood pressure, pulse)a, b 
Xd 
X 
X 
Electrocardiogram (12-lead)a,c
Xd 
X 
X 
Oral Temperaturea 
Xd 
X 
Weight
Xd 
X 
Biochemistry, hematology, and 
urinalysisa 
X 
Pregnancy (females only)a 
X 
Investigational drug administration 
X 
Pharmacokinetic blood samplingf
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment
Xe 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn 
beyond 4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
Page 40
For non-commercial use only


Shire  
CONFIDENTIAL                                     
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019                                                                                              18 Dec 2019 
Table 11: Schedule of Assessments Part 2 
Visita 
Screening 
Treatment 
Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment 
Period 4 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Randomization 
 
 
Xk 
 
 
 
 
 
 
 
 
 
 
 
High-fat meal prior to 
dose administration 
 
 
Xn 
 
 
Xn 
 
 
Xn 
 
 
Xn 
 
 
Vital signs (blood 
pressure, pulse)b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oral temperature 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Height and weightd 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Electrocardiogram (12-
lead)b,e 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Biochemistry, 
hematology, and 
urinalysisb, f, m 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
HIV, HBsAg, and HCV 
antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (females 
only)b, g 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
FSHh test in perimenopausal 
women 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug and alcohol 
screeningi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Drug 
Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetic blood 
samplingj, o 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Palatability Assessment 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Admit to the CSU (Day -
1) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from the CSU 
(Day 11 after last 
assessment) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Page 41
For non-commercial use only


Shire  
CONFIDENTIAL                                     
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019                                                                                              18 Dec 2019 
Visita 
Screening 
Treatment 
Period 1 
Treatment 
Period 2 
Treatment 
Period 3 
Treatment 
Period 4 
Follow-
upl 
Study Day 
-28 to -2 
-1 
1j 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Washout between 
treatment periods 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse events/serious 
adverse eventsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E-hCG=beta-human chorionic gonadotropin; CSU=clinical study unit; ECG=electrocardiogram; HBsAg=hepatitis B surface antigen; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; PK=pharmacokinetic; SAE=serious adverse event; TSH=thyroid-stimulating 
hormone 
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 3-day washout period between administration of the last dose of 
investigational product in Treatment Period 2 and Treatment Period 3 and between administration of the last dose in Treatment 4. Treatment 
Period 1 includes washout (Days 1 through 3), Treatment Period 2 includes washout (Days 4 through 6), and Treatment Period 3 is from Days 
7 through 9. 
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. Subjects should be in the appropriate position for at 
least 5 minutes prior to obtaining vital signs. 
d Height will be recorded at the screening visit only.  
e Twelve-lead ECGs will be measured in the supine position. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG. 
f Clinical laboratory assessments include serum biochemistry, (TSH and FT4 at screening only), hematology, and urinalysis.  
g Serum β-HCG test at Screening is required for all females. Urine pregnancy test is required for all females at subsequent scheduled time 
points 
h Females only, to confirm menopausal status 
i Drugs of abuse and alcohol at screening, and drugs of abuse and alcohol Day -1.  
j See Table 12, Table 13, Table 14, and Table 15 for detailed collection time points 
k Randomization is for Treatment Period 1, Day 1 only.  
l There will be a follow-up telephone call approximately 7±2 days following the last dose of investigational product in Treatment Period 43 
(Day 10). Adverse events/SAEs occurring up to the time of the follow-up telephone call will be captured. The follow-up telephone call should 
be completed for all subjects including those who withdraw or are removed from the study prior to Day 11 of Treatment Period 4. 
m If screening occurs on Day -2, biochemistry, hematology and urinalysis is not required on Day -1. 
n Subjects in Part 2 will receive maribavir depending on his/her randomized assignment to treatment sequence following an overnight fast of 
at least 10 hours. The study subjects should start the high-fat meal 30 minutes before administration of the drug product. Trial subjects should 
eat this meal in 30 minutes or less and consume 100 percent of the meal. 
o 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 r5 
minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn beyond 4 hours post-dose.  Samples 
drawn outside these parameters will be considered a protocol deviation. 
 
Page 42
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 12: Detailed Schedule of Assessments for Treatment Period 1 (Day 1), Part 2 
Study Day 
Day 1 
Day 2 
Hour (relative to dosing time) 
Predose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
Randomizationb
X
Vital signs (blood pressure, pulse)a, c
Xe 
 
X 
X 
Oral Temperaturea 
X 
Weight
Xe 
Electrocardiogram (12-lead)a,d
Xe
 
X 
X 
Biochemistry, hematology, and 
urinalysisa 
X 
Investigational drug administration 
X 
Pharmacokinetic blood samplingg,
Xe,  h
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment
Xf 
ECG=electrocarodiogram; 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 Randomization will occur in Treatment Period 1, Day 1 only. 
c Vital signs will be obtained while subject is in the supine position on study days noted.  Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 60 minutes prior to dose administration. 
f Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must 
not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn beyond 
4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
h The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration. 
Page 43
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 13: Detailed Schedule of Assessments for Treatment Period 2 (Day 4), Part 2 
Study Day  
Day 4 
Day 5 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Vital signs (blood pressure, pulse)a, b 
Xd 
 
 
 
 
 
X 
 
 
 
 
X 
Oral Temperaturea 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (12-lead)a,c 
Xd 
 
 
 
 
 
X 
 
 
X 
Biochemistry, hematology, and 
urinalysisa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Investigational drug administration 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic blood samplingf 
X d, g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 60 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must 
not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn beyond 
4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration. 
 
 
 
Page 44
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 14: Detailed Schedule of Assessments for Treatment Period 3 (Day 7), Part 2 
Study Day 
Day 7 
Day 8 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examination a 
X 
Vital signs (blood pressure, pulse)a, b 
Xd 
X 
X 
Electrocardiogram (12-lead)a,c
Xd 
X 
X 
Oral Temperaturea 
Xd 
Weight
Xd 
Biochemistry, hematology, and 
urinalysisa 
X 
Investigational drug administration 
X 
Pharmacokinetic blood samplingf
Xd, g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment
Xe 
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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 30 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose. 
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.  Pharmacokinetic blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn 
beyond 4 hours post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration. 
Page 45
For non-commercial use only


Shire  
CONFIDENTIAL 
Statistical Analysis Plan v1.0 
Protocol Number: TAK-620-1019 
18 Dec 2019 
Table 15: Detailed Schedule of Assessments for Treatment Period 4 (Day 10), Part 2 
Study Day 
Day 10 
Day 11 
Hour (relative to dosing time) 
Pre-dose 
0 
0.08 
0.25 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
Physical examinationa 
X 
X 
Vital signs (blood pressure, pulse)a, b
Xd 
X 
X 
Electrocardiogram (12-lead)a,c
Xd 
X 
X 
Oral Temperaturea 
Xd 
X 
Weight
Xd 
X 
Biochemistry, hematology, and urinalysisa 
X 
Pregnancy (females only)a 
X 
Investigational drug administration 
X 
Pharmacokinetic blood sampling f
Xd, g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Palatability Assessment
Xe 
ECG=electrocarodiogram; 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. Subjects should be in the appropriate position for at least 5 minutes prior to obtaining vital signs. 
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 These assessments should be performed within 60 minutes prior to dose administration. 
e Palatability questionnaire should be given within 5 minutes of receiving dose 
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.  Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than r5 minutes from samples drawn within 4 hours post-dose or by more than r15 minutes for samples drawn beyond 4 hours 
post-dose.  Samples drawn outside these parameters will be considered a protocol deviation. 
g The pre-dose PK sample for subjects on Treatment G should be collected after the high-fat breakfast and before dose administration. 
Page 46
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