Clinical trial NCT02541669
Conditions: Healthy Volunteer
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-11-20; Completion date: 2017-03-17
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the pharmacokinetics and safety of single- and multiple-dose of TAK-491 in healthy Chinese participants.

Detailed description:
The drug being tested in this study is called TAK-491. TAK-491 is being tested to treat people who have hypertension. This study will look at the pharmacokinetics of TAK-491 in Chinese participants who take TAK-491.

The study will enroll approximately 64 participants.

The first 16 enrolled participants have been randomly assigned (by chance, like flipping a coin) to 1 of the 2 treatment groups:

* TAK-491 40 mg
* TAK-491 80 mg

All participants will be asked to take 1 tablet at the same time on Day 1 and Day 4 to 10 during the study.

The following 48 randomized participants will be randomly assigned (by chance, like flipping a coin) to 1 of the 3 treatment groups:

* TAK-491 40 mg
* TAK-491 80 mg
* TAK-491 placebo

All participants will be asked to take two tablets at the same time on Day 1 and Day 4 to 10 during the study.

This single-center trial will be conducted in China. The overall time to participate in this study is approximately 52 days. Participants will be admitted in the clinic for the first 12 days, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-491 40 milligram (mg), tablet, orally, once daily on Day 1 and Days 4 to 10 as an open-label treatment. arm 2: TAK-491 80 mg, tablet, orally, once daily on Day 1 and Days 4 to 10 as an open-label treatment. arm 3: TAK-491 40 mg, tablet, orally, once daily and TAK-491 80 mg placebo-matching tablet, orally, once daily on Day 1 and Days 4 to 10 in double-blind manner. arm 4: TAK-491 80 mg, tablet, orally, once daily and TAK-491 40 mg placebo-matching tablet, orally, once daily on Day 1 and Days 4 to 10 in double-blind manner. arm 5: TAK-491 40 mg placebo-matching tablet, orally, once daily and TAK-491 80 mg placebo-matching tablet, orally, once daily on Day 1 and Days 4 to 10.
Interventions: intervention 1: TAK-491 intervention 2: TAK-491 placebo
Intervention descriptions: intervention 1: TAK-491 tablets intervention 2: TAK-491 placebo-matching tablets

Protocol documents:
Prot_000.pdf: 


•
Title: A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single- and Multiple-
Dose, Phase 1 Study of the Pharmacokinetics of TAK-491 40 mg and 80 mg in Healthy Chinese 
Subjects
NCT Number: NCT02541669
Protocol Approve Date: 05 August 2016
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PHASE 1 PROTOCOL
A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single- and 
Multiple-Dose, Phase 1 Study of the Pharmacokinetics of TAK-491 40 mg and 80 mg in 
Healthy Chinese Subjects
Pharmacokinetic Study of TAK-491 in Healthy Chinese Subjects
Sponsor:
Takeda Development Center Asia, Pte. Ltd.
21 Biopolis Road, Nucleos North Tower,
Level 4, Singapore 138567
Study Number:
TAK-491_112
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
TAK-491
Date:
05 August 2016
Amendment Number: 04
Amendment History: 
Date
Amendment Number
Amendment Type
Region
27 April 2011
Initial Protocol
Not applicable
China
25 March 2013
1
Substantial
China
30 January 2014
2
Substantial
China
18 March 2016
3
Substantial
China
05 August 2016
4
Substantial
China
CONFIDENTIAROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided.
Takeda sponsored European and Asian Pacific investigators will be provided with emergency 
medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Issue
Contact
Serious adverse event and pregnancy reporting
Medical Monitor (medical advice on protocol, compound, and 
medical management of subjects)
Responsible Medical Officer (carries overall responsibility for 
the conduct of the study)
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonization E6 Good Clinical Practice Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
Electronic signatures of the Responsible Medical Officer and other signatories are located on the 
last page of this document.
PPD


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being of 
study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B - Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State)
Location of Facility (Country)


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1.3
Protocol Amendment No. 4 Summary of Changes
This document describes the changes in reference to Protocol Amendment No. 3 dated 18 March 
2016.
The primary purpose of this amendment was to add collection of plasma for pharmacokinetic 
sampling after Day 10, diet requirement update, and independent liver safety review. Full details 
on changes of text are given in Appendix F including detailed rationale. The following is a 
summary of the changes made in the amendment:

The fat content of the diet of healthy volunteers during their hospital confinement was
modified in Section 7.4.
Justification: To align the protocol with Ethic Committee’s comments.

The collection of plasma for pharmacokinetic sampling was added in Section 9.1.12.1.
Justification: To align the protocol with Ethic Committee’s comments.

The independent liver safety monitoring process was added in Section 11.0.
Justification: To align the protocol with Ethic Committee’s comments.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 4 Summary of Changes .....................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator...............................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.2
Summary of Nonclinical Data..................................................................................18
4.3
Summary of Relevant Clinical Studies.....................................................................19
4.4
Rationale for the Study ............................................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective .......................................................................................21
5.1.2
Secondary Objectives..................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoints.......................................................................................21
5.2.2
Additional Endpoints ..................................................................................21
5.2.3
Safety Endpoints.........................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Justification for Study Design, Dose, and Endpoints ................................................24
6.3
Premature Termination or Suspension of Study or Investigational Site.....................25
6.3.1
Criteria for Premature Termination or Suspension of the Study...................25
6.3.2
Criteria for Premature Termination or Suspension of Investigational Site....25
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site.............................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................26


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7.3
Excluded Medications and Dietary Products ............................................................28
7.4
Diet, Fluid, and Activity Control, and Subject Housing............................................28
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................29
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................30
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................31
8.1
Study Medication and Materials...............................................................................31
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................31
8.1.2
Storage........................................................................................................31
8.1.3
Dose and Regimen ......................................................................................32
8.1.4
Overdose.....................................................................................................32
8.2
Study Medication Assignment and Dispensing Procedures.......................................33
8.3
Randomization Code Creation and Storage..............................................................33
8.4
Investigational Drug Blind Maintenance ..................................................................33
8.5
Unblinding Procedure..............................................................................................33
8.6
Accountability and Destruction of All Study Medication .........................................34
9.0
STUDY PLAN ..............................................................................................................36
9.1
Study Procedures.....................................................................................................36
9.1.1
Informed Consent Procedure.......................................................................36
9.1.2
Demographics, Medical History, and Medication History Procedure...........36
9.1.3
Physical Examination Procedure .................................................................36
9.1.4
Weight, Height, and BMI............................................................................37
9.1.5
Vital Sign Procedure ...................................................................................37
9.1.6
Documentation of Concomitant Medications...............................................37
9.1.7
Documentation of Concurrent Medical Conditions......................................37
9.1.8
Procedures for Clinical Laboratory Samples................................................37
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................39
9.1.10
Pregnancy ...................................................................................................40
9.1.11
ECG Procedure ...........................................................................................40
9.1.12
Pharmacokinetic Sample Collection ............................................................41
9.1.12.1
Collection of Plasma for Pharmacokinetic Sampling...............................41
9.1.12.2
Collection of Urine for Pharmacokinetic Sampling.................................41
9.1.12.3
Bioanalytical Methods............................................................................42
9.1.13
Pharmacokinetic Parameters........................................................................42
9.1.14
Documentation of Screen Failure ................................................................43
9.1.15
Documentation of Study Entrance/Randomization ......................................43


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9.2
Monitoring Subject Treatment Compliance..............................................................43
9.3
Schedule of Observations and Procedures................................................................43
9.3.1
Screening ....................................................................................................43
9.3.2
Day -1 (Check-in) .......................................................................................44
9.3.3
Day 1: Study Entrance.................................................................................45
9.3.4
Days 2 and 3 ...............................................................................................45
9.3.5
Day 4 ..........................................................................................................45
9.3.6
Days 5 and 6 ...............................................................................................45
9.3.7
Days 7 through 10.......................................................................................46
9.3.8
Day 11 ........................................................................................................46
9.3.9
Days 12 through 13.....................................................................................46
9.3.10
Day 14: F/U Visit........................................................................................47
9.3.11
Early Termination .......................................................................................47
9.3.12
Follow-up Telephone Call...........................................................................47
9.4
Blood Volume .........................................................................................................47
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................49
10.1
Definitions...............................................................................................................49
10.1.1
PTEs...........................................................................................................49
10.1.2
AEs.............................................................................................................49
10.1.3
Additional Points to Consider for PTEs and AEs.........................................49
10.1.4
SAEs...........................................................................................................51
10.1.5
Severity of PTEs and AEs ...........................................................................52
10.1.6
Causality of AEs .........................................................................................52
10.1.7
Relationship to Study Procedures................................................................52
10.1.8
Start Date....................................................................................................53
10.1.9
Stop Date ....................................................................................................53
10.1.10
Frequency ...................................................................................................53
10.1.11
Action Concerning Study Medication..........................................................53
10.1.12
Outcome .....................................................................................................53
10.2
Procedures...............................................................................................................54
10.2.1
Collection and Reporting of AEs.................................................................54
10.2.1.1
PTE and AE Collection Period ...............................................................54
10.2.1.2
PTE and AE Reporting ...........................................................................54
10.2.2
Collection and Reporting of SAEs...............................................................55
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................55


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10.3
Follow-up of SAEs ..................................................................................................55
10.3.1
Safety Reporting of SAEs ...........................................................................55
10.3.2
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................56
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................57
12.0
DATA HANDLING AND RECORDKEEPING............................................................58
12.1
(e)CRFs ...................................................................................................................58
12.2
Record Retention .....................................................................................................58
13.0
STATISTICAL METHODS..........................................................................................60
13.1
Statistical and Analytical Plans ................................................................................60
13.1.1
Analysis Sets...............................................................................................60
13.1.1.1
Safety Set ...............................................................................................60
13.1.1.2
Pharmacokinetic Set ...............................................................................60
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................60
13.1.3
Pharmacokinetic Analysis ...........................................................................60
13.1.4
Safety Analysis ...........................................................................................61
13.2
Interim Analysis and Criteria for Early Termination ................................................62
13.3
Determination of Sample Size..................................................................................62
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................63
14.1
Study-Site Monitoring Visits ...................................................................................63
14.2
Protocol Deviations..................................................................................................63
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................64
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................65
15.1
IRB and/or IEC Approval ........................................................................................65
15.2
Subject Information, Informed Consent, and Subject Authorization .........................65
15.3
Subject Confidentiality ............................................................................................67
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................67
15.4.1
Publication and Disclosure..........................................................................67
15.4.2
Clinical Trial Registration...........................................................................67
15.4.3
Clinical Trial Results Disclosure .................................................................68
15.5
Insurance and Compensation for Injury....................................................................68
16.0
REFERENCES..............................................................................................................69
LIST OF IN-TEXT TABLES
Table 6.a
Open-Label Study Regimen and Subject Allocation...........................................23


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Table 6.b
Double-Blind Study Regimen and Subject Allocation ........................................23
Table 7.a
Prohibited Medications, Foods, and Supplements...............................................28
Table 8.a
Study Medication Supplies.................................................................................32
Table 9.a
Clinical Laboratory Tests...................................................................................38
Table 9.b
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis ...............41
Table 9.c
Collection of Urine Samples for Pharmacokinetic Analysis................................41
Table 9.d
Approximate Blood Volume ..............................................................................47
Table 10.a
Takeda Medically Significant AE List................................................................52
Table 16.a
Windows for Pharmacokinetic Sample Collection..............................................63
Table 18.a
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis ...............83
Table 18.b
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis ...............83
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................24
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................70
Appendix B
Responsibilities of the Investigator.....................................................................72
Appendix C
Elements of the Subject Informed Consent.........................................................74
Appendix D
Investigator Consent to Use Personal Information..............................................77
Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples..............................78
Appendix F
Detailed Description of Amendments to Text.....................................................81


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Asia, Pte. Ltd.
Compound:
TAK-491
Title of Protocol: A Randomized, Open-Label and 
Double-Blind, Placebo-Controlled, Single- and 
Multiple-Dose, Phase 1 Study of the Pharmacokinetics of 
TAK-491 40 mg and 80 mg in Healthy Chinese Subjects
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: TAK-491_112
Phase: 1
Study Design:
This is a randomized, open-label and double-blind, placebo-controlled, single- and multiple-dose, phase 1 study 
involving 64 healthy Chinese subjects aged 18 to 45 years, inclusive, and considered eligible based on the inclusion 
and exclusion entry criteria. Subjects will receive TAK-491 or placebo as a single dose followed by multiple doses.
Sixteen subjects were allocated equally and randomly to 1 of 2 TAK-491 regimens (40 mg or 80 mg) in the open-label 
part of the study; the 2 regimens were conducted in parallel.
Open-Label Part
Regimen
Regimen Description
Number of Subjects
A
TAK-491 40 mg as a single dose followed by multiple doses
8
B
TAK-491 80 mg as a single dose followed by multiple doses
8 
Forty-eight subjects will be allocated equally and randomly to 1 of 3 regimens (TAK-491 40 mg or 80 mg, or placebo) 
in the double-blind part of the study; the 3 regimens will be conducted in parallel. To maintain the study blind, subjects 
in this part of the study will receive a least 1 placebo tablet; the TAK-491 40 mg and TAK-491 80 mg tablets differ in 
size; therefore, placebo tablets for each size will be utilized as appropriate.
Double-Blind Part
Regime
n
Regimen Description
Number of Subjects
A
TAK-491 40 mg + placebo as a single dose followed by multiple doses
16 
B
TAK-491 80 mg + placebo as a single dose followed by multiple doses
16 
C
Placebo (2 tablets) as a single dose followed by multiple doses
16 
The pre-dosing study period will consist of a Screening Period (Study Days -28 to -2) and Check-in (Study Day -1). 
On Day 1, a single dose of TAK-491 or placebo will be administered followed by a pharmacokinetic sampling period 
through 72 hours postdose (Days 1-4). On Days 4 through 10, subjects will be on a daily dosing regimen, followed by 
a 24-hour pharmacokinetic assessment period prior to Study Exit (Day 11). The total confinement period for a subject 
who completes the study will be 12 days. All subjects will return to the site for PK sampling on Days 12-13 and 
follow-up serum chemistry tests on Day 14. A Follow-up telephone call will be made by the site at 14 (±2) days 
following the last dose of study medication (Day 24 [± 2 days]) to inquire for any ongoing adverse events or serious 
adverse events (SAEs), new adverse events or SAEs, and concomitant medications taken since the final dose of study 
medication or Early Termination Visit.


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Screening
Check-in
Dosing 
and PK
72-hr 
PK
Dosing 
(a)
Dosing 
and AM 
Trough 
Level (b)
Dosing 
and 
24-hr 
PK
Study 
Exit
PK 
collect
ion
F/U
Visi
t (c)
F/U Call
Days -28 
to -2
Day -1
Day 1
Days 2-4
Day 4
Days 5-9
Day 10
Day 11
Days
12-13
Day 
14
Day 24
(± 2)
Confinement 
PK=pharmacokinetics.
(a) Dosing will occur after the collection of the 72-hr pharmacokinetic sample.
(b) PK trough samples will be collected on Days 7 to 9.
(c) Serum chemistry testing.
Primary Objective:
To assess the pharmacokinetics of TAK-491 40 mg and 80 mg in healthy Chinese subjects after both single and 
multiple dose administration.
Secondary Objectives:
To evaluate the safety and tolerability of TAK-491 40 mg and 80 mg in healthy Chinese subjects after both single and 
multiple dose administration.
Subject Population: Healthy male and female subjects aged 18-45 years, inclusive. 
Number of Subjects:
Estimated total: 64
Number of Sites:
1 site in China
Dose Levels:
TAK-491 40 mg
TAK-491 80 mg
Matched placebos
Route of Administration:
oral
Duration of Treatment:
Single dose with sample collection followed with 7 days of 
daily dosing and sample collection.
Period of Evaluation:
Approximately 52 days (including Screening, Day -1 
through Study Exit and Follow-up telephone call).
Main Criteria for Inclusion:
Healthy male or non-pregnant, non-lactating female subjects of Chinese descent who are 18 to 45 years of age, 
inclusive, at signing of the informed consent form and first study medication dose. In addition, the subjects must be 
willing and able to comply with the protocol requirements, must be able to understand and sign a written informed 
consent form prior to the initiation of any study procedures, have a body mass index between ≥19.0 kg/m2 and 
<24.0 kg/m2; and must have clinical laboratory results within reference range unless the investigator deems the results 
not to be clinically significant.
Main Criteria for Exclusion:
The subject has a known hypersensitivity or allergy to any angiotensin type II receptor blocker or to any of the 
excipients in the TAK-491 formulation to be taken. Subjects will also be excluded if they are unwilling or unable to 
comply with the protocol or if they use any excluded medications, supplements, or food products outlined in the 
protocol. The subject has a systolic blood pressure <110 and ≥160 mm Hg or a diastolic blood pressure of <60 and 
≥100 mm Hg. Additionally, subjects will be excluded if they have abnormal Screening or Day -1 laboratory values 
that suggest a clinically significant underlying disease or have the following laboratory abnormalities: alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST) that exceeds >1.5the upper limit of normal, 
hemoglobin value <12 g/dL, or who has positive anti-HIV, anti-HCV, or positive HBsAg test results at Screening.


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Main Criteria for Evaluation and Analyses:
Pharmacokinetics:
Plasma pharmacokinetic parameters to be calculated for TAK-536 (the active moiety): area under the 
concentration-time curve from time 0 to 24 hours (AUC24), area under the concentration-time curve from time 0 to the 
last quantifiable concentration (AUClast) (after single dose only), area under the concentration-time curve from time 0 
to infinity (AUC) (after single dose only), average concentration during a dosing interval, at steady state (Cav,ss) (after 
multiple dose only), maximum observed concentration (Cmax), minimum observed concentration during a dosing 
interval (Cmin) (after multiple dose only), observed concentration at the end of a dosing interval (Ctrough) (after multiple 
dose only), apparent clearance after extravascular administration (CL/F) (after single dose only), terminal disposition 
phase rate constant (λz) (after single dose only), terminal disposition phase half-life (t1/2z) (after single dose only), time 
of first occurrence of Cmax (tmax), and apparent volume of distribution during the terminal disposition phase after 
extravascular administration (Vz/F) (after single dose only).
Urine pharmacokinetic parameters to be calculated for TAK-536: amount of drug excreted in urine (Ae24, Ae72 [after 
single dose only], Ae0-2, Ae2-4, Ae4-8, Ae8-12, Ae12-24, Ae24-48 [after single dose only], Ae48-72 [after single dose only]), 
renal clearance (CLR), and fraction of administered dose of drug excreted in urine during a dosing interval (fe24 andfe72) 
(fe72 after single dose only).
Safety and Tolerability:
Safety and tolerability assessment will include physical examination findings, vital signs, 12-lead electrocardiogram 
(ECG) results, laboratory evaluations (hematology, serum chemistry, and urinalysis), and adverse events (AEs).
Statistical Considerations:
Pharmacokinetic Measures:
Concentrations of TAK-536 in plasma will be summarized by regimen over each scheduled sampling time using 
descriptive statistics for the open-label and double-blind parts separately and overall.
The amount of TAK-536 excreted in urine will be summarized by regimen over each scheduled sampling interval 
using descriptive statistics for each part separately and overall.
Plasma and urine PK parameters of TAK-536 will be summarized by regimen using descriptive statistics for each part 
separately and overall.
Safety:
AEs will be presented in the listings, and TEAEs will be summarized. Clinical laboratory variables, vital sign, and 
ECG parameters will be summarized with descriptive statistics for Baseline, postdose, and change from Baseline to 
postdose values. The percentage of subjects with at least 1 postdose laboratory variable, vital sign, and ECG parameter 
that meet Takeda’s predefined criteria will be summarized. Physical examination findings will be presented in the data 
listings. All summaries will be performed by regimen for each part separately and overall. 
Sample Size Justification:
A total sample size of 64 subjects will be enrolled in this study. Sixteen subjects, 8 per regimen (TAK-491 40 mg and 
80 mg) were randomized to the open-label part of the study. Forty-eight subjects, 16 per regimen (TAK-491 40 mg, 80 
mg, and placebo) will be randomized to the double-blind part of the study. The sample size is considered sufficient for 
evaluation of safety, tolerability, and PK of each part of the study, and was not based on statistical power 
considerations. 


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
PPD


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3.3
List of Abbreviations
z
terminal disposition phase rate constant
%CV
percent coefficient of variation
ACE
angiotensin-converting enzyme
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t
Aet1-t2
amount of drug excreted in urine from time 1 to time 2
AII
angiotensin II
ALT
alanine aminotransferase
ARB
AT1 receptor blockers
AT1
angiotensin II type 1
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC
area under the concentration-time curve from time 0 to infinity, calculated using the observed value 
of the last quantifiable concentration
AUClast
area under the concentration-time curve from 0 to time of the last quantifiable concentration
BMI
body mass index
bpm
beats per minute
Cav,ss
average concentration during a dosing interval, at steady state
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
apparent clearance after extravascular administration, calculated using the observed value of the last 
quantifiable concentration
CLR
renal clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration during a dosing interval
CMV
cytomegalovirus
CRF
case report form
CRO
Contract Research Organization
CS
clinically significant
Ctrough
observed concentration at the end of a dosing interval
CYP
cytochrome P-450
EBV VCA
Epstein-Barr virus viral capsid antigen
ECG
electrocardiogram
(e)CRF
electronic case report form
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
fet
fraction of administered dose of drug excreted in urine from time 0 to time t


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FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
HBcAb
hepatitis B core antibody
HBeAb
hepatitis B envelope antibody
HBeAg
hepatitis B envelope antigen
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
K2EDTA
potassium ethylenediamine tetraacetic acid
LDL-C
low-density lipoprotein cholesterol
MedDRA
Medical Dictionary for Regulatory Activities
NCS
not clinically significant
PK
pharmacokinetic(s)
PTE
pretreatment event
RAAS
renin-angiotensin-aldosterone system
RCF
relative centrifugal force
SAE
serious adverse event
SAP
statistical analysis plan
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
TAK-491
azilsartan medoxomil
TAK-491F
salt free form of TAK-491
TAK-536
azilsartan
TAK-536 M-I
metabolite of TAK-536
TAK-536 M-II
metabolite of TAK-536
TEAE
treatment emergent adverse event
tmax
time of first occurrence of Cmax
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration
WHO
World Health Organization


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3.4
Corporate Identification
TDC (Asia)
Takeda Development Center Asia Pte. Ltd.
TDC (EU)
Takeda Development Centre Europe Ltd.
TDC (US)
Takeda Development Center Americas, Inc.
TDC
TDC Asia, TDC Europe, and/or TDC Americas, as applicable
TPC
Takeda Pharmaceutical Company Limited
Takeda
TDC Asia, TDC Americas, TDC Europe, and/or TPC, as applicable


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4.0
INTRODUCTION
4.1
Background
A major component of blood pressure regulation is the renin-angiotensin-aldosterone system 
(RAAS), a system of hormone-mediated feedback interactions that results in the relaxation or 
constriction of blood vessels in response to various stimuli. Angiotensin II (AII), a polypeptide 
hormone, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme 
(ACE) as part of the RAAS. AII is the principal pressor agent of the RAAS with a myriad of effects 
on the cardiovascular system and on electrolyte homeostasis [1]. Two receptors for AII have been 
identified. Angiotensin II type 1 (AT1) receptors are located predominantly in vascular smooth 
muscle, where activation by AII results in vasoconstriction, hypertrophic proliferation, and 
inflammation. In contrast, stimulation of angiotensin II type 2 receptors by AII results in 
vasodilation, antiproliferative effects, and other effects that are opposite from those of AT1 
receptor stimulation [2].
Drugs that modulate the RAAS are used commonly worldwide for the treatment of hypertension. 
Of these, some block the synthesis of AII by inhibiting ACE (ACE inhibitors), while others (AT1 
receptor blockers [ARBs]) inhibit the action of AII by binding directly to the AT1 receptor, 
thereby allowing blood vessels to dilate, resulting in a reduction in blood pressure [3]. The effects 
of ARBs on other conditions in which the RAAS plays an important role, such as congestive heart 
failure, postmyocardial infarction management, and diabetic nephropathy, have also been 
investigated. ARBs are generally considered to be more tolerable than other classes of 
antihypertensive agents and are often used to treat hypertension in patients who are intolerant to
ACE inhibitors [4]. Cough and angioedema occur less frequently with ARBs than with ACE 
inhibitors, and common side effects such as symptomatic hypotension, flushing, tachycardia, 
palpitations, and dizziness, along with headache and lightheadedness, are generally mild and well 
tolerated [5].
There is still a need for compounds that improve tolerability and efficacy for the treatment of 
hypertension; therefore, azilsartan medoxomil, or TAK-491, a prodrug that is rapidly hydrolyzed 
to the active moiety, azilsartan, or TAK-536, which is a highly potent, long-acting ARB is being 
evaluated by Takeda to treat subjects with essential hypertension.
4.2
Summary of Nonclinical Data
Nonclinical studies have indicated that TAK-491 reduces blood pressure after single or multiple 
daily dosing without tachycardia and without rebound hypertension after the withdrawal of 
treatment. TAK-491 also demonstrated antiproteinuric effects in Wistar fatty rats with overt 
nephropathy and increased insulin sensitivity in spontaneously hypertensive rats. TAK-491 is not 
expected to have any untoward effects on the central nervous system or respiratory system. Its 
effect on the cardiovascular system in conscious dogs was limited to a reduction in systolic blood 
pressure, an observation consistent with the pharmacodynamic profile of the compound.
Please refer to the TAK-491 Global Investigator’s Brochure for additional information [6].


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4.3
Summary of Relevant Clinical Studies
TAK-491 is rapidly hydrolyzed to TAK-536, with no detectable TAK-491F (salt free form of 
TAK-491) plasma concentrations following doses of up to 320 mg for 7 days. TAK-536 undergoes 
extensive metabolism to TAK-536 M-I and M-II, the latter mainly by CYP2C9. Following both 
single and multiple dosing, dose proportionality was established for TAK-536 and M-II area under 
the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) 
values over the TAK-491 dose range of 20 mg to 320 mg. Approximately 15% of the TAK-491 
dose is excreted as TAK-536 in urine.
Plasma exposure to TAK-536 following single doses of TAK-536 tablet and TAK-491 tablet 
under fasting conditions suggest that an equivalent dose of TAK-491 is approximately twice that 
of TAK-536 on a mg:mg basis. Administration of TAK-491 tablets with a high fat meal has no 
clinically significant effect on plasma exposure.
Several drug-drug interaction studies have been conducted with TAK-536, including warfarin, 
glyburide, pioglitazone, metformin fluconazole, and ketoconazole; no clinically meaningful 
interactions were observed. Since TAK-491 is rapidly converted to TAK-536, it is not expected 
that coadministration of TAK-491 and these agents will result in any drug-drug interaction. An 
additional TAK-491 study with a cocktail of cytochrome P-450 (CYP) probes did not indicate the 
potential for drug-drug interactions with drugs metabolized by CYP3A4, CYP2C9, CYP2D6, or 
CYP1A2.
Administration of single doses of TAK-491 from 5 mg to 320 mg and of multiple doses from 
20 mg to 320 mg was well tolerated in phase 1 studies. Adverse events (AEs) tended to be mild in 
intensity in these studies and no dose-related increase in the overall incidence of AEs was 
observed. In a study of age, gender, and race, no interactions based on these subject characteristics 
were observed. AEs with the greatest incidence that were considered to be related to TAK-491 in 
the phase 1 studies were dizziness and headache.
Steady-state total exposures to TAK-536 after multiple doses of TAK-491 in a phase 1 hepatic 
impairment study were approximately 28% and 64% greater in subjects with mild and moderate 
hepatic impairment, respectively, than in healthy subjects. These increases in exposure to 
TAK-536 are not considered to be clinically meaningful as TAK-491 was well-tolerated in other 
pharmacokinetic studies in which exposures to TAK-536 were greater than those observed in 
subjects with hepatic impairment. All AEs in the hepatic impairment study were mild, no subjects 
discontinued due to an AE, and neither mild nor moderate hepatic impairment had an impact on 
the relationship of AEs to study drug. Severe hepatic impairment was not studied.
Total exposure (AUC) to TAK-536, after a single dose of TAK-491 in a phase 1 renal impairment 
study, tended to be higher in subjects with renal impairment than in healthy subjects, with 
increases of 30%, 25%, 95%, and 4% in subjects with mild, moderate, and severe renal 
impairment, and ESRD, respectively. These increases in exposure to TAK-536 are not considered 
to be clinically meaningful, as TAK-491 was well-tolerated in a high-dose (TAK-491 160 to 
320 mg) pharmacokinetic study in healthy subjects in which exposures 2- to 5-fold greater than 
those observed in subjects with renal impairment were observed. The mean t1/2z of TAK-536 was 


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not substantially different in subjects with renal impairment than in healthy subjects; therefore, 
daily dosing of TAK-491 is not expected to result in clinically significant accumulation of 
TAK-536 in patients with renal impairment. All AEs in the renal impairment study were mild, no 
subjects discontinued due to an AE, and no degree of renal impairment had an impact on the 
relationship of AEs to study drug.
In humans, the effects of TAK-491 on the RAAS are consistent with its mechanism of action and 
include increases in plasma renin activity and decreases in plasma aldosterone concentrations. In a 
phase 2 and multiple phase 3 studies in hypertensive subjects, TAK-491 administration resulted in 
significant reductions of blood pressure compared with placebo and active comparators. Further, 
incremental reductions in blood pressure were observed when TAK-491 was coadministered with 
other antihypertensive agents (eg, thiazide-like diuretics and calcium channel blockers). 
Additionally, TAK-491 was well tolerated, with an adverse event profile similar to that of placebo 
and active comparators.
TAK-491 (Edarbi) is approved in many countries and regions, including the United States (US) 
and the European Union, for the treatment of hypertension, either alone or in combination with 
other antihypertensive agents.
Please refer to the TAK-491 Global Investigator’s Brochure and the US and EU Edarbi package 
inserts for additional information [7-9].
4.4
Rationale for the Study
The clinical pharmacology program of TAK-491 was extensive and designed to evaluate 
pharmacokinetics, pharmacodynamics, extrinsic factors (ie, drug-drug interactions and food 
effect), and intrinsic factors (ie, age, gender, race, renal impairment, and hepatic impairment). 
Studies were conducted primarily in the United States with some studies conducted in Europe; 
additional studies are needed to bridge between the data previously acquired and the populations 
of other countries. Though Asian populations are known to have differences in drug metabolizing 
enzymes compared to other populations, these differences are not expected to affect the 
pharmacokinetics of TAK-491 as TAK-536, the active moiety, is mainly metabolized by CYP2C9, 
a CYP enzyme not known to be significantly different between populations. In addition, an 
analysis of TAK-536 pharmacokinetic parameters between Japanese and Caucasian subjects did 
not detect a difference. The main objectives of this open-label and double-blind, randomized, 
placebo-controlled, single- and multiple-dose, phase 1 study are to assess the pharmacokinetics, 
and safety of TAK-491 in healthy Chinese subjects.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To assess the pharmacokinetics of TAK-491 40 mg and 80 mg in healthy Chinese subjects after 
both single and multiple dose administration.
5.1.2
Secondary Objectives
To evaluate the safety and tolerability of TAK-491 40 mg and 80 mg in healthy Chinese subjects 
after both single and multiple dose administration.
5.2
Endpoints
5.2.1
Primary Endpoints
Primary endpoints for TAK-536 (the active moiety derived from TAK-491) are as follows:

Maximum observed concentration (Cmax).

Time of first occurrence of Cmax (tmax).

Area under the concentration-time curve from time 0 to infinity (AUC).

Area under the concentration-time curve from time 0 to 24 hours (AUC24)

Terminal disposition phase half-life (t1/2z).
5.2.2
Additional Endpoints
Additional endpoints for TAK-536 are as follows:

Area under the concentration-time curve from time 0 to time of last quantifiable concentration
(AUClast).

Terminal disposition phase rate constant (λz).

Observed concentration at the end of a dosing interval (Ctrough).

Minimum observed concentration during a dosing interval (Cmin).

Average concentration during a dosing interval, at steady state (Cav,ss).

Amount of drug excreted in urine from time 1 to time 2 (Aet1-t2).

Renal clearance, (CLR).

Fraction of administered dose of drug excreted in urine from time 0 to 24 hours (fe0-24) and time
0 to 72 hr (fe0-72). Molecular weight adjustment needed from TAK-491 to TAK-536.


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5.2.3
Safety Endpoints
The safety and tolerability endpoints of TAK-491 40 mg and 80 mg for the study will be 
determined from the primary safety variables that will include: physical examination findings, 
vital signs, 12-lead electrocardiogram (ECG) results, laboratory evaluations (hematology, serum 
chemistry, and urinalysis), and adverse events (AEs).


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, open-label and double-blind, placebo-controlled, single- and multiple-dose, 
phase 1 study involving 64 healthy Chinese subjects aged 18 to 45 years, inclusive, and considered 
eligible based on the inclusion and exclusion entry criteria. Subjects will receive TAK-491 or 
placebo as a single dose followed by multiple doses.
Sixteen subjects were allocated equally and randomly to 1 of 2 TAK-491 regimens (40 mg or 
80 mg) in the open-label part of the study; the 2 regimens were conducted in parallel as shown in 
Table 6.a.
Table 6.a
Open-Label Study Regimen and Subject Allocation
Regimen
Regimen Description
Number of Subjects
A
TAK-491 40 mg as a single dose followed by multiple doses
8
B
TAK-491 80 mg as a single dose followed by multiple doses
8 
Forty-eight subjects will be allocated equally and randomly to 1 of 3 regimens (TAK-491 40 mg or 
80 mg, or placebo) in the double-blind part of the study; the 3 regimens will be conducted in 
parallel as shown in Table 6.b. To maintain the study blind, subjects in this part of the study will 
receive a least 1 placebo tablet; the TAK-491 40 mg and TAK-491 80 mg tablets differ in size; 
therefore, placebo tablets for each size will be utilized as appropriate.
Table 6.b
Double-Blind Study Regimen and Subject Allocation
Regimen
Regimen Description
Number of Subjects
A
TAK-491 40 mg + placebo as a single dose followed by multiple doses
16
B
TAK-491 80 mg + placebo as a single dose followed by multiple doses
16
C
Placebo (2 tablets) as a single dose followed by multiple doses
16
The pre-dosing study period will consist of a Screening Period (Study Days -28 to -2) and 
Check-in (Study Day -1). On Day 1, a single dose of TAK-491 or placebo will be administered 
followed by a pharmacokinetic sampling period through 72 hours postdose (Days 1-4). On Days 4 
through 10, subjects will be on a daily dosing regimen, followed by a 24-hour pharmacokinetic 
assessment period prior to Study Exit (Day 11). The total confinement period for a subject who 
completes the study will be 12 days. All subjects will return to the site for PK sampling on Days 12 
to 13 and follow-up serum chemistry tests on Day 14. A Follow-up telephone call will be made by 
the site at 14 (±2) days following the last dose of study medication (Day 24 ±2 days) to inquire for 
any ongoing adverse events or serious adverse events (SAEs), new adverse events or SAEs, and 
concomitant medications taken since the final dose of study medication or Early Termination 
Visit.


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A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
Screening
Check-in
Dosing 
and PK
72-hr
PK
Dosing 
(a)
Dosing 
and AM 
Trough 
Level (b)
Dosing 
and 24-hr 
PK
Study 
Exit
PK 
Collection
F/U
Visit 
(c)
F/U Call
Days -28 to 
-2
Day -1
Day 1
Days 
2-4
Day 4
Days 5-9
Day 10
Day 11
Days 
12-13
Day 14 Day 24 
(±) 2
Confinement
PK=pharmacokinetic.
(a) Dosing will occur after the collection of the 72-hr pharmacokinetic sample.
(b) PK Trough samples will be collected on Days 7 to 9.
(c) Serum chemistry testing.
6.2
Justification for Study Design, Dose, and Endpoints
This randomized, open-label and double-blind, placebo-controlled, single- and multiple-dose, 
phase 1 study was designed with the following justification. The parameters listed as primary 
endpoints are considered appropriate for evaluation of pharmacokinetic profiles associated after 
single- and multiple-doses, and the additional safety endpoints comprise established safety 
assessments recognized as reliable, accurate, and relevant.
The pharmacokinetics of TAK-536 after administration of TAK-491 has been thoroughly 
characterized from data collected during the phase 1 clinical pharmacology program conducted in 
the United States and Europe. The t1/2z for TAK-536 following TAK-491 administration is 
approximately 11 hours; the planned sampling scheme after the single dose is approximately 
6 half-lives and appropriate. Steady state of TAK-536 is achieved within 5 days of dosing of 
TAK-491; the multiple-dose duration is appropriate. A total of 64 healthy subjects will be enrolled 
into the study. An open-label design was used during the dosing of the first 16 subjects (in 
2 consecutive cohorts) because the primary outcomes are based on objective measurements, that 
is, plasma concentrations of TAK-536. Fifteen of these first 16 subjects had a higher ALT and/or 
AST level on Day 11 than on Day -1. While none of these subjects had Day 11 ALT and/or AST 
values that exceeded 3ULN of protocol mandated monitoring criteria (see Section 7.5 [No.1] and 
Section 10.2.3), 7 of these exceeded the ULN. None of these ALT/AST elevations were 
accompanied by symptoms or signs of liver injury or by bilirubin elevation, and resolved without 
intervention. High frequency of subjects with elevations in ALT and/or AST levels were 
unexpected and unprecedented, as no similar findings were observed in previous TAK-491 phase 
1 through 3 studies with the enrollment of subjects from different races and ethnicities (ie, 
Caucasians, African Americans, Mexican Americans, Native Americans, Asians, and other 
ethnicities). While other procedure-related factors, such as high-carbohydrate diet and minimal 
physical activity during the confinement period in the phase 1 unit, as described in the medical 
literature [10-12], might have been accountable for these asymptomatic ALT/AST elevations in 
the present study, a potential drug-related phenomenon has to be definitively ruled out. Hence, a 


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double-blind, placebo-controlled study design was adopted to complete the study. A 
randomization schedule for dose assignment will be used to reduce the potential for selection bias.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Site
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites during 
the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to the first dose of study drug on 
Day 1.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures.
3. The subject is a healthy adult male or female subject of Chinese descent.
4. The subject is aged 18 to 45 years, inclusive, at the time of informed consent and first study 
medication dose.
5. The subject has a body mass index (BMI) ≥19.0 kg/ m2 and <24.0 kg/ m2, at Screening.
6. The subject has clinical laboratory evaluations (including clinical chemistry [fasted for at least 
8 hours for the screening assessment], hematology, and complete urinalysis) within the 
reference range for the testing laboratory, unless the results were deemed by the investigator to 
be not clinically significant at Screening and Check-in (Day -1).
7. The subject is willing to refrain from strenuous exercise, from 72 hours before Check-in 
(Day-1) until after Final Visit.
8. A female subject of childbearing potential* who is sexually active with a nonsterilized* male 
partner agrees to use routinely adequate contraception* from signing of informed consent 
throughout the duration of the study and for 30 days after the last dose of study drug.
*Definitions and acceptable methods of contraception are defined in Section 9.1.9
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities are 
defined in Section 9.1.10 Pregnancy.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study:
1. The subject has received any investigational compound within 30 days prior to Screening.
2. The subject has received TAK-491 in a previous clinical study or as a therapeutic agent.
3. The subject is an immediate family member, study site employee, or in a dependant 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling) or may consent under duress.


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4. The subject has history of uncontrolled, clinically significant manifestations of metabolic
(including diabetes mellitus, hypercholesterolemia, or dyslipidemia), endocrine, hematologic,
pulmonary, cardiovascular, gastrointestinal, neurological, rheumatologic, skin and
subcutaneous tissue disorders, infectious, hepatic, renal, urologic, immunologic, psychiatric or
mood disorders (including any past history of suicide attempt), or a history of lactose
intolerance, which may impact the ability of the subject to participate or potentially confound
the study results.
5. The subject has a known hypersensitivity to any component of the formulation of TAK-491 or
other AII inhibitors or related compounds.
6. The subject has a positive urine drug result for drugs of abuse or breath alcohol test at
Screening or Check-in (Day -1).
7. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
abuse within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol
and drugs throughout the study.
8. Subject has taken any excluded medication, supplements, or food products listed in the
Excluded Medications and Dietary Products table.
9. If female, the subject is pregnant or lactating or intending to become pregnant before, during,
or within 30 days after participating in this study; or intending to donate ova during such time
period.
10. Subject has current or recent (within 6 months) gastrointestinal disease that would be expected
to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic
ulcer disease, erosive esophagitis frequent [more than once per week] occurrence of heartburn,
or any surgical intervention [eg, cholecystectomy]).
11. Subject has a history of cancer, except basal cell carcinoma that has been in remission for at
least 5 years prior to Day 1.
12. Subject has positive test result for anti-HIV, anti-HCV antibodies, or for HBsAg at Screening.
13. Subject has used nicotine-containing products (including but not limited to cigarettes, pipes,
cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in
(Day -1). Cotinine test is positive at Screening or Check-in (Day -1).
14. The subject has poor peripheral venous access.
15. Subject has donated or lost 450 mL or more of his or her blood volume (including
plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1.
16. Subject has a Screening or Check-in (Day -1) abnormal (clinically significant) ECG. Entry of
any subject with an abnormal (not clinically significant) ECG must be approved, and
documented by signature by the principal investigator.
17. Subject has abnormal Screening or Check-in (Day -1) laboratory values that suggest a
clinically significant underlying disease or subject with the following laboratory


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abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
>1.5the upper limit of normal.
18. Subject has a hemoglobin value <12 g/dL at Screening.
19. The subject has a systolic blood pressure <110 and ≥160 mm Hg or a diastolic blood pressure
<60 and ≥100 mm Hg at Screening or Check-in (Day -1).
7.3
Excluded Medications and Dietary Products
Use of the agents (prescription or nonprescription), foods, and supplements listed in Table 7.a is 
prohibited from the time points specified until completion of all study activities.
Table 7.a
Prohibited Medications, Foods, and Supplements
28 days prior to Check-in (Day -1)
7 days prior to Check-in (Day -1)
72 hours prior to Check-in 
(Day -1)
Prescription medications
Nicotine-containing products
Nutraceuticals (eg, St. John’s wort, 
ginseng, kava kava, ginkgo biloba, 
Chinese herbs, and melatonin)
Immunization/Vaccines (b)
Known OTC inhibitors/inducers of CYPs 
3A4/5, 2C9, 2C19, 2D6, 1A2, 2B6, 2E1, 
and 2A6 (c)
OTC medications (a)
Vitamin supplements
Foods or beverages containing 
grapefruit or grapefruit juice, star fruit 
or star fruit juice, Seville-type (sour) 
oranges and marmalade, apple, orange, 
or pineapple juice, vegetables from the 
mustard green family (eg, kale, 
broccoli, watercress, collard greens, 
kohlrabi, Brussels sprouts, mustard), 
and charbroiled meats
Alcohol-containing products
Products containing caffeine or 
xanthine
Poppy seeds
OTC=over-the-counter.
(a) Occasional use of acetaminophen (1 g/day) or other medication as approved by Takeda on a case-by-case basis is
allowed except on Day 1.
(b) Inclusive of but not limited to flu vaccinations.
(c) Omeprazole, lansoprazole, cimetidine, ranitidine, and chlorpheniramine.
Subjects must be instructed not to take any medications, including over-the-counter medications, 
without first consulting with the investigator.
7.4
Diet, Fluid, and Activity Control, and Subject Housing
Subjects will be confined to the clinic from Day -1 through Day 11, and will return to the clinic for 
PK sampling on Days 12 to 13 and follow-up serum chemistry testing on Day 14.
During the confinement period, subjects will be given a menu consistent with local guideline and 
local dietary practice. Subjects will be given 3 meals and an evening snack every day, each 
containing approximately 20% fat (relative to the total calories). The meals served on Day 1 and 
Day 10 should be identical between study days and for each subject in the study. The study menu 


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should be recorded and submitted to the study file with a copy provided to the sponsor prior to the 
start of the study.
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence 
followed by the study procedure and then the meal.
TAK-491 will be administered on Day 1 and Day 10 with 240 mL of water after a fast of at least 
8 hours. On Day 1 and Day 10, subjects will also continue to fast for an additional 4 hours after 
dosing and subjects may consume water ad libitum with the exception of 1 hour before and 1 hour 
after drug administration. For Days 4 to 9, fasting is not required for dosing.
Subjects will remain upright (seated, standing, or ambulatory) for 1 hour following the dose 
administration, except as necessitated by the occurrence of an adverse event /or study procedures 
(eg, obtaining 12-lead ECG). Subjects will refrain from strenuous exercise throughout the entire
course of the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study should be 
recorded in the case report form (CRF) using the following categories. For screen failure subjects, 
refer to Section 9.1.14.
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that
requires early termination because continued participation imposes an unacceptable risk to the
subject’s health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test Abnormalities
Study medication should be discontinued immediately with appropriate clinical follow-up
(including repeat laboratory tests, until a subject’s laboratory profile has returned to
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time
during study medication treatment:
–
ALT or AST >8 × ULN, or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or
international normalized ratio (INR) >1.5, or ALT or AST >3 × ULN with appearance
of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or
eosinophilia (>5%).
2. Significant protocol deviation. The discovery after administration of the first dose of study
medication that the subject failed to meet protocol entry criteria or did not adhere to protocol
requirements, and continued participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject
were unsuccessful. Attempts to contact the subject must be documented.


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4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the
CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and,
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an
AE should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the CRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may terminate a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded. In 
addition, efforts should be made to perform all procedures scheduled for the Study Exit Visit.
Discontinued or withdrawn subjects will not be replaced after the first dose of study drug.


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Medication and Materials
A sufficient quantity of the following study drug for study conduct will be provided to the 
investigator.

TAK-491 40 mg and matching placebo tablets.

TAK-491 80 mg and matching placebo tablets.
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
Dosage Form
TAK-491 40 mg and 80 mg white, round biconvex tablets and matching 
placebo. Tablets of the TAK-491 investigational drug for oral administration 
contain 40 mg or 80 mg of TAK-491F (the salt-free form of TAK-491) and will 
be provided in blister cards, matching placebo will also be provided in blister 
cards. The active formulation contains drug substance and excipients; placebo 
contains excipients only.
Manufacturing
Takeda Pharmaceutical Company Limited, Osaka, Japan.
Packaging
TAK-491 investigational medicinal product and matching placebo will be 
foil/foil blistered and packaged in 10-day (8 daily doses+2 extra doses) 
child-resistant blister cards. Each tablet is connected to a desiccant through a 
linked channel. Each blister card contains 10 TAK-491 tablets and 10 
desiccants for the open-label part, and 20 TAK-491 or matching placebo tablets
and 20 desiccants for the double-blind part. The tablets should not be removed 
from the blister card until immediately prior to dosing.
Labeling
Each blister card provided to the clinical site will be labeled with a single panel 
label with pertinent study information and appropriate country specific 
regulatory caution statement. Each label will include a space for the pharmacist 
to include a subject specific reference number. The blister cards will be labeled 
in an open labeled fashion for the open-label part and in a double-blind fashion 
for the double-blind part of the study.
8.1.2
Storage
TAK-491 investigational medicinal product and matching placebo should be stored at 25°C 
(77°F); with excursions permitted to 15C to 30°C (59F to 86°F). The blister cards in which the 
tablets are contained should not be opened until immediately prior to dosing in order to protect 
from moisture and humidity.


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All investigational medicinal product must be kept in an appropriate, limited-access, secure place 
until it is used or returned to the sponsor or designee for destruction. All study medication must be 
stored under the conditions specified on the label, and remain in the original container until 
dispensed. A daily temperature log of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
Table 8.a describes the dose and tablet count that will be provided to each group.
Table 8.a
Study Medication Supplies
Regimen
Dose
Treatment Description
Active
Placebo (a)
A
TAK-491 40 mg
One TAK-491 40 mg tablet
One placebo for TAK-491 80 mg tablet 
B
TAK-491 80 mg
One TAK-491 80 mg tablet
One placebo for TAK-491 40 mg tablet
C (a)
TAK-491 placebo
Not applicable
One placebo for TAK-491 40 mg tablet
One placebo for TAK-491 80 mg tablet
(a) Double-blind part of study only.
On Days 1 and 4 through 10, study drug will be administered. The investigator or investigator’s 
designee will instruct the subject on dosing procedures.
Following administration of study drug, hand-and-mouth checks will be performed to ensure that 
the dose was swallowed and will be recorded on the source document. Although timing of events 
requires that each subject receive the appropriate dose at specific times, the exact dose time of 
consecutive subjects may be staggered to obviate the need to have all subjects on precisely the 
same study schedule. The actual date and time of administration of the dose of study drug will be 
recorded on the source documents and the appropriate CRF.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of investigational drug, 
to or by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol.
All cases of overdose (with or without associated adverse events) will be documented on an 
Overdose page of the CRF, in order to capture this important safety information consistently in the 
database. Adverse events associated with an overdose will be documented on AE CRF(s) 
according to Section 10.0, Pretreatment Events and Adverse Events.
Serious adverse events (SAEs) of overdose should be reported according to the procedure outlined 
in Section 10.2.2, Collection and Reporting of SAEs.
In the event of drug overdose, the subject should be treated symptomatically.


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8.2
Study Medication Assignment and Dispensing Procedures
Subjects will be assigned, in the order in which they are randomized into the study to receive their 
treatment according to the randomization schedule allocated to the site. The Randomization 
Sequence Number will be entered onto the CRF.
Subjects will be assigned to receive a 4-digit randomization sequence number. The number will be 
assigned by the clinic site personnel in sequential order beginning with 1001 and ending with 1016 
for the open-label part, and beginning with 2001 and ending with 2048 for the double-blind part.
This 4-digit number will be used by the clinical site to facilitate the prelabeling of pharmacokinetic 
samples, and will be the only subject identifier used on all sample collections. It should also be 
contained on the pharmacokinetic transport vials shipped to the bioanalytical laboratory, and will 
be used by the laboratory to report the subject data results. This 4-digit number should only be used 
for the purposes described in this section. It does not replace the 3-digit subject number which is 
assigned at the time the informed consent is obtained and which is used for all other procedures to 
identify the subjects throughout the study.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule, 
which will be provided to the site pharmacist prior to the start of this study. All randomization 
information will be stored in a secured area, accessible only by authorized personnel.
8.4
Investigational Drug Blind Maintenance
For the double-blind part of the study, the investigational drug blind information is maintained 
through a randomization schedule held by the dispensing pharmacist.
8.5
Unblinding Procedure
For the double-blind part of the study, the investigational drug blind shall not be broken by the 
investigator unless information concerning the investigational drug is necessary for the medical 
treatment of the subject. All study assessments and causality should be performed, if possible, 
prior to unblinding. In the event of a medical emergency, if possible, the medical monitor should 
be contacted before the investigational drug blind is broken to discuss the need for unblinding.
For unblinding a subject, the investigational drug blind can be obtained by opening sealed 
envelope, or contacting the dispensing pharmacist.
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The
date, time, and reason the blind is broken must be recorded in the source documents and the same 
information (except the time) must be recorded on the (e)CRF.
If any site personnel are unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study.
No change should be made to any assessment of the subject after unblinding.


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8.6
Accountability and Destruction of All Study Medication
Drug supplies will be counted and reconciled at the site before being returned to Takeda or 
designee or being destroyed.
The investigator or designee must ensure that the study medication is used in accordance with the 
approved protocol and is dispensed only to subjects enrolled in the study. To document appropriate 
use of study medication (TAK-491 or placebo) the investigator must maintain records of all study 
medication delivery to the site, site inventory, use by each subject, and return to the sponsor or 
designee.
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labeled storage conditions, and is in good condition. If quantity 
and conditions are acceptable, investigator or designee should acknowledge the receipt of the 
shipment. If there are any discrepancies between the packing list versus the actual product 
received, Takeda must be contacted to resolve the issue. The packing list should be filed in the 
investigator’s essential document file.
The investigator must maintain 100% accountability for all study medication received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Continuously monitoring expiration dates if expiration date is provided to the investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator must record the current inventory of all study medication (TAK-491 or placebo) 
on a sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of study medication, expiry and/or retest date, date and amount dispensed, including the initials of 
the person dispensing and receiving the study medication. The log should include all required 
information as a separate entry for each subject to whom study medication is dispensed.
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction or destroyed at the site, as 
applicable. The investigator will retain the original documentation regarding clinical study 
material accountability, return, and/or destruction, and copies will be sent to the sponsor or 
designee.


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The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee for destruction.
In the event of expiry date extension of supplies already at the study site, supplies may be relabeled 
with the new expiry date at that site. In such cases, Takeda or its designee will prepare additional 
labels and all necessary documentation for completion of the procedure at the sites.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, and smoking status of the subject at Screening.
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the condition/disease under study that stopped at or prior to 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A physical examination will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other.
Any abnormal finding on a pretreatment physical examination assessment must be assessed as Not 
Clinically Significant (NCS) or Clinically Significant (CS) by the investigator and recorded in the 
source document and CRF. All CS findings/changes will be recorded as a PTE or concurrent 
medical condition in the source document and on the appropriate CRF described in Section 9.1.7
or Section 10.0.
On subsequent examinations, any abnormal change from the pretreatment physical examination 
assessment occurring immediately prior to the start of the investigational drug (Day 1) must be 
assessed as NCS or CS by the investigator and recorded in the source document and CRF. Any CS 
change, as determined by the investigator, will be recorded as an AE in source documentation and 
on the PTE/AE CRF described in Section 10.0.


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9.1.4
Weight, Height, and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below:
Metric:
BMI = weight (kg)/height (m)2
Height will be collected in centimeters without decimal places and weight will be collected in 
kilograms to 1 decimal place. Results for BMI will be expressed with 1 decimal place.
Example:
Height=176 cm (or 1.76 m), weight=79.2 kg; BMI=79.2/1.762=25.6 kg/m2.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature (oral) measurement, sitting blood pressure (after 
5 minutes resting), respiration rate and pulse (bpm).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the CRF. Documentation will
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use.
9.1.7
Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. This includes clinically significant laboratory, electrocardiogram 
(ECG), or physical examination abnormalities noted at the Screening examination. The condition 
(ie, diagnosis) should be described.
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The 
approximate total volume of blood for the study is 243 mL. Laboratory samples will be taken 
following a minimum 8-hour overnight fast on the days stipulated in the Schedule of Study 
Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells with differential 
(neutrophils, eosinophils, basophils, 
lymphocytes, monocytes)
Hemoglobin
Hematocrit
Platelets
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Potassium
Sodium
Glucose
Chloride
Triglycerides
HDL-C
LDL-C
Total cholesterol
pH
Specific gravity
Protein
Glucose
Blood
Ketones
Microscopic Analysis (a):
RBC/high power field WBC/high 
power field
Epithelial cells, casts etc.
Diagnostic Screening:
Serum
Urine
Breath
HBsAg, anti-HCV, anti-HIV (b)
Additional Virology Tests:
Anti-HBsAb, HBeAg, anti-HBeAb, 
anti-HBcAb, EBV VCA IgG, 
EBV VCA IgM, Anti-CMV IgG, and 
Anti-CMV IgM (c)
Female Subjects only:
Serum hCG at Screening, Check-in, and 
Study Exit or Early Termination
Drug screen, including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and 
cotinine
Breath alcohol test
EBV= Epstein-Barr virus viral capsid antigen, hCG=human chorionic gonadotropin, RBC=red blood cell, 
WBC=white blood cell.
(a) Microscopic analysis should be performed only if urine evaluations are abnormal.
(b) HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects.
(c) The results for the additional virology tests performed at Screening will be recorded in the (e)CRF for randomized 
subjects only.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be performed within a 
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was found. (Please 
refer to Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate guidance on 
Reporting of Abnormal Liver Function Tests in relation to ALT or AST >3 ×ULN in conjunction 
with total bilirubin >2 ×ULN.)


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If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, discussion of the relevant subject details and 
possible alternative etiologies.
Subjects with ALT/AST elevations >1ULN on Day 11 and/or 14 will be followed-up every 5 to 
7 days until resolution.
All laboratory safety data will be transferred electronically to Takeda or designee in the format 
requested by Takeda. If the laboratory is unable to electronically transfer data, the study site 
coordinator or designee is responsible for transcribing laboratory results to the CRF. The 
investigator will maintain a copy of the laboratory accreditation and the reference ranges for the 
laboratory used.
Laboratory reports must be signed and dated by the principal investigator or subinvestigator 
indicating that the report has been reviewed and any abnormalities have been assessed for clinical 
significance.
All clinically significant laboratory abnormalities must be recorded as a PTE/AE in the subject’s 
source documents and on the appropriate CRF. A clinically significant laboratory abnormality that 
has been verified by retesting will be followed until the abnormality returns to an acceptable level 
or a satisfactory explanation has been obtained. Please refer to Section 10.2.3 Reporting of 
Abnormal Liver Function Tests for reporting requirements.
9.1.9
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 30 days after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use adequate contraception. In addition they must be advised 
not to donate ova during this period.
*Females NOT of childbearing potential are defined as those who have been surgically sterilized 
(hysterectomy, bilateral oophorectomy or tubal ligation) or who are postmenopausal (eg, defined 
as at least 1 year since last regular menses with an FSH >40 IU/L or at least 5 years since last 
regular menses, confirmed before any study medication is implemented).
**Sterilized males should be at least 1 year postvasectomy and have confirmed that they have 
obtained documentation of the absence of sperm in the ejaculate.
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are included, the only 
acceptable methods of contraception are:


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Barrier methods (each time the 
subject has intercourse):
Intrauterine devices (IUDs):
Hormonal contraceptives:

Male condom PLUS 
spermicide

Cap (plus spermicidal cream 
or jelly) PLUS male condom 
and spermicide

Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide

Copper T PLUS condom or 
spermicide

Progesterone T PLUS 
condom or spermicide

Implants

Hormone shot/injection

Combined pill

Mini pill

Patch

Vaginal ring PLUS male 
condom and spermicide
Subjects will be provided with information on acceptable methods of contraception as part of the
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course of 
the study.
During the course of the study, regular serum human chorionic gonadotropin (hCG) pregnancy 
tests will be performed only for women of childbearing potential and subjects will receive 
continued guidance with respect to the avoidance of pregnancy as part of the study procedures. In 
addition to a negative serum hCG pregnancy test at Screening, subjects also must have a negative 
serum hCG pregnancy test at Check-in (Day -1) prior to receiving any dose of study medication on 
Day 1.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug (TAK-491 or placebo) should be immediately discontinued.
If the pregnancy occurs during administration of active study medication, eg, after Day 1 or within 
30 days of the last dose of study medication, the pregnancy should be reported immediately, using 
a pregnancy notification form, to the contact listed in Section 1.0.
If the female subject agrees to the primary care physician being informed, the investigator should 
notify the primary care physician that the subject was participating in a clinical study at the time 
she became pregnant and provide details of treatment the subject received.
All reported pregnancies will be followed up to final outcome, using the pregnancy form. The 
outcome, including any premature termination, must be reported to the sponsor.
9.1.11 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified physician at the 
investigational site) will interpret the ECG using 1 of the following categories: within normal 
limits, abnormal but not clinically significant, or abnormal and clinically significant. The time that 
the ECG was performed will be recorded. The following parameters will be recorded on the CRF 


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from the subject’s ECG trace: heart rate, QT interval, PR interval, QRS interval, and QT 
(Fridericia corrected).
9.1.12 Pharmacokinetic Sample Collection
9.1.12.1 Collection of Plasma for Pharmacokinetic Sampling
Blood samples (one 6-mL sample per scheduled time) for determination of TAK-536 plasma 
concentrations will be collected according to the schedule in Table 9.b. Instructions for sample 
processing and shipment are provided in Appendix E.
Table 9.b
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis
Matrix
Dosing Day(s)
Scheduled Time
Plasma
1
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
24, 36, 48, and 72 hours postdose
Plasma
7, 8, 9
Predose (up to 15 minutes prior to dose [0 hour])
Plasma
10
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
and 24, 36, 48, and 72 hours postdose
The actual time of sample collection will be recorded on the source document and CRF. 
Instructions for sample processing and shipment are provided in Appendix E.
Placebo samples will not be analyzed by the bioanalytical laboratory except 4 samples per subject 
receiving placebo, 2 on Day 1 and 2 on Day 10 at predose and the other around the expected time at 
which Cmax occurred (3 hours), to ensure from a safety perspective that no additional subjects 
could have been on active treatment.
9.1.12.2 Collection of Urine for Pharmacokinetic Sampling
Serial urine samples for determination of TAK-536 will be collected according to Table 9.c.
Table 9.c
Collection of Urine Samples for Pharmacokinetic Analysis
Matrix
Dosing Day
Scheduled Time
Urine
1
Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 
to 72 hours postdose
Urine
10
0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 hours postdose
Instructions for sample processing and shipment are provided in Appendix E.
Urine samples for subjects randomized to placebo will not be analyzed.


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9.1.12.3 Bioanalytical Methods
Plasma and urine concentrations of TAK-536 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry. The bioanalytical method is a validated 
LC-MS/MS method for TAK-536.
9.1.13 Pharmacokinetic Parameters
The pharmacokinetic parameters of TAK-536 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. The following pharmacokinetic 
parameters will be calculated from plasma concentration values of TAK-536:
Symbol/Term
Definition
Plasma
AUC24
(ng·hr/mL)
Area under the concentration-time curve from time 0 to 24 hours (multiple dose only).
AUClast
(ng∙hr/mL)
Area under the concentration-time curve from time 0 to time of the last quantifiable concentration 
(single dose only).
AUC
(ng∙hr/mL)
Area under the concentration-time curve from time 0 to infinity (single dose only), calculated using 
the observed value of the last quantifiable concentration.
Cav,ss
(ng/mL)
Average concentration during a dosing interval at steady state.
Cmax
(ng/mL)
Maximum observed concentration.
Cmin
(ng/mL)
Minimum observed concentration during a dosing interval.
Ctrough
(ng/mL)
Observed concentration at the end of a dosing interval.
z
(1/hr)
Terminal disposition phase rate constant (single dose only).
t1/2z
(hr)
Terminal disposition phase half-life (single dose only).
tmax
(hr)
Time of first occurrence of Cmax.
The following pharmacokinetic parameters will be derived from urine concentrations of 
TAK-536:
Symbol/Term
Definition
Urine
Aet1-t2
Amount of drug excreted in urine from time 1 to time 2.
Aet
Amount of drug excreted in urine from time 0 to time t.
fet
Fraction of administered dose of drug excreted in urine from time 0 to time t. Molecular weight 
adjustment needed for metabolites
CLR
Renal clearance.


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9.1.14 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is found to be 
not eligible at this visit, the investigator should complete the CRF.
The primary reason for screen failure is recorded in the CRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Major protocol deviation.

Lost to follow-up.

Voluntary withdrawal, specify reason.

Study termination.

Other, specify reason.
Subject numbers assigned to subjects who fail screening should not be reused.
9.1.15 Documentation of Study Entrance/Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for entrance, the investigator should record the primary 
reason for failure on the applicable CRF.
9.2
Monitoring Subject Treatment Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study medication, appropriate mouth and/or hand checks will 
be performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the (e)CRFs. An inventory of 
the study medication supplies dispensed will be performed by the site pharmacist or authorized 
study designee and recorded onto the Drug Accountability Log in the subject’s source document 
records or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate 
logistics at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening
Subjects will be screened for the study within 28 days prior to the first dose of study medication. 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.1.14 for procedures for documenting screening failures.


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Procedures to be completed at Screening Visit include:

Informed consent.

Demographics, medical history, and medication history.

Physical examination.

Vital signs.

Weight, height and BMI.

Concomitant medications.

Concurrent medical conditions.

PTE assessment.

HBsAg, anti-HCV, and anti-HIV tests (exclusion criteria)

Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG and EBV VCA IgM, and 
Anti-CMV IgG and Anti-CMV IgM.

Screening clinical laboratory tests (including pregnancy test for all female subjects).

Urine drug and cotinine

Breath alcohol screen.

12-lead ECG.
9.3.2
Day -1 (Check-in)

Physical examination.

Vital signs.

Concomitant medications assessment.

Concurrent medical conditions.

PTE assessment.

Clinical laboratory tests (including pregnancy test for all female subjects).

Urine drug and cotinine

Breath alcohol screen.

12-lead ECG.

PK urine collection.


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9.3.3
Day 1: Study Entrance
Study entrance will take place on Day 1. The following procedures will be performed and 
documented:

Vital signs.

PK urine collection.

PK blood collection.

Administration of study drug.

AE assessment.

Concomitant medications assessment.
Subjects will be administered study drug in the unit under the supervision of the investigator or 
designee, as described in Section 8.2. The procedure for documenting Screening failures is 
provided in Section 9.1.14.
9.3.4
Days 2 and 3

Vital signs.

PK urine collection.

PK blood collection.

AE assessment.

Concomitant medications assessment.
9.3.5
Day 4

Vital signs.

Clinical laboratory tests.

PK urine collection.

PK blood collection.

Administration of study drug.

AE assessment.

Concomitant medications assessment.
9.3.6
Days 5 and 6

Vital signs.

Administration of study drug.


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
AE assessment.

Concomitant medications assessment.
9.3.7
Days 7 through 10

Vital signs.

PK urine collection (Day 10 only).

PK blood collection.

Administration of study drug.

AE assessment.

Concomitant medications assessment.
9.3.8
Day 11

Physical examination.

Vital signs.

Weight measurement.

Clinical laboratory tests (including pregnancy test for all female subjects).

12-lead ECG.

PK urine collection.

PK blood collection.

Concomitant medications assessment.

AE assessment.
Subjects will be discharged from the clinic after the completion of all scheduled procedures and at 
the investigator’s discretion.
For all subjects receiving study medication, the investigator must complete the End of Study CRF 
page.
9.3.9
Days 12 through 13

Vital signs.

PK blood collection.

Concomitant medications assessment.

AE assessment.


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9.3.10 Day 14: F/U Visit

Clinical laboratory tests.

Concomitant medications assessment.

AE assessment.
9.3.11 Early Termination
The reason for discontinuation must be documented in the source document and CRF. The 
following procedures will be performed and documented:

Physical examination.

Vital signs.

Weight measurement.

Clinical laboratory tests (including pregnancy test for all female subjects).

12-lead ECG.

Concomitant medications assessment.

AE assessment.
For all subjects receiving study medication, the investigator must complete the End of Study CRF 
page.
9.3.12 Follow-up Telephone Call
A Follow-up telephone call will be made by the site at 14 (±2) days following the last dose of study 
medication (Day 24 2 days) to inquire for any ongoing adverse events or serious adverse events 
(SAEs), new adverse events or SAEs, and concomitant medications taken since final dose of study 
medication or Early Termination Visit.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.d.
Table 9.d
Approximate Blood Volume
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Single 
Dose
Multiple Dose with 
Study Exit
Safety Laboratory Samples
15
2
1
2
75
Pharmacokinetic Samples
6
N/A
14
17
186
Total Blood Sampling Volume
261


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Direct venipuncture is the method of blood collection. Additional blood samples may be collected 
at the discretion of the investigator to assess safety.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.

PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs if they 
are judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory re-test and/or continued monitoring of an abnormal value are not considered an 


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intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”).
Changes in severity of AEs /Serious PTEs:

If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded.


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Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as adverse events.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as adverse 
events.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
PTEs or AEs, but instead will be documented on an Overdose page of the CRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the CRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” 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 that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Malignant hypertension
Convulsive seizures
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/Stevens-Johnson syndrome
Hepatic necrosis
Acute liver failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis
Confirmed or suspected endotoxin shock
Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 Severity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.6 Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Yes:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible.
No:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments.
10.1.7 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Yes if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as No.


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10.1.8 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician.
10.1.9
Stop Date
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.10
Frequency
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous.
10.1.11
Action Concerning Study Medication

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE.
10.1.12
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.


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10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study medication 
(Day 1) or until screen failure. For subjects who discontinue prior to study medication 
administration, PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study 
medication (Day 1). Routine collection of AEs will continue until 30 days after the last dose of 
study drug.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the CRF, whether 
or not the investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term.

Start and stop date and time.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (yes or no) (not completed for PTEs).

Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.

Action concerning study medication (not applicable for PTEs).

Outcome of event.

Seriousness.


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10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed and signed by the investigator immediately or within 
24 hours of first onset or notification of the event. The information should be completed as fully as 
possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
10.2.3 Reporting of Abnormal Liver Function Tests
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE if assessed as clinically significant. In addition, an LFT 
Increases CRF must be completed providing additional information on relevant recent history, risk 
factors, clinical signs and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease. Follow-up laboratory tests as described in Section 9.1.8 must also be 
performed. In addition, an LFT Increases CRF must be completed and transmitted with the Takeda 
SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
10.3.1 Safety Reporting of SAEs
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 


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(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.3.2 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted within 7 days for fatal 
and life-threatening events and 15 days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
products administration or in the overall conduct of the trial. The investigational site also will 
forward a copy of all expedited reports to his or her IRB or IEC in accordance with national 
regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee or clinical endpoint committee will be used in this study.
Takeda will designate an external hepatologist as an independent assessor of any liver enzyme 
elevation in the study. Takeda will also designate a Pharmacovigilance physician who is not 
involved in the study conduct as a sponsor liaison to participate and facilitate the safety 
communication between the external expert, the study site and Takeda. 
All liver enzyme elevations occurring in the study subjects will be initially submitted to blinded 
review by the external hepatologist. The unblinded aggregate data from a series of patients will 
also be reviewed by the external hepatologist, a designated independent physician from the site,
and a sponsor liaison before the next cohort is dosed with the support of an independent 
statistician, and a written assessment will be provided to Takeda liaison and the study PI in a real 
time.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary.
12.1
(e)CRFs
Completed (e)CRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to (e)CRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. (e)CRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Corrections to (e)CRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for the change. Reasons for significant corrections should additionally be included. 
All new additions are to be made with the date and signature.
The principal investigator must review the (e)CRFs for completeness and accuracy and must sign 
and date the appropriate (e)CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the (e)CRFs.
After submission of the (e)CRFs to the sponsor, any change of, modification of, or addition to the 
data on the (e)CRFs should be made by the investigator with use of change and modification 
records of (e)CRFs (Data Clarification Form) provided by the sponsor. The principal investigator 
must review the Data Clarification Form for completeness and accuracy, and must sign, and date 
the form.
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the (e)CRFs. The completed 
(e)CRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper should be 
copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 


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informed consent forms), electronic copy of (e)CRFs, including the audit trail, and detailed 
records of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor 
or its designees. Any source documentation printed on degradable thermal sensitive paper should 
be photocopied by the site and filed with the original in the subject’s chart to ensure long-term 
legibility. Furthermore, International Conference on Harmonization (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the investigator 
and sponsor.
Refer to the Phase 1 Site Specifications document for the sponsor’s requirements on record 
retention. The investigator should contact and receive written approval from the sponsor before 
disposing of any such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subjects’ 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
13.1.1 Analysis Sets
13.1.1.1 Safety Set
The safety set will include all randomized subjects who receive at least 1 dose of study drug, 
including subjects who do not complete the study. Subjects in this set will be used for PK 
parameter summaries.
13.1.1.2 Pharmacokinetic Set
The pharmacokinetic set will consist of all subjects who received study drug and have at least 
1 measurable plasma concentration for TAK-536.
If any subjects are found to have incomplete data, a decision will be made on a case-by-case basis 
as to their inclusion in the analysis, but will be presented in the subject listings.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by regimen for each part separately 
and overall. Summary statistics (N, mean, SD, median, minimum, and maximum) will be 
generated for continuous variables (eg, age, height, weight and BMI), and the number and 
percentage of subjects within each category will be presented for categorical variables (eg, gender, 
race). Individual subject demographic and baseline characteristics data will be listed.
13.1.3 Pharmacokinetic Analysis
Descriptive statistics (N, mean, SD, SE, median, minimum, and maximum) will be used to 
summarize the plasma concentration values of TAK-536 at each sampling time point for each 
profile day by regimen for each part separately and overall. Individual plasma concentrations of 
TAK-536 will be presented in listing.
The concentration of TAK-536 excreted in urine will be summarized at each scheduled sampling 
interval using descriptive statistics (N, mean, SD, SE, median, minimum, and maximum) by 
regimen for each part separately and overall. Individual concentration of TAK-536 in urine 
excretion data will be presented in a data listing.
Descriptive statistics (N, mean, SD, SE, %CV, median, minimum, and maximum) will be used to 
summarize all pharmacokinetic parameters of TAK-536 by regimen for each part separately and 
overall. Geometric means will also be computed for AUCs, Cmax, and Cmin.
All derived pharmacokinetic parameters will be presented in the data listings.


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Additional statistical methods will be considered if deemed appropriate.
A more detailed analysis will be presented in the SAP.
13.1.4 Safety Analysis
Safety analysis will be performed using the safety set. All safety assessments, including AEs, 
clinical laboratory evaluations, 12-lead ECG results, physical examination, and vital signs will be 
summarized with descriptive statistics by regimen for each part separately and overall, where 
appropriate, and presented in the data listings.
All PTE/AEs, and treatment emergent adverse events (TEAE) will be coded using the MedDRA.
A TEAE is defined as an AE or SAE that occurs after the subject receives the first dose of study 
drug and until either within 30 days after the last dose of study medication is received. A TEAE 
may also be a continuing AE reported prior to the date of the first dose of study medication, which 
increases in severity after the start of dosing.
Summary of TEAEs will include numbers and percentages of subjects experiencing AE by system 
organ class and preferred term. TEAEs will also be summarized based on their intensity and 
relationship to study drug by system organ class and preferred term. If a subject has more than 
1 AE that codes to the same preferred term, the subject will be counted only once for that preferred 
term within treatment. Similarly, if a subject has more than 1 AE within a system organ class 
category, the subject will be counted only once in the system organ class category within the 
treatment. In the intensity summary, a subject will be counted only in the highest intensity category 
for each preferred term and each organ class. In the relationship to study drug summary, a subject 
will be counted only in the highest relationship category for each preferred term and each system 
organ class. Each summary table will include incidences of adverse events for each regimen and 
overall.
All TEAE summary tables will be listed in SAP.
PTE will be summarized by system organ class and preferred term and by regimen.
All PTEs/TEAEs will be presented in the data listings.
Clinical laboratory variables will be summarized with descriptive statistics for Baseline, postdose 
and change from Baseline to postdose values. Individual results for clinical hematology, serum 
chemistry, and urinalysis laboratory tests that are outside of normal range will be identified in a 
summary table as well as those that meet Takeda predefined criteria for markedly abnormal values 
if applicable. All laboratory values will be provided in the listing.
Vital signs will be summarized with descriptive statistics for Baseline, postdose, and change from 
Baseline to postdose values. Individual vital sign values which meet Takeda predefined criteria for 
markedly abnormal values will be identified in a summary table. All vital signs data will be 
presented in the data listing.
Individual ECG measurements that meet Takeda predefined criteria for markedly abnormal values 
will be flagged and displayed in a table. All ECG data will be listed in the data listings.


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13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
Total sample size of 64 subjects will be enrolled in this study. Sixteen subjects, 8 per regimen 
(TAK-491 40 mg and 80 mg), were randomized to the open-label part of the study. Forty-eight 
subjects, 16 per regimen (TAK-491 40 mg, 80 mg and placebo), will be randomized to the 
double-blind part of the study. The sample size is considered sufficient for evaluation of safety, 
tolerability, and PK of each part of the study, and was not based on statistical power 
considerations.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data
recorded on the (e)CRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of (e)CRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that sufficient 
time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospective approved deviation) from the inclusion or exclusion criteria.
Every attempt will be made to collect each pharmacokinetic blood sample at the designated time 
point, and the actual time of each blood sample will be recorded on the source document and CRF. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for pharmacokinetic samples collected outside of 
the following intervals:
Table 14.a
Windows for Pharmacokinetic Sample Collection
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
immediately postdose to ≤6 hours
±10
>6 hours to 12 hours postdose
±15
>12 hours to 24 hours
±30
>24 hours


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14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonized Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements. The principles of 
Helsinki are addressed through the protocol and through appendices containing requirements for 
informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will [ship drug/notify site] once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received written permission from competent authority to begin the trial. Until the site receives 
[drug/notification] no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 


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applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.


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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the State Food and Drug Administration, the FDA, the Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the subject’s original 
medical records (source data or documents), including, but not limited to, laboratory test result 
reports, ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original medical 
records requires the specific authorization of the subject as part of the informed consent process 
(see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During the study, only the sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Master Services Agreement or equivalent agreement. In the event of any 
discrepancy between the protocol and the Master Services Agreement or equivalent agreement the 
Master Services Agreement or equivalent agreement will prevail.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Takeda will, at a minimum, register all 


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clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation.
15.4.3 Clinical Trial Results Disclosure
Takeda will minimally post the results of clinical trials conducted in patients, regardless of 
outcome, on ClinicalTrials.gov or other publicly accessible websites, as required by applicable 
laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Master Services Agreement or equivalent agreement regarding the sponsor’s policy on 
subject compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or sponsor’s designee.


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16.0
REFERENCES
1. Appel GB, Appel AS. Angiotensin II receptor antagonists: role in hypertension, cardiovascular
disease, and renoprotection. Prog Cardiovasc Dis 2004;47(2):105-15.
2. Messerli FH, Weber MA, Brunner HR. Angiotensin II receptor inhibition. A new therapeutic
principle. Arch Intern Med 1996;156(17):1957-65.
3. Weber MA. The angiotensin II receptor blockers: opportunities across the spectrum of
cardiovascular disease. Rev Cardiovasc Med 2002;3(4):183-91.
4. Neutel JM. Choosing among renin-angiotensin system blockers for the management of
hypertension: from pharmacology to clinical efficacy. Curr Med Res Opin 2010;26(1):213-22.
5. Shusterman N. Risk-benefit assessment of angiotensin II receptor antagonists. Expert Opin
Drug Saf 2002;1(2):137-52.
6. TAK-491 Investigator’s Brochure. 7th Edition. Takeda Global Research & Development
Center, Inc., 01 November 2010.
7. TAK-491 Global Investigator's Brochure. 10th Edition. Takeda Development Centre Europe
Ltd., 22 April 2015.
8. Edarbi 20, 40, and 80 mg tablets. Summary of Product Characteristics. Taastrup, Denmark:
Takeda Pharma A/S, Revised 09 September 2014.
9. Edarbi (azilsartan medoxomil) Tablets. Full Prescribing Information. Atlanta, GA: Arbor
Pharmaceuticals, LLC, Revised May 2014.
10. Xia Z, Pei-hong S, Ying Z, Yi-min C. Influence of placebo and duration in hospital on
transaminase. Chin J Clin Pharmacol 2007;23(2):141-5.
11. Rosenzweig P, Miget N, Brohier S. Transaminase elevation on placebo during phase I trials:
prevalence and significance. Br J Clin Pharmacol 1999;48(1):19-23.
12. Purkins L, Love ER, Eve MD, Wooldridge CL, Cowan C, Smart TS, et al. The influence of diet
upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit.
Br J Clin Pharmacol 2004;57(2):199-208.


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Appendix A
Schedule of Study Procedures
Study Day
Screening
Check-
in
Single and Multiple Dose
Study 
Exit
(o)
PK
collec
tion
F/U
Visit
ET 
Visit
(a)
F/U 
Phone 
Call 
(b)
Days -28 to 
-2
Day
-1
Day
1
Days 
2-3
Day
4
Days 
5-6
Days 
7-9
Day 
10
Day
11
Days 
12-13
Day 
14
Informed consent (c)
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
Weight, height and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical
conditions (g)
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
Virology testing (i)
X
Pregnancy test (hCG) (j)
X
X
X
X
Urine drug and cotinine 
screens and breath alcohol
X
X
12-lead ECG
X
X
X
X
Study drug dosing (k)
X
X
X
X
X
PK blood collection (l)
X
X
X
X
X
X
X
PK urine collection (m)
X
X
X
X
X
X
PTE assessment (n)
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Footnotes for Appendix A are on the next page.


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Footnotes for Appendix A
ET=early termination.
(a) Conduct procedures for subjects discontinued early. The PK sample collection should not be collected at the Early Termination 
Visit if a PK sample is not scheduled. Additional procedures may be performed at the discretion of the investigator to assess safety.
(b) A Follow-up telephone call will be made by the site at 14 (±2) days following the last dose of study medication (Day 24 2) to 
inquire for any ongoing adverse events or serious adverse events (SAEs), new adverse events or SAEs, and concomitant 
medications taken since final dose of study medication or Early Termination Visit. Any spontaneously reported AEs will continue 
to be collected for 30 days after the last dose of study medication or Early Termination.
(c) ICF must be signed before any study specific procedures are performed.
(d) Sitting blood pressure, pulse, respiration rate and oral temperature will be measured on Day -1, and on confinement days, vitals 
are to be measured pre-dose or upon morning rising. Vitals will be collected prior to the PK blood collection.
(e) Height (for calculation of BMI) will only be measured at Screening. Weight will be measured at Screening, Check-in (Day -1), 
and Study Exit or Early Termination Visit.
(f) Record all ongoing medications.
(g) Concurrent conditions are medical conditions that are present at Screening (time of informed consent).
(h) Hematology, serum chemistries, and urinalysis tests. Blood and urine samples to be obtained before study drug dosing on Day 4. 
On Day 14, serum chemistry only; subjects with ALT/AST elevations on Day 11 and/or 14 will be followed-up every 5-7 days until 
resolution.
(i) HBsAg, anti-HCV, anti-HIV, Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, 
Anti-CMV IgG, and Anti-CMV IgM. HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects. The results for 
Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-CMV IgG, and Anti-CMV IgM tests 
performed at Screening will be recorded in the (e)CRF for randomized subjects only.
(j) Women of childbearing potential.
(k) Study drug will be administered on Day 1 and Day 10 with 240 mL of water after a fast of at least 8 hours. On Day 1 and Day 10, 
subjects will also continue to fast for an additional 4 hours after dosing and subjects may consume water ad libitum with the 
exception of 1 hour before and 1 hour after drug administration. For Days 4 to 9, fasting is not required for dosing.
(l) TAK-536 plasma PK: 6 mL blood samples will be collected on Day 1 at Predose (up to 15 minutes prior to dose [0 hour]) and at 
0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. On Days 7, 8, and 9 at predose (up to 15 minutes prior to dose [0 hour]) 
and on Day 10 at predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours postdose.
(m) TAK-536 urine PK: urine will be collected starting on Day 1 at Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12
to 24, 24 to 48, and 48 to 72 hours postdose and on Day 10 at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 hours 
postdose.
(n) PTEs will be collected from the time of the informed consent to immediately prior to dosing on Day 1 of Period 1.
(o) Subjects will be discharged from the clinic after completion of all scheduled procedures and at the investigator’s discretion.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all applicable local 
laws and regulations.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel)
screening assessments are NOT performed on potential subjects, prior to the receipt of written
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to
ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are
met.
8. Obtain valid informed consent from each subject who participates in the study, and document
the date of consent in the subject’s medical chart. Valid informed consent is the most current
version approved by the IRB/IEC. Each informed consent form should contain a subject
authorization section that describes the uses and disclosures of a subject’s personal
information (including personal health information) that will take place in connection with the
study. If an informed consent form does not include such a subject authorization, then the
investigator must obtain a separate subject authorization form from each subject or the
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including
(e)CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of
2 years following notification by the sponsor that all investigations have been discontinued or
that the regulatory authority has approved the marketing application. The investigator should
contact and receive written approval from the sponsor before disposing of any such
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.


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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening and throughout the duration of the study and for 30 days following the last 
dose of study drug. Regular pregnancy tests will be performed throughout the study for all 


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female subjects of childbearing potential. If a subject is found to be pregnant during study, 
study medication will be discontinued.


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Appendix D
Investigator Consent to Use Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Storage, and Shipment of Bioanalytical Samples
Instructions for Processing of Plasma Samples for Pharmacokinetic Analysis of TAK-536
1. Collect 6 mL of venous blood into a chilled 
ontaining 
K2EDTA.
2. Gently invert the Vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Centrifuge the Vacutainers for 10 minutes at approximately 1100 to 1300 (RCF) at 
approximately 4°C in a refrigerated centrifuge. Note: if using a collection device other than 
refer to manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 2 aliquots. A minimum of 1.0 mL needs to be obtained for 
each sample. Labeling will include protocol number (TAK-491_112), matrix (ie, plasma), 
analyte (TAK-536), subject randomization number, nominal day and time, and either “SET 1” 
(for original sample) or “SET 2” (for duplicate sample).
5. Cap the labeled storage tubes and freeze the plasma samples immediately at approximately 
-20°C or lower. No more than 60 minutes will elapse between blood collection and freezing the 
plasma sample.
6. Keep samples frozen at approximately -20°C or lower until shipment to bioanalytical 
laboratory. SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate 
SET 2 samples after SET 1 samples have been received by the bioanalytical laboratory.
Instructions for Processing of Urine Samples for Pharmacokinetic Analysis of TAK-536
1. Collect urine into polypropylene containers. During the collection interval the urine will be 
stored at approximately 4°C.
2. Stir the urine in the polypropylene container vigorously.
3. Measure the urine volume at the end of the collection period.
4. Place two 10 mL aliquots of urine in polypropylene containers. Labeling may include protocol 
number (TAK-491_112), matrix (ie, urine), analyte (TAK-536), enrollment number, nominal 
day and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate sample).
5. Freeze the urine samples within 4 hours of the end of the collection period and store frozen at 
approximately -20°C or lower.
6. Keep samples frozen at approximately -20°C or lower until shipment to bioanalytical 
laboratory. SET 1 samples will be shipped first on dry ice, followed by shipment of duplicate 
SET 2 samples after SET 1 samples have been received by the bioanalytical laboratory.
CCI
CCI


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Instructions for Shipping of Samples for Pharmacokinetic Analysis
Site may adhere to the site’s Standard Operating Procedures on shipping samples if the 
Standard Operating Procedure differs from the sample instruction provided.
1. Biological samples (ie, plasma or urine) should be shipped on dry ice to prevent thawing
during transit. Ship samples only on Monday, Tuesday or Wednesday, and at least 2 days prior
to a national holiday, to minimize the possibility of samples in transit over a weekend or
holiday. If duplicate samples are to be shipped, send SET 1 samples and await confirmation of
arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into a self-sealing zipper-lock (eg, Ziploc®) bag
containing additional absorbent material.
5. Using a permanent marker, write the subject randomization number, sample matrix
(ie, plasma), analyte (TAK-536), number of samples, and “SET 1” on each Ziploc bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. Repeat
steps 3-6 above when preparing duplicate samples for shipment, except Ziploc bags should be
marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and should include the
Sponsor’s name (Takeda), study drug (TAK-491), protocol number TAK-491_112,
investigator’s name, sample type (ie, plasma, urine), subject’s randomization number, nominal
collection day and time, and intended sample storage conditions. When duplicate SET 2
samples are being shipped, make a copy of the original SET 1 sample inventory and mark as
“SET 2.” Place the inventory paperwork into a large Ziploc bag. SET 1 samples will be
shipped first on dry ice, followed by shipment of duplicate SET 2 samples after SET 1 samples
have been received by the analytical laboratory.
8. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to
safeguard against longer than expected shipping times and delays. Use newspaper or other
material to insulate the double-bagged samples from direct contact with the dry ice. Place the
sample bundles into a styrofoam container (or other suitable container) and fill the excess
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated
weight of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large Ziploc bag) on top of the dry ice in the styrofoam
container. Place the lid on the styrofoam container and seal completely with strapping tape.
Place the styrofoam container in a cardboard shipping carton and seal securely with strapping
tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).


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11. Affix an address label to each shipping carton. Complete the address label with the following 
information: Contact name, telephone and fax number. The bioanalytical laboratory contact 
detail will be provided in a separate document.
12. Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
13. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on each 
carton. Specify a return address and contact person on the carton.
14. Obtain the airway bill number and a receipt of shipment from the carrier.
After shipping of the samples, please contact the analytical site and Takeda Study Manager to 
notify them of next day delivery. When calling, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number


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Appendix F
Detailed Description of Amendments to Text
Rationale for Amendment
Protocol Amendment 3, dated 18 March 2016 was submitted to the EC and reviewed by the EC. 
The EC requested that Takeda update the protocol. The EC letter stated, “Among the 16 subjects, 
15 subjects in the open-label trial were known to have increased ALT and AST levels on Day 11 
and the exposure was increased correspondingly in case of moderate hepatic impairment, 
indicating that repeated-dose drug administration had a certain impact on hepatic function, 
conversely, hepatic function also affected the in vivo behavior of drug. Therefore, it is 
unreasonable to collect samples for calculating terminal elimination constant (λz) and terminal 
half-life (T1/2) only after single-dose administration; sample collection should also be carried out 
after multiple-dose administration.”
Takeda agrees to add PK sample collection at 36, 48, and 72 hours after the Day 10 dose to address 
this EC comment. 
Pages 12 and 24, Study Summary: Study Design and Section 6.1 
Existing Text
The pre-dosing study period will consist of a Screening Period (Study Days -28 to -2) and 
Check-in (Study Day -1). On Day 1, a single dose of TAK-491 or placebo will be administered 
followed by a pharmacokinetic sampling period through 72 hours postdose (Days 1-4). On Days 4 
through 10, subjects will be on a daily dosing regimen, followed by a 24-hour pharmacokinetic 
assessment period prior to Study Exit (Day 11). The total confinement period for a subject who 
completes the study will be 12 days. All subjects will return to the site for follow-up serum 
chemistry tests on Day 14. A Follow-up telephone call will be made by the site at 14 (±2) days 
following the last dose of study medication (Day 24 [± 2 days]) to inquire for any ongoing adverse 
events or serious adverse events (SAEs), new adverse events or SAEs, and concomitant 
medications taken since the final dose of study medication or Early Termination Visit.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Figure 6.a
Schematic of Study Design
Screening
Check-in
Dosing 
and PK
72-hr PK
Dosing (a)
Dosing and 
AM Trough 
Level (b)
Dosing 
and 
24-hr PK
Study 
Exit
F/U
Visit 
(c)
F/U Call
Days -28 
to -2
Day -1
Day 1
Days 2-4
Day 4
Days 5-9
Day 10
Day 11
Day 14
Day 24
(± 2)
Confinement 
PK=pharmacokinetics.
(a) Dosing will occur after the collection of the 72-hr pharmacokinetic sample.
(b) PK trough samples will be collected on Days 7 to 9.
(c) Serum chemistry testing.


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Revised Text
The pre-dosing study period will consist of a Screening Period (Study Days -28 to -2) and 
Check-in (Study Day -1). On Day 1, a single dose of TAK-491 or placebo will be administered 
followed by a pharmacokinetic sampling period through 72 hours postdose (Days 1-4). On Days 4 
through 10, subjects will be on a daily dosing regimen, followed by a 24-hour pharmacokinetic 
assessment period prior to Study Exit (Day 11). The total confinement period for a subject who 
completes the study will be 12 days. All subjects will return to the site for PK sampling on 
Days 12 to 13 and follow-up serum chemistry tests on Day 14. A Follow-up telephone call will 
be made by the site at 14 (±2) days following the last dose of study drug (Day 24 ±2 days) to 
inquire for any ongoing adverse events or serious adverse events (SAEs), new adverse events or 
SAEs, and concomitant medications taken since the final dose of study drug or Early Termination 
Visit.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.
Screening
Check-in
Dosing 
and PK
72-hr 
PK
Dosing 
(a)
Dosing and 
AM 
Trough 
Level (b)
Dosing 
and 24-hr 
PK
Study 
Exit
PK 
collection
F/U
Visit 
(c)
F/U Call
Days -28 to 
-2
Day -1
Day 1
Days 
2-4
Day 4
Days 5-9
Day 10
Day 11
Days 
12-13
Day 14 Day 24 
(±) 2
Confinement
PK=pharmacokinetic.
(a) Dosing will occur after the collection of the 72-hr pharmacokinetic sample.
(b) PK Trough samples will be collected on Days 7 to 9.
(c) Serum chemistry testing.


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GLOBAL CHANGES TO ADD ASSOCIATED CHANGES TO BLOOD VOLUMES FOR 
ALL SUBJECTS
Rationale for Amendment
To add mandatory PK collection from Days 12 to 13 to address the EC’s comments.
Page 41, Section 9.1.12 Pharmacokinetic Sample Collection
Existing Text
Table 9b
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis
Matrix
Dosing Day(s)
Scheduled Time
Plasma
1
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
24, 36, 48, and 72 hours postdose
Plasma
7, 8, 9
Predose (up to 15 minutes prior to dose [0 hour])
Plasma
10
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
and 24 hours postdose
Revised Text
Table 9.b
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis
Matrix
Dosing Day(s)
Scheduled Time
Plasma
1
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
24, 36, 48, and 72 hours postdose
Plasma
7, 8, 9
Predose (up to 15 minutes prior to dose [0 hour])
Plasma
10
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
and 24, 36, 48, and 72 hours postdose
Page 46, Section 9.3.9: Days 12 -13
Existing Text
Not applicable.
Revised Text

Vital signs.

PK blood collection.

Concomitant medications assessment.

AE assessment.


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Page 47, Section 9.4: Blood Volume (Table 9.d)
Existing Text
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Single 
Dose
Multiple Dose with 
Study Exit
Safety Laboratory Samples
15
2
1
2
75
Pharmacokinetic Samples
6
N/A
14
14
168
Total Blood Sampling Volume
243
Revised Text
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening
Single 
Dose
Multiple Dose with 
Study Exit
Safety Laboratory Samples
15
2
1
2
75
Pharmacokinetic Samples
6
N/A
14
17
186
Total Blood Sampling Volume
261
Page 70, Appendix A: Schedule of Study Procedures
Existing Text
Study Day
Screening
Check-
in
Single and Multiple Dose
Study 
Exit
F/U
Visit
ET 
Visit 
(a)
F/U 
Phone 
Call 
(b)
Days -28 to 
-2
Day
-1
Day
1
Days 
2-3
Day
4
Days 
5-6
Days 
7-9
Day 
10
Day
11
Day 
14
Informed consent (c)
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
Weight, height and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical
conditions (g)
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
Virology testing (i)
X
Pregnancy test (hCG) (j)
X
X
X
X
Urine drug and cotinine screens 
and breath alcohol
X
X
12-lead ECG
X
X
X
X
Study drug dosing (k)
X
X
X
X
X
PK blood collection (l)
X
X
X
X
X
X
PK urine collection (m)
X
X
X
X
X
X
PTE assessment (n)
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X


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ET=early termination.
(a) Conduct procedures for subjects discontinued early. The PK sample collection should not be collected at the Early Termination 
Visit if a PK sample is not scheduled. Additional procedures may be performed at the discretion of the investigator to assess safety.
(b) A Follow-up telephone call will be made by the site at 14 (±2) days following the last dose of study medication (Day 24 2) to 
inquire for any ongoing adverse events or serious adverse events (SAEs), new adverse events or SAEs, and concomitant 
medications taken since final dose of study medication or Early Termination Visit. Any spontaneously reported AEs will continue 
to be collected for 30 days after the last dose of study medication or Early Termination.
(c) ICF must be signed before any study specific procedures are performed.
(d) Sitting blood pressure, pulse, respiration rate and oral temperature will be measured on Day -1, and on confinement days, vitals 
are to be measured pre-dose or upon morning rising. Vitals will be collected prior to the PK blood collection.
(e) Height (for calculation of BMI) will only be measured at Screening. Weight will be measured at Screening, Check-in (Day -1), 
and Study Exit or Early Termination Visit.
(f) Record all ongoing medications.
(g) Concurrent conditions are medical conditions that are present at Screening (time of informed consent).
(h) Hematology, serum chemistries, and urinalysis tests. Blood and urine samples to be obtained before study drug dosing on Day 4. 
On Day 14, serum chemistry only; subjects with ALT/AST elevations on Day 11 and/or 14 will be followed-up every 5-7 days until 
resolution.
(i) HBsAg, anti-HCV, anti-HIV, Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-CMV 
IgG, and Anti-CMV IgM. HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects. The results for 
Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-CMV IgG, and Anti-CMV IgM tests 
performed at Screening will be recorded in the (e)CRF for randomized subjects only.
(j) Women of childbearing potential.
(k) Study drug will be administered on Day 1 and Day 10 with 240 mL of water after a fast of at least 8 hours. On Day 1 and Day 10, 
subjects will also continue to fast for an additional 4 hours after dosing and subjects may consume water ad libitum with the 
exception of 1 hour before and 1 hour after drug administration. For Days 4 to 9, fasting is not required for dosing.
(l) TAK-536 plasma PK: 6 mL blood samples will be collected on Day 1 at Predose (up to 15 minutes prior to dose [0 hour]) and at 
0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. On Days 7, 8, and 9 at predose (up to 15 minutes prior to dose [0 hour]) 
and on Day 10 at predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24 hours postdose.
(m) TAK-536 urine PK: urine will be collected starting on Day 1 at Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 
to 24, 24 to 48, and 48 to 72 hours postdose and on Day 10 at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24 hours postdose.
(n) PTEs will be collected from the time of the informed consent to immediately prior to dosing on Day 1 of Period 1.


TAK-491
Study No. TAK-491_112
Page 86 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
Revised Text
Study Day
Screening
Check-
in
Single and Multiple Dose
Study 
Exit
(o)
PK
collec
tion
F/U
Visit
ET 
Visit
(a)
F/U 
Phone 
Call 
(b)
Days -28 to 
-2
Day
-1
Day
1
Days 
2-3
Day
4
Days 
5-6
Days 
7-9
Day 
10
Day
11
Days 
12-13
Day 
14
Informed consent (c)
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
Weight, height and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical
conditions (g)
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
Virology testing (i)
X
Pregnancy test (hCG) (j)
X
X
X
X
Urine drug and cotinine 
screens and breath alcohol
X
X
12-lead ECG
X
X
X
X
Study drug dosing (k)
X
X
X
X
X
PK blood collection (l)
X
X
X
X
X
X
X
PK urine collection (m)
X
X
X
X
X
X
PTE assessment (n)
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Footnotes for Appendix A are on the next page.


TAK-491
Study No. TAK-491_112
Page 87 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
Footnotes for Appendix A
ET=early termination.
(a) Conduct procedures for subjects discontinued early. The PK sample collection should not be collected at the Early Termination
Visit if a PK sample is not scheduled. Additional procedures may be performed at the discretion of the investigator to assess safety.
(b) A Follow-up telephone call will be made by the site at 14 (±2) days following the last dose of study medication (Day 24 2) to
inquire for any ongoing adverse events or serious adverse events (SAEs), new adverse events or SAEs, and concomitant
medications taken since final dose of study medication or Early Termination Visit. Any spontaneously reported AEs will continue
to be collected for 30 days after the last dose of study medication or Early Termination.
(c) ICF must be signed before any study specific procedures are performed.
(d) Sitting blood pressure, pulse, respiration rate and oral temperature will be measured on Day -1, and on confinement days, vitals
are to be measured pre-dose or upon morning rising. Vitals will be collected prior to the PK blood collection.
(e) Height (for calculation of BMI) will only be measured at Screening. Weight will be measured at Screening, Check-in (Day -1),
and Study Exit or Early Termination Visit.
(f) Record all ongoing medications.
(g) Concurrent conditions are medical conditions that are present at Screening (time of informed consent).
(h) Hematology, serum chemistries, and urinalysis tests. Blood and urine samples to be obtained before study drug dosing on Day 4.
On Day 14, serum chemistry only; subjects with ALT/AST elevations on Day 11 and/or 14 will be followed-up every 5-7 days until
resolution.
(i) HBsAg, anti-HCV, anti-HIV, Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM,
Anti-CMV IgG, and Anti-CMV IgM. HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects. The results for
Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-CMV IgG, and Anti-CMV IgM tests
performed at Screening will be recorded in the (e)CRF for randomized subjects only.
(j) Women of childbearing potential.
(k) Study drug will be administered on Day 1 and Day 10 with 240 mL of water after a fast of at least 8 hours. On Day 1 and Day 10,
subjects will also continue to fast for an additional 4 hours after dosing and subjects may consume water ad libitum with the
exception of 1 hour before and 1 hour after drug administration. For Days 4 to 9, fasting is not required for dosing.
(l) TAK-536 plasma PK: 6 mL blood samples will be collected on Day 1 at Predose (up to 15 minutes prior to dose [0 hour]) and at
0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. On Days 7, 8, and 9 at predose (up to 15 minutes prior to dose [0 hour])
and on Day 10 at predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours postdose.
(m) TAK-536 urine PK: urine will be collected starting on Day 1 at Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12
to 24, 24 to 48, and 48 to 72 hours postdose and on Day 10 at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72 hours
postdose.
(n) PTEs will be collected from the time of the informed consent to immediately prior to dosing on Day 1 of Period 1.
(o) Subjects will be discharged from the clinic after completion of all scheduled procedures and at the investigator’s
discretion.


TAK-491
Study No. TAK-491_112
Page 88 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
GLOBAL CHANGE TO MODIFY DIET FOR ALL SUBJECTS
Page 28, Section 7.4 Diet, Fluid, and Activity Control, and Subject Housing: Second 
paragraph
Rationale for Amendment
The fat content of the diet of healthy volunteers during their hospital confinement was modified to 
align the protocol with Ethic Committee’s comments.
Existing Text
During the confinement period, subjects will be given a menu for the dosing period that includes 
3 meals and an evening snack, each containing approximately 30% fat (relative to the total 
calories). The meals served on Day 1 and Day 10 should be identical between study days and for 
each subject in the study. The study menu should be recorded and submitted to the study file with 
a copy provided to the sponsor prior to the start of the study.
Revised Text
During the confinement period, subjects will be given a menu consistent with local guideline and 
local dietary practice. Subjects will be given 3 meals and an evening snack every day, each 
containing approximately 20% fat (relative to the total calories). The meals served on Day 1 
and Day 10 should be identical between study days and for each subject in the study. The study 
menu should be recorded and submitted to the study file with a copy provided to the sponsor prior 
to the start of the study.


TAK-491
Study No. TAK-491_112
Page 89 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
GLOBAL CHANGES TO ADD LIVER SAFETY MONITORING PROCESS FOR ALL 
SUBJECTS
Rationale for Amendment
To add liver safety monitoring process to address the EC’s comments.
Page 57, Section 11.0 STUDY-SPECIFIC COMMITTEES
Existing Text
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
Revised Text
No steering committee or clinical endpoint committee will be used in this study.
Takeda will designate an external hepatologist as an independent assessor of any liver 
enzyme elevation in the study. Takeda will also designate a Pharmacovigilance physician 
who is not involved in the study conduct as a sponsor liaison to participate and facilitate the 
safety communication between the external expert, the study site and Takeda. 
All liver enzyme elevations occurring in the study subjects will be initially submitted to 
blinded review by the external hepatologist. The unblinded aggregate data from a series of 
patients will also be reviewed by the external hepatologist, a designated independent 
physician from the site, and a sponsor liaison before the next cohort is dosed with the 
support of an independent statistician, and a written assessment will be provided to Takeda 
liaison and the study PI in a real time.


TAK-491
Study No. TAK-491_112
Page 90 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
OTHER TEXT CHANGES
Page 3, Section 1.2: Approval
Existing Text
SIGNATURES
Electronic signatures of the Responsible Medical Officer and other signatories are located 
on the last page of this document.
PPD


TAK-491
Study No. TAK-491_112
Page 91 of 91
Protocol Incorporating Amendment No. 04
05 August 2016
CONFIDENTIAL
Revised Text
SIGNATURES
Electronic signatures of the Responsible Medical Officer and other signatories are located 
on the last page of this document.
PPD


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single- and Multiple-
Dose, Phase 1 Study of the Pharmacokinetics of TAK-491 40 mg and 80 mg in Healthy Chinese
Subjects
NCT Number: NCT02541669
SAP Approve Date: 28 April 2017
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-491_112
A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single-and Multiple-Dose, 
Phase 1 Study of the Pharmacokinetics of TAK-491 40 mg and 80 mg in Healthy Chinese 
Subjects
Pharmacokinetic Study of TAK-491 in Healthy Chinese Subjects
PHASE I
Version: Amendment 1
Date:$SULO
Based on:
Protocol Version: Amendment 04
Protocol Date: 05 August 2016
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


TAK-491_112
Page 2 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
1.1
Approval Signatures
Study Title:
A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single-
and Multiple-Dose, Phase 1 Study of the Pharmacokinetics of TAK-491 40 
mg and 80 mg in Healthy Chinese Subjects
Pharmacokinetic Study of TAK-491 in Healthy Chinese Subjects
PPD


TAK-491_112
Page 3 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoint.....................................................................................................11
5.2
Additional Endpoints ...............................................................................................11
5.3
Safety Endpoints......................................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Summary Statistics and Precision.......................................................................13
7.1.2
Derived Datasets and Variables..........................................................................13
7.1.3
Definition of Study Days and Baseline...............................................................13
7.1.4
Statistical Software ............................................................................................14
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................14
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................16
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Endpoint(s).............................................................................16
7.8.2
Secondary Efficacy Endpoint(s).........................................................................16
7.8.3
Additional Efficacy Endpoint(s).........................................................................16
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................16
7.9.1
Pharmacokinetic Concentrations ........................................................................16
7.9.2
Pharmacokinetic Parameters ..............................................................................17
7.9.3
Pharmacodynamic Analysis ...............................................................................17


TAK-491_112
Page 4 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
7.10
Other Outcomes.......................................................................................................17
7.11
Safety Analysis........................................................................................................18
7.11.1 Adverse Events ..................................................................................................18
7.11.2 Clinical Laboratory Evaluations .........................................................................19
7.11.3 Vital Signs .........................................................................................................21
7.11.4 12-Lead ECGs ...................................................................................................21
7.11.5 Other Observations Related to Safety.................................................................21
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................22
8.0
REFERENCES..............................................................................................................23
APPENDIX ..............................................................................................................................24
LIST OF IN-TEXT TABLES
Table 4.a
Open-Label Study Regimen and Subject Allocation.............................................7
Table 4.b
Double-Blind Study Regimen and Subject Allocation ..........................................7
Table 4.c
Schedule of Study Procedures..............................................................................9
Table 7.a
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis ...............16
Table 7.b
Collection of Urine Samples for TAK-536 Pharmacokinetic Analysis................16
Table 7.c
Pharmacokinetic Parameters ..............................................................................17
Table 7.d
Clinical Laboratory Tests...................................................................................20
LIST OF IN-TEXT FIGURES
Figure 4.a
Schematic of Study Design ..................................................................................8
LIST OF APPENDICES
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values .................24
Appendix B
Criteria for Markedly Abnormal Values for Vital Signs......................................26
Appendix C
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters....................27


TAK-491_112
Page 5 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS
z
terminal disposition phase rate constant
%CV
percent coefficient of variation
AE
adverse event
Aet
amount of drug excreted in urine from time 0 to time t
Aet1-t2
amount of drug excreted in urine from time 1 to time 2
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUC
area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration
AUClast
area under the concentration-time curve from 0 to time of the last quantifiable 
concentration
BMI
body mass index
bpm
Beats per minute
BUN
blood urea nitrogen
Cav,ss
average concentration during a dosing interval, at steady state
CI
confidence interval
CLR
renal clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration during a dosing interval
CPK
creatine phosphokinase
CRF
case report form
Ctrough
observed concentration at the end of a dosing interval
ECG
electrocardiogram
FAS
full analysis set
fet
fraction of administered dose of drug excreted in urine from time 0 to time t
GGT
-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IVRS
Interactive Voice Response System
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
QOL
quality-of-life
PRO
patient-reported outcome
SAE
serious adverse event


TAK-491_112
Page 6 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
SAP
statistical analysis plan
SDB
standard database
TLGs
tables, listings, and graphs
t1/2z
terminal disposition phase half-life
tmax 
time of first occurrence of Cmax
ULN
upper limit of normal
Vz/F
apparent volume of distribution during the terminal disposition phase after 
extravascular administration, calculated using the observed value of the last 
quantifiable concentration
WHODrug
World Health Organization Drug Dictionary


TAK-491_112
Page 7 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objectives
To assess the pharmacokinetics (PK) of TAK-491 40 mg and 80 mg in healthy Chinese subjects 
after both single and multiple dose administration.
4.2
Secondary Objectives
To evaluate the safety and tolerability of TAK-491 40 mg and 80 mg in healthy Chinese subjects 
after both single and multiple dose administration.
4.3
Additional Objectives
Not applicable.
4.4
Study Design
This is a randomized, open-label and double-blind, placebo-controlled, single- and multiple-
dose, phase 1 study to evaluate the PK, and safety of TAK-491 or placebo as a single dose 
followed by multiple doses in healthy adult Chinese subjects.
Sixteen subjects will be randomized 1:1 to TAK-491 40 mg or 80 mg, eight subjects per each 
TAK-491 arm, in the open-label part of the study; the 2 regimens will be conducted in parallel as 
shown in Table 4.a. 
Table 4.a
Open-Label Study Regimen and Subject Allocation
Regimen
Regimen Description
Number of Subjects
A
TAK-491 40 mg as a single dose followed by multiple doses
8
B
TAK-491 80 mg as a single dose followed by multiple doses
8 
Forty-eight subjects will be randomized 1:1:1 to TAK-491 40 mg or 80 mg, or placebo, sixteen 
subjects per each arm, in the double-blind part of the study; the 3 regimens will be conducted in 
parallel as shown in Table 4.b. To maintain the study blind, subjects in this part of the study will 
receive a least 1 placebo tablet; the TAK-491 40 mg and TAK-491 80 mg tablets differ in size; 
therefore, placebo tablets for each size will be utilized as appropriate. 
Table 4.b
Double-Blind Study Regimen and Subject Allocation
Regimen
Regimen Description
Number of Subjects
A
TAK-491 40 mg + placebo as a single dose followed by multiple doses
16
B
TAK-491 80 mg + placebo as a single dose followed by multiple doses
16
C
Placebo (2 tablets) as a single dose followed by multiple doses
16


TAK-491_112
Page 8 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
The pre-dosing study period will consist of a Screening Period (Study Days -28 to -2) and 
Check-in (Study Day -1). On Day 1, a single dose of TAK-491 or placebo will be administered 
followed by a pharmacokinetic sampling period through 72 hours postdose (Days 1-4). On 
Days 4 through 10, subjects will be on a daily dosing regimen, followed by a 24-hour 
pharmacokinetic assessment period prior to Study Exit (Day 11). The total confinement period 
for a subject who completes the study will be 12 days. All subjects will return to the site for PK 
sampling on Days 12 to 13 and follow-up serum chemistry tests on Day 14. A Follow-up 
telephone call will be made by the site at 14 (±2) days following the last dose of study 
medication (Day 24±2 days) to inquire for any ongoing adverse events or serious adverse events 
(SAEs), new adverse events or SAEs, and concomitant medications taken since the final dose of 
study medication or Early Termination Visit.
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in 
Table 4.c.
Figure 4.a
Schematic of Study Design
Screening
Check-in
Dosing 
and PK
72-hr 
PK
Dosing 
(a)
Dosing 
and AM 
Trough 
Level (b)
Dosing 
and 24-
hr PK
Study 
Exit
F/U
Visit 
(c)
F/U Call
Days -28 
to -2
Day -1
Day 1
Days 
2-4
Day 4
Days 5-9
Day 10
Day 11
Day 14
Day 24 
(±) 2
Confinement
PK=pharmacokinetic.
(a) Dosing will occur after the collection of the 72-hr pharmacokinetic sample.
(b) PK Trough samples will be collected on Days 7 to 9.
(c) Serum chemistry testing.


TAK-491_112
Page 9 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
Table 4.c
Schedule of Study Procedures
Study Day
Screen
ing
Check-
in
Single and Multiple Dose
Study 
Exit
(o)
PK
collec
tion
F/U
Visit
ET 
Visit
(a)
F/U 
Phone 
Call 
(b)
Days -28 
to -2
Day
-1
Day
1
Days 
2-3
Day
4
Days 
5-6
Days 
7-9
Day 
10
Day
11
Days 
12-13
Day 
14
Informed consent (c)
X
Inclusion/exclusion criteria
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
X
Weight, height and BMI (e)
X
X
X
X
Concomitant medications (f)
X
X
X
X
X
X
X
X
X
X
X
X
X
Concurrent medical
conditions (g)
X
X
Clinical laboratory tests (h)
X
X
X
X
X
X
Virology testing (i)
X
Pregnancy test (hCG) (j)
X
X
X
X
Urine drug and cotinine 
screens and breath alcohol
X
X
12-lead ECG
X
X
X
X
Study drug dosing (k)
X
X
X
X
X
PK blood collection (l)
X
X
X
X
X
X
X
PK urine collection (m)
X
X
X
X
X
X
PTE assessment (n)
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Footnotes for Table 4.c are on the next page.


TAK-491_112
Page 10 of 27
Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
Footnotes for Table 4.c
ET=early termination.
(a) Conduct procedures for subjects discontinued early. The PK sample collection should not be collected at the Early 
Termination Visit if a PK sample is not scheduled. Additional procedures may be performed at the discretion of the investigator 
to assess safety.
(b) A Follow-up telephone call will be made by the site at 14 (±2) days following the last dose of study medication (Day 24 2) 
to inquire for any ongoing adverse events or serious adverse events (SAEs), new adverse events or SAEs, and concomitant 
medications taken since final dose of study medication or Early Termination Visit. Any spontaneously reported AEs will 
continue to be collected for 30 days after the last dose of study medication or Early Termination.
(c) ICF must be signed before any study specific procedures are performed.
(d) Sitting blood pressure, pulse, respiration rate and oral temperature will be measured on Day -1, and on confinement days, 
vitals are to be measured pre-dose or upon morning rising. Vitals will be collected prior to the PK blood collection.
(e) Height (for calculation of BMI) will only be measured at Screening. Weight will be measured at Screening, Check-in 
(Day -1), and Study Exit or Early Termination Visit.
(f) Record all ongoing medications.
(g) Concurrent conditions are medical conditions that are present at Screening (time of informed consent).
(h) Hematology, serum chemistries, and urinalysis tests. Blood and urine samples to be obtained before study drug dosing on 
Day 4. On Day 14, serum chemistry only; subjects with ALT/AST elevations on Day 11 and/or 14 will be followed-up every 5-7 
days until resolution.
(i) HBsAg, anti-HCV, anti-HIV, Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-
CMV IgG, and Anti-CMV IgM. HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects. The results for 
Anti-HBsAb, HBeAg, anti-HBeAb, anti-HBcAb, EBV VCA IgG, EBV VCA IgM, Anti-CMV IgG, and Anti-CMV IgM tests 
performed at Screening will be recorded in the (e)CRF for randomized subjects only.
(j) Women of childbearing potential.
(k) Study drug will be administered on Day 1 and Day 10 with 240 mL of water after a fast of at least 8 hours. On Day 1 and 
Day 10, subjects will also continue to fast for an additional 4 hours after dosing and subjects may consume water ad libitum with 
the exception of 1 hour before and 1 hour after drug administration. For Days 4 to 9, fasting is not required for dosing.
(l) TAK-536 plasma PK: 6 mL blood samples will be collected on Day 1 at Predose (up to 15 minutes prior to dose [0 hour]) and 
at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. On Days 7, 8, and 9 at predose (up to 15 minutes prior to dose [0 
hour]) and on Day 10 at predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 hours 
postdose.
(m) TAK-536 urine PK: urine will be collected starting on Day 1 at Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 
12 to 24, 24 to 48, and 48 to 72 hours postdose and on Day 10 at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 48 to 72
hours postdose.
(n) PTEs will be collected from the time of the informed consent to immediately prior to dosing on Day 1 of Period 1.
(o) Subjects will be discharged from the clinic after completion of all scheduled procedures and at the investigator’s discretion.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
Primary endpoints for TAK-536 (the active moiety derived from TAK-491) of this study are as 
follows:

Maximum observed concentration (Cmax).

Time of first occurrence of Cmax (tmax).

Area under the concentration-time curve from time 0 to infinity (AUC) (single dose only).

Area under the concentration-time curve from time 0 to 24 hours (AUC24) (multiple dose 
only)

Terminal disposition phase half-life (t1/2z) (single dose only). 
5.2
Additional Endpoints
Additional endpoints for TAK-536 are as follows:

Area under the concentration-time curve from time 0 to time of last quantifiable 
concentration (AUClast) (single dose only).

Terminal disposition phase rate constant (λz) (single dose only).

Observed concentration at the end of a dosing interval (Ctrough) (multiple dose only).

Minimum observed concentration during a dosing interval (Cmin) (multiple dose only).

Average concentration during a dosing interval, at steady state (Cav,ss) (multiple dose only).

Amount of drug excreted in urine from time 1 to time 2 (Aet1-t2).

Renal clearance, (CLR).

Fraction of administered dose of drug excreted in urine from time 0 to 72 hr (fe0-72) in single 
dose and time 0 to 24 hours (fe0-24) for multiple dose. Molecular weight adjustment needed 
from TAK-491 to TAK-536,
5.3
Safety Endpoints
The safety and tolerability endpoints of TAK-491 40 mg and 80 mg for the study will be 
determined from the primary safety variables that will include: physical examination findings, 
vital signs, 12-lead electrocardiogram (ECG) results, laboratory evaluations (hematology, serum 
chemistry, and urinalysis), and adverse events (AEs).


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6.0
DETERMINATION OF SAMPLE SIZE
Total sample size of 64 subjects will be enrolled in this study. Sixteen subjects, 8 per regimen 
(TAK-491 40 mg and 80 mg), will be randomized to the open-label part of the study. Forty-eight 
subjects, 16 per regimen (TAK-491 40 mg, 80 mg and placebo), will be randomized to the 
double-blind part of the study. The sample size is considered sufficient for evaluation of safety, 
tolerability and PK of each part of the study, and was not based on statistical analysis power 
considerations.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
7.1.1
Summary Statistics and Precision
All tabulations of analysis results will include summaries by following regimens: TAK-491 
40 mg (open-label), TAK-491 80 mg (open-label), TAK-491 40 mg (double-blind), TAK-491 
80 mg (double-blind) and placebo (double-blind).
No formal statistical test will be performed in this study. Summaries will be based on descriptive 
analysis.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Exceptions may be made for derived data in the database where decimal precision is beyond 
necessary.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by regimen. 
Percentages will be reported to 1 decimal place. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated. 
The data summaries will be accompanied by individual subjects data listings sorted by study 
part, regimen, and subject number. All data available from raw data will be listed. The actual day 
relative to the start of study drug will be determined and included in the listing.
Derived analysis datasets will be produced from raw data. This allows for convenient review of 
the data as well as any necessary supplemental analyses. All data from the raw data will be 
included in the derived datasets. Derived dataset specifications will be developed to include the 
names and definitions of derived variables in the derived SAS datasets. All analyses and data 
listings will be performed using the derived datasets.
Screen failure subjects will be grouped and listed.
7.1.2
Derived Datasets and Variables
Derived datasets will be generated according to GDDB Implementation Guide (G-SPEC-RD-
004), version 01 (30 April 2011). Following are definitions of derived variables:

Body mass index (BMI) will be calculated as weight (kg)/(height (m))2 and will be presented 
to 1 decimal place. BMI will be calculated for Screening.
7.1.3
Definition of Study Days and Baseline
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.


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
If the date of the event is on or after the date of first dose:
Study Day = date of event – date of first dose +1.

If the date of the event is prior to the date of first dose:
Study Day = date of event – date of first dose.
Baseline values are defined as the last observed value before the first dose of study medication 
(including a screening value and unscheduled assessments if necessary). In the case where the 
last observed value and the first dose coincide, that value will be considered as baseline value, 
unless actual time (hour: minute) indicate otherwise. Unless otherwise specified, AEs and 
medications commencing on the first dose date (i.e. Study Day 1) will be considered as post 
baseline events, unless actual time (hour : minute) indicate otherwise. 
7.1.4
Statistical Software
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
7.2
Analysis Sets
Randomized Set: The randomized set will include all subjects who are randomized. 
Safety Set: The safety set will include all randomized subjects who received at least 1 dose of 
study drug, including subjects who do not complete the study. 
Pharmacokinetic Set: The pharmacokinetic set will consist of all subjects who received study 
drug and have at least 1 measurable plasma concentration for TAK-536. If any subjects are found 
to have incomplete data, a decision will be made on a case-by-case basis as to their inclusion in 
the analysis, but will be presented in the subject listings.
7.3
Disposition of Subjects
Study Information, including date first subject signed ICF, date of first and last open-label dose, 
date of first and last double-blind dose, date of last subjects’ last visit/contact for open-label part 
and double-blind part, Medical Dictionary for Regulatory Activities (MedDRA) Version, World 
Health Organization (WHO) Drug Dictionary Version, and SAS Version will be presented.
All screened subjects will be presented, number of subjects who signed informed consent, 
number of subjects who were or not randomized and primary reason for screen failure 
(pretreatment event/adverse event, significant protocol deviation, lost to follow-up, voluntary 
withdrawal, study termination, did not meet entrance criteria or other) will be summarized as 
recorded on the eCRF.
Disposition of all randomized subjects will be tabulated by randomized regimen and study part. 
Subjects with significant protocol deviations will be summarized, and categories will be 
tabulated as entered on the eCRF. Number of subjects within each analysis set will be tabulated.


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7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized and listed by regimen for each part 
and overall using the Randomized Set. Demographic and baseline characteristics will include age 
(years) at date of informed consent, gender, race, height (cm), baseline weight (kg), baseline 
body mass index (BMI) (kg/m2), smoking classification, and female reproductive status.
Summary statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous variables (eg, age, height, weight and BMI), and the number and percentage of 
subjects within each category will be presented for categorical variables (eg, gender, race, 
ethnicity, smoking classification and female reproductive status). Individual demographic and 
baseline characteristics will be listed by study part and regimen.
Demographic variables of screen failure subjects and reasons for screen failures will be 
summarized for all subjects who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, any available safety data and reason for 
screen failure will also be presented in the data listing.
7.5
Medical History and Concurrent Medical Conditions
Medical history (significant conditions or diseases that stopped at or prior to the time of 
informed consent) and concurrent medical conditions will be listed. Medical history and 
concurrent medical conditions will be coded as system organ class (SOC) and preferred term 
(PT) using the MedDRA, Version 19.0, or higher coding system. 
All medical history and concurrent medical condition data will be listed by study part, regimen, 
site number and subject number.
7.6
Medication History and Concomitant Medications
Medication history and concomitant medications will be listed
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
Concomitant medications are recorded on the eCRF and include any medication other than study 
drug taken at any time between time of informed consent through the end of the study (including 
the follow-up visit). 
Medication history and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary (Version 01March2014, Enhanced, or higher) coding 
system. 
Separate listings for medication history and concomitant medications will be produced by study 
part, regimen and site number and subject number.


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7.7
Study Drug Exposure and Compliance
The date and time of each dose for each subject will be reported in the data listing for all 
subjects. Summaries of PK data will be provided by regimen. No other summary statistics for the 
extent of exposure to study drug or compliance calculations will be performed for this study.
7.8
Efficacy Analysis
Not applicable.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable.
7.8.2
Secondary Efficacy Endpoint(s)
Not applicable.
7.8.3
Additional Efficacy Endpoint(s)
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Concentrations
Serial blood samples for determination of TAK-536 will be collected according to Table 7.a.
Table 7.a
Collection of Blood Samples for TAK-536 Pharmacokinetic Analysis
Matrix
Dosing Day(s)
Scheduled Time
Plasma
1
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
24, 36, 48, and 72 hours postdose
Plasma
7, 8, 9
Predose (up to 15 minutes prior to dose [0 hour])
Plasma
10
Predose (up to 15 minutes prior to dose [0 hour]) and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 
and 24 hours postdose
Serial urine samples for determination of TAK-536 will be collected according to Table 7.b.
Table 7.b
Collection of Urine Samples for TAK-536 Pharmacokinetic Analysis
Matrix
Dosing Day
Scheduled Time
Urine
1
Predose (-12 to 0 hour) and at 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 48, and 
48 to 72 hours postdose
Urine
10
0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 hours postdose
All pharmacokinetic analyses will be based on Pharmacokinetic Set.


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Concentrations of TAK-536 in plasma and the amount of TAK-536 excreted in urine will be 
summarized by regimen over each scheduled sampling time using descriptive statistics (N, mean, 
SD, SE, median, minimum and maximum) for the open-label and double-blind parts separately. 
Individual plasma and urine concentrations data will be listed. 
7.9.2
Pharmacokinetic Parameters
Plasma and urine PK parameters of TAK-536 are listed in Table 7.c.
Table 7.c
Pharmacokinetic Parameters
Symbol/Term
Definition
Plasma
AUC24 (h* ng /mL)
Area under the concentration-time curve from time 0 to 24 hours (multiple dose only).
AUClast (h*ng/mL)
Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (single dose only).
AUC(h*ng/mL)
Area under the concentration-time curve from time 0 to infinity (single dose only), calculated 
using the observed value of the last quantifiable concentration.
Cav,ss (ng/mL)
Average concentration during a dosing interval at steady state (multiple dose only).
Cmax (ng/mL)
Maximum observed concentration.
Cmin (ng/mL)
Minimum observed concentration during a dosing interval (multiple dose only).
Ctrough (ng/mL)
Observed concentration at the end of a dosing interval (multiple dose only).
z (1/h)
Terminal disposition phase rate constant (single dose only).
t1/2z (h)
Terminal disposition phase half-life (single dose only).
tmax (h)
Time of first occurrence of Cmax.
Urine
Aet1-t2 (mg)
Amount of drug excreted in urine from time 1 to time 2.
Aet (mg)
Amount of drug excreted in urine from time 0 to time t.
fet (%)
Fraction of administered dose of drug excreted in urine from time 0 to time t. 
Molecular weight adjustment needed for metabolites
CLR (L/h)
Renal clearance.
Plasma and urine PK parameters of TAK-536 will be summarized by regimen using descriptive 
statistics (N, mean, SD, SE, %CV, median, minimum and maximum) for each part separately. 
Geometric means (GM) and %GM CV will also be computed for AUCs, Cmax and Cmin. All 
individual PK parameters data will be listed.
Additional plasma PK parameters and/or analyses may be added in the presentation as 
considered appropriate.
7.9.3
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable. 


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7.11
Safety Analysis
Safety summaries will be based on the Safety Set. All safety assessments, including AEs, clinical 
laboratory evaluations, 12-lead ECG results, physical examination, and vital signs will be 
summarized with descriptive statistics by regimen for each part separately and overall, where 
appropriate, and presented in the data listings.
7.11.1 Adverse Events
Pretreatment events (PTEs) and AEs will be coded using MedDRA Version 19.0 or higher. 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study, but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, including placebo; it does not necessarily have to have a 
causal relationship with this regimen. 
Treatment-emergent adverse events (TEAE) are defined as any AEs, regardless of relationship to 
study drug, which occurred or worsened in severity on or after the first dose of study medication 
and until 30 days after the last dose of study medication is received. 
When calculating the frequency and percentage of subjects who reported TEAEs, a subject will 
be counted only once for each SOC or PT when multiple TEAEs are coded to the same SOC or 
PT. Thus, if a subject has two distinct AEs, each of which corresponds to a distinct PT but both 
of which correspond to the same SOC, then that subject will be counted once at that SOC 
subject-count summary level and once at each of the two PTs subject-count summary levels. For 
the intensity summaries, if a subject reports multiple TEAE coded to the same SOC or PT, the 
TEAE with maximum intensity will be included in the summary. For the relationship summaries, 
if a subject reports multiple TEAEs coded to the same SOC or PT, the TEAE most related to 
study drug will be included in the summary. 
Adverse events will be summarized by study part, regimen and TAK-491 overall for double 
blind part, which will include the number and percentage of subjects as follows:

Overview of Treatment-Emergent Adverse Events

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Subject Mappings for Treatment-Emergent Adverse Events

Treatment-Emergent Adverse Events by Preferred Term 

Non-Serious Treatment-Emergent Adverse Events by and Preferred Term 

Relationship of Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 

Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term 


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
Intensity of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 

Intensity of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term

Pretreatment Adverse Events (PTE) by System Organ Class and Preferred Term 

Pretreatment Serious Events by System Organ Class and Preferred Term 
7.11.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be evaluated by central laboratory and presented using the 
International System of Units (SI) units unless otherwise stated. Table 4.c shows the scheduled 
measurements for clinical laboratory tests and Table 7.d shows a list of all clinical laboratory 
tests. 


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Table 7.d
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Red blood cells
White blood cells with differential 
(neutrophils, eosinophils, basophils, 
lymphocytes, monocytes)
Hemoglobin
Hematocrit
Platelets
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
Total bilirubin
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Potassium
Sodium
Glucose
Chloride
Triglycerides
HDL-C
LDL-C
Total cholesterol
pH
Specific gravity
Protein
Glucose
Blood
Ketones
Microscopic Analysis (a):
RBC/high power field 
WBC/high power field
Epithelial cells, casts etc.
Diagnostic Screening:
Serum
Urine
Breath
HBsAg, anti-HCV, anti-HIV (b)
Additional Virology Tests:
Anti-HBsAb, HBeAg, anti-HBeAb, 
anti-HBcAb, EBV VCA IgG, 
EBV VCA IgM, Anti-CMV IgG, and 
Anti-CMV IgM (c)
Female Subjects only:
Serum hCG at Screening, Check-in, 
and Study Exit or Early Termination
Drug screen, including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, and 
cotinine
Breath alcohol test
EBV= Epstein-Barr virus viral capsid antigen, hCG=human chorionic gonadotropin, RBC=red blood cell, WBC=white blood 
cell.
(a) Microscopic analysis should be performed only if urine evaluations are abnormal.
(b) HBsAg, anti-HCV, and anti-HIV test results will be collected for all subjects.
(c) The results for the additional virology tests performed at Screening will be recorded in the (e)CRF for randomized subjects 
only.
The following summaries will be provided for laboratory data by part and regimen:

Baseline, postdose, and, change from baseline to postdose values for quantitative 
measurements.

Number and percent of urine parameters results for categorical measurements.

Number and percent of subjects with markedly abnormal value (MAV) which identified by 
the criteria in Appendix A.

Shift from baseline of high/low/normal values according to normal range criteria (baseline 
versus each post-baseline visit).


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If a subject has multiple values within a particular visit window, the most abnormal result will be 
used for summary. 
All clinical laboratory results data will be presented by subject in listing.
7.11.3 Vital Signs
Vital signs’ (including pulse rate, weight, SBP, DBP, body temperature and respiratory rate) 
collection schedule is presented in Table 4.c, and baseline, postdose, and changes from baseline 
to each post-dose values will be summarized using descriptive statistics by visit and regimen for 
each part. 
Number and percentage of subjects with markedly abnormal value (MAV) will also be tabulated 
based on the criteria listed in Appendix B. 
All vital signs data will be presented in the listings.
7.11.4 12-Lead ECGs
ECG data collection schedule is presented in Table 4.c. and will be summarized with descriptive 
statistics by regimen for baseline, postdose and change from baseline to postdose value for each 
part. 
Overall ECG interpretation category (within normal limits, not clinically significant abnormal, 
clinically significant abnormal) is collected by eCRF according to the scheduled measurements. 
Shifts in ECG interpretation will be presented as cross-tabulations of numbers of subjects with 
normal, not clinically significant abnormal, and clinically significant abnormal ECG 
interpretation results and will include categories for missing and totals.
ECG parameters with markedly abnormal value (MAV) will be tabulated based on the value 
categories listed in Appendix C. 
Summary of Subjects with QTcF in various pre-defined categories will also be tabulated. 
Categories are listed in Appendix C.
ECG data will be presented in the subject data listings.
7.11.5 Other Observations Related to Safety
All physical examination findings will be listed by study part, and regimen. Data on study drug 
overdose and interruption will be listed. 
Data related to liver function test will be listed, including signs and symptoms, event history, test 
results and reports, and additional comments.
7.12
Interim Analysis
No formal interim analysis is planned for the study. However, Takeda will designate an external 
hepatologist as an independent assessor of any liver enzyme elevation in the study. Takeda will 
also designate a Pharmacovigilance physician who is not involved in the study conduct as a 


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sponsor liaison to participate and facilitate the safety communication between the external 
expert, the study site and Takeda.
7.13
Changes in the Statistical Analysis Plan 
PK data will not be summarized for combining open-label and double blind parts of the study. 


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8.0
REFERENCES
1. Guideline on Structure and Content of Clinical Study Reports, International Conference on 
Harmonisation, Section ICH E3, 1996. 
2. Guideline on Statistical Principles for Clinical Trials, International Conference on 
Harmonisation, Section ICH E9, 1998. 
3. A Randomized, Open-Label and Double-Blind, Placebo-Controlled, Single- and Multiple-
Dose, Phase 1 Study of the Pharmacokinetics of TAK-491 40 mg and 80 mg in Healthy 
Chinese Subjects, Pharmacokinetic Study of TAK-491 in Healthy Chinese Subjects, Takeda 
Development Center Asia, Pte. Ltd., Protocol No. TAK-491_112, Amendment Number 4, 
05 August 2016. 
4. Guidance for Defining Markedly Abnormal Values Used in Statistical Analyses, Takeda 
Development Center Asia, Pte. Ltd.m C-GUID-PV-001, Version 1.2, 02-Jun-2016.
5. Guidelines for Statistical Reporting, Takeda Development Center Asia, Pte. Ltd., C-GUID-
DO-812, Version 1.0, 02-Apr-2014.
6. Guideline for Data Handling Rules for Analysis, Takeda Development Center Asia, Pte. Ltd., 
Version 1.0, 20-Sep-2011.


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APPENDIX
Appendix A
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
SI
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
SI
< 0.8 × LLN
> 1.2 × ULN
RBC count 
SI
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
SI
<0.5 x LLN
>1.5 x ULN
Platelet count
SI
<75 x 109/L
>600 x 109/L
LLN=lower limit of normal, RBC=red blood cell, ULN=upper limit of normal, WBC=white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
SI
--
>3x ULN
AST
SI
--
>3x ULN
GGT
SI
--
>3x ULN
Alkaline phosphatase
SI
--
>3x ULN
Total bilirubin
SI
--
>34.2 mol/L
Albumin
SI
<25 g/L
--
Total protein
SI
<0.8x LLN
>1.2x ULN
Creatinine
SI
--
>177 mol/L
Blood urea nitrogen
SI
--
>10.7 mmol/L
Sodium
SI
<130 mmol/L
>150 mmol/L
Potassium
SI
<3.0 mmol/L
>6.0 mmol/L
Creatine Kinase
SI
--
>5x ULN
Glucose
SI
< 2.8 mmol/L
>19.4 mmol/L
Chloride
SI
<75 mmol/L
>126 mmol/L
Triglycerides
SI
--
>2.5x ULN
HDL-C
SI
--
--
LDL-C
SI
--
--
Total cholesterol
SI
--
>7.72 mmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal.


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Urinalysis—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
Blood
SI
--
≥1+
Glucose
SI
--
≥1+
Ketones
SI
--
≥2+
Casts
SI
--
>1/1pf
Microscopic RBCs*
SI
--
≥5/hpf
Microscopic WBC
SI
--
≥20/hpf
pH
SI
≤4
≥8
Protein
SI
--
≥1+
Specific Gravity
SI
--
--
Epithelial Cells
SI
--
--
Hpf=high power field.
*Markedly abnormal if repeated values both meet the criteria: ie, if two values are greater than or equal to 5/hpf 
within 30 days of one another.


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Appendix B
Criteria for Markedly Abnormal Values for Vital Signs
Parameter
Unit
Lower Criteria 
Upper Criteria
Pulse
bpm
<50 
>120
Systolic blood pressure
mm Hg
<85 
>180 
Diastolic blood pressure
mm Hg
<50 
>110
Body temperature
oC
<35.6
>37.7


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Statistical Analysis Plan Amendment 1
28 April 2017
CONFIDENTIAL
Appendix C
Criteria for Out-of-Range Values for the 12-Lead ECG Parameters
Parameter
Lower Criteria
Upper Criteria
Heart rate
<50 beats per minute
>120 beats per minute
QT Interval
≤ 50 milliseconds
≥ 460 milliseconds
QTcF Interval
≤ 50 milliseconds
≥ 500 milliseconds OR
≥ 30 milliseconds change from baseline and 
≥ 450 milliseconds
QTcF interval in pre-defined various criteria categories:

Increase from baseline ≥30 msec

Increase from baseline ≥60 msec

> 500 msec

> 500 msec and increase from baseline ≥60 msec


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