Clinical trial NCT02480764
Conditions: Essential Hypertension
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2015-08-27; Completion date: 2017-10-13
Enrollment: 612 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the antihypertensive effect of azilsartan medoxomil compared with valsartan in Chinese participants with essential hypertension.

Detailed description:
The drug being tested in this study is called TAK-491 (azilsartan medoxomil). Azilsartan medoxomil is being tested to treat Chinese people who have essential hypertension. This study will look at change in blood pressure after 8 weeks of treatment in people who take azilsartan medoxomil compared to people who take valsartan.

The study enrolled 612 patients. Prior to the start of study treatment, participants who have not received antihypertensive treatment within 28 days participated in a 2-week -run in period. Upon completion of the run-in period, participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

* azilsartan medoxomil 40 mg
* azilsartan medoxomil 80 mg
* Valsartan 160 mg

All participants were asked to take study medication at the same time each day throughout the study.

This multi-centre trial was conducted in China. The overall time to participate in this study is up to 14 weeks. Participants made 9 visits to the clinic and contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: azilsartan medoxomil 40 mg tablets, orally, once daily, azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for up to 8 weeks. arm 2: Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: azilsartan medoxomil 80 mg tablets, orally, once daily, azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for up to 8 weeks. arm 3: Run-in Period: azilsartan medoxomil 40 mg placebo-matching tablets, azilsartan medoxomil 80 mg placebo-matching tablets, and valsartan two 80 mg placebo-matching capsules, orally, once daily, for 2 weeks prior to the start of the treatment period. Treatment Period: valsartan two 80 mg capsules, orally, once daily, azilsartan medoxomil 40 mg placebo-matching tablets, orally, once daily, and azilsartan medoxomil 80 mg placebo-matching tablets, orally, once daily, for up to 8 weeks.
Interventions: intervention 1: Azilsartan medoxomil intervention 2: Valsartan intervention 3: Azilsartan medoxomil Placebo intervention 4: Valsartan Placebo
Intervention descriptions: intervention 1: Azilsartan medoxomil tablets intervention 2: Valsartan 80 mg capsules intervention 3: Azilsartan medoxomil placebo-matching tablets intervention 4: Valsartan placebo-matching capsules

Protocol documents:
Prot_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: A  Phase 3, Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and 
Safety of TAK-491 with Valsartan in Chinese Subjects with Essential Hypertension
NCT Number: NCT02480764
 Protocol Approve Date: 09 May 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 or company confidential information. 
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
PROTOCOL
A Phase 3, Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and 
Safety of TAK-491 with Valsartan in Chinese Subjects with Essential Hypertension
TAK-491 Compared to Valsartan in Chinese Subjects with Hypertension
Sponsor:
Takeda Development Center Asia, Pte. Ltd.
21 Biopolis Road, Nucleos North Tower,
Level 4, Singapore 138567
Study Number:
TAK-491_305
IND Number:
N/A
EudraCT Number:
N/A
Compound:
TAK-491 (azilsartan medoxomil)
Date:
09 May 2016
Amendment Number: 4
Amendment History:
Date
Amendment Number
Amendment Type
Region
27 April 2011
Initial Protocol
Not applicable
China
26 March 2013
1
Non-Substantial
China
27 January 2014
2
Substantial
China
11 December 2014 
3
Substantial 
China
09 May 2016
4
Substantial 
China
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 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 to each site.
Takeda sponsored 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 will be 
provided to the site.
Issue
China Contact
Serious adverse event and pregnancy reporting
Quintiles Integrated Safety Management
Lifecycle Safety
Contact details: See Study Reference Materials
Medical Monitor
(medical advice on protocol, compound, and medical 
management of subjects)
Quintiles Medical Services Department
Contact details: See Study Reference Materials
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 Harmonisation 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 may be found on the last page of this document.
Date
Date
Date
Date
PPD
PPD
PPD
PPD


TAK-491 (azilsartan medoxomil)
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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 Harmonisation, 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)
China 
Location of Facility (Country)


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1.3
Protocol Amendment 4 Summary of Changes
This document describes the changes in reference to Protocol Amendment No. 3 dated 
11 December 2014.
The primary purpose of this amendment is to add Week 2 clinical laboratory tests. Minor 
grammatical and editorial changes are included for clarification proposes only. 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:

Clinical chemistry tests, hematology tests, urinalysis, and estimated GFR were added at
Week 2 (Visit 6).
Justification: Clinical laboratory tests were added at Week 2 (Visit 6) to be consistent with the 
current Takeda standard. Week 2 blood draw will allow full characterization of possible early 
postdose laboratory parameter changes that are considered relevant for monitoring with use of 
an ARB class of drug, including serum creatinine, electrolytes, liver enzyme tests, CPK, and 
hemoglobin. Mild ALT and AST elevations above ULN (but not exceeding 3×ULN) were 
observed in 7 of 16 subjects on Day 11 of a phase 1 study of TAK-491 in healthy Chinese 
subjects.

Testing of serum lipids was added at Week 2 (Visit 6) and Week 4 (Visit 7).
Justification: Lipids were added to the list of serum chemistry tests and are now tested at the 
same time points as other serum chemistry tests.

The definition of “trough” in the primary endpoint was changed from “22-24 hours after the 
previous dose” to “approximately 24 hours after the previous dose”.
Justification: For consistency with the required timing for blood pressure measurements stated 
in Section 9.1.5 (Vital Sign Procedures).

The maximum volume of blood drawn at any single Visit was changed from 40 mL to 15 mL, 
and the approximate total amount of blood drawn for the study was changed from 185 mL for 
all subjects to 75 mL for male subjects and 80 mL for female subjects.
Justification: The central laboratory only requires 15 mL of blood per Visit. Blood for all 
clinical laboratory tests will now be drawn at 5 Visits with the addition of Week 2 (Visit 6). An 
additional 5 mL of blood will be drawn on Day -14 (Visit 2) for serum pregnancy testing in 
female subjects only.

A serum pregnancy test was added to Day -14 (Visit 2), and urine pregnancy tests were 
removed from Day -7 (Visit 3) and Week 4 (Visit 7), such that serum pregnancy tests will be 
performed at Screening (Visit 1), on Day -14 (Visit 2), on Day 1 (Visit 5), at Week 4 (Visit 7), 
and at Week 8/ET (Visit 9), and urine pregnancy tests will only be performed on Day 1
(Visit 5).


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Justification: For consistency with the current Takeda standard as serum pregnancy tests are 
more sensitive than urine pregnancy tests.

Treatment information for overdose of TAK-491 was updated to include the results from the 
TAK-491 phase 1 renal impairment study.
Justification: It was concluded from the TAK-491 phase 1 renal impairment study that 
hemodialysis does not significantly remove TAK-536 or TAK-536 M-II from the systemic
circulation.

The definition of “postmenopausal” in the Contraception and Pregnancy Avoidance Procedure 
section (Section 9.1.9) was updated.
Justification: To make the definition consistent with the current Takeda standard.

The definition for an SAE of congenital anomaly was corrected in Section 10.1.4.
Justification: To align Takeda’s definition with ICH and the USFDA definitions.
Administrative and Other Changes

The name of the responsible medical officer was updated in Section 1.1.

The names of the signatories and/or job titles were updated in Section 1.2.

The List of Abbreviations was updated (Section 3.3).

“TDC” was changed to “Takeda” throughout where applicable.

References were updated/added, including the current US prescribing information and EU 
Summary of Product Characteristics (SmPC).


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 4 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................17
3.1
Study-Related Responsibilities.................................................................................17
3.2
Coordinating Investigator.........................................................................................17
3.3
List of Abbreviations ...............................................................................................18
3.4
Corporate Identification...........................................................................................19
4.0
INTRODUCTION.........................................................................................................20
4.1
Background .............................................................................................................20
4.2
Summary of Nonclinical Data..................................................................................21
4.3
Summary of Clinical Data........................................................................................21
4.4
Rationale for the Proposed Study.............................................................................23
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objective .......................................................................................24
5.1.2
Secondary Objective ...................................................................................24
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoint........................................................................................24
5.2.2
Secondary Endpoints...................................................................................24
5.2.3
Additional Endpoints ..................................................................................24
5.2.4
Safety..........................................................................................................25
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................26
6.1
Study Design ...........................................................................................................26
6.2
Justification for Study Design, Dose, and Endpoints ................................................27
6.3
Premature Termination or Suspension of Study or Investigational Site.....................28
6.3.1
Criteria for Premature Termination or Suspension of the Study...................28
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites ..29
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ...........................................................29
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............30
7.1
Inclusion Criteria .....................................................................................................30


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7.2
Exclusion Criteria ....................................................................................................30
7.3
Excluded Medications and Treatments.....................................................................32
7.4
Diet, Fluid, Activity Control ....................................................................................33
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................33
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................34
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................35
8.1
Study Medication and Materials...............................................................................35
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................35
8.1.1.1
Investigational Drug ...............................................................................35
8.1.1.2
Sponsor-Supplied Drug ..........................................................................36
8.1.1.3
Ancillary Materials.................................................................................36
8.1.2
Storage........................................................................................................36
8.1.3
Dose and Regimen ......................................................................................36
8.1.4
Overdose.....................................................................................................37
8.2
Investigational drug Assignment and Dispensing Procedures...................................38
8.3
Randomization Code Creation and Storage..............................................................38
8.4
Investigational Drug Blind Maintenance ..................................................................38
8.5
Unblinding Procedure..............................................................................................38
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................39
9.0
STUDY PLAN ..............................................................................................................41
9.1
Study Procedures.....................................................................................................41
9.1.1
Informed Consent Procedure.......................................................................41
9.1.2
Demographics, Medical History, and Medication History Procedure...........41
9.1.3
Physical Examination Procedure .................................................................41
9.1.4
Weight, Height and BMI.............................................................................41
9.1.5
Vital Sign Procedure ...................................................................................42
9.1.6
Documentation of Concomitant Medications...............................................42
9.1.7
Documentation of Concurrent Medical Conditions......................................43
9.1.8
Procedures for Clinical Laboratory Samples................................................43
9.1.8.1
Clinical Laboratory Tests........................................................................43
9.1.8.2
Management, Withdrawal, and Follow-up of Subjects with Creatinine 
Elevations...............................................................................................45
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................45
9.1.10
Pregnancy ...................................................................................................46
9.1.11
ECG Procedure ...........................................................................................47


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9.1.12
Documentation of Screen Failure ................................................................47
9.1.13
Documentation of Randomization and Run-In Failure.................................47
9.1.14
Ambulatory Blood Pressure Monitoring (for subset patients).......................48
9.2
Monitoring Subject Treatment Compliance..............................................................48
9.3
Schedule of Observations and Procedures................................................................49
9.3.1
Screening (Visit 1) ......................................................................................49
9.3.2
Washout, Day -28 or Day -21 through Day -1 .............................................50
9.3.3
Placebo Run-in, Day -14 through Day -1 (Visits 2 and 3)............................50
9.3.3.1
Placebo Run-in, Day -14 (Visit 2)...........................................................50
9.3.3.2
Placebo Run-in, Day -7 (Visit 3).............................................................51
9.3.4
Day -1 (Visit 4)...........................................................................................51
9.3.5
Randomization, Day 1 (Visit 5)...................................................................52
9.3.6
Treatment Visits, Week 2 through Week 6 (Visit 6 through Visit 8)............53
9.3.7
Week 8/Final Visit or Early Termination (Visit 9).......................................53
9.3.8
ABPM Removal (Visit 10)..........................................................................54
9.3.9
Follow-up ...................................................................................................54
9.3.10
Post Study Care...........................................................................................55
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................56
10.1
Definitions...............................................................................................................56
10.1.1
Pretreatment Events ....................................................................................56
10.1.2
AEs.............................................................................................................56
10.1.3
Additional Points to Consider for PTEs and AEs.........................................56
10.1.4
SAEs...........................................................................................................58
10.1.5
Severity of PTEs and AEs ...........................................................................59
10.1.6
Causality of AEs .........................................................................................59
10.1.7
Relationship to Study Procedures................................................................59
10.1.8
Start Date....................................................................................................60
10.1.9
Stop Date ....................................................................................................60
10.1.10
Frequency ...................................................................................................60
10.1.11
Action Concerning Study Medication..........................................................60
10.1.12
Outcome .....................................................................................................60
10.2
Procedures...............................................................................................................61
10.2.1
Collection and Reporting of AEs.................................................................61
10.2.1.1
PTE and AE Collection Period ...............................................................61
10.2.1.2
PTE and AE Reporting ...........................................................................61


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10.2.2
Collection and Reporting of SAEs...............................................................62
10.2.3
Reporting of Abnormal Liver Function Tests (LFT)....................................62
10.3
Follow-up of SAEs ..................................................................................................63
10.3.1
Safety Reporting of SAEs ...........................................................................63
10.3.2
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................63
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................64
12.0
DATA HANDLING AND RECORDKEEPING............................................................65
12.1
CRFs (Electronic)....................................................................................................65
12.2
Record Retention .....................................................................................................65
13.0
STATISTICAL METHODS..........................................................................................67
13.1
Statistical and Analytical Plans ................................................................................67
13.1.1
Analysis Sets...............................................................................................67
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................67
13.1.3
Efficacy Analysis........................................................................................67
13.1.4
Safety Analysis ...........................................................................................69
13.1.4.1
Adverse Events.......................................................................................69
13.1.4.2
Laboratory Analysis ...............................................................................70
13.1.4.3
Additional Safety Values........................................................................70
13.2
Interim Analysis and Criteria for Early Termination ................................................70
13.3
Determination of Sample Size..................................................................................71
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................72
14.1
Study-Site Monitoring Visits ...................................................................................72
14.2
Protocol Deviations..................................................................................................72
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................72
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................73
15.1
IRB and/or IEC Approval ........................................................................................73
15.2
Subject Information, Informed Consent, and Subject Authorization .........................74
15.3
Subject Confidentiality ............................................................................................75
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................75
15.4.1
Publication and Disclosure..........................................................................75
15.4.2
Clinical Trial Registration...........................................................................76
15.4.3
Clinical Trial Results Disclosure .................................................................76
15.5
Insurance and Compensation for Injury....................................................................76
16.0
REFERENCES..............................................................................................................77


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LIST OF IN-TEXT TABLES
Table 8.a
Sponsor-Supplied Drug......................................................................................37
Table 9.a
Clinical Laboratory Tests...................................................................................44
Table 10.a
Takeda Medically Significant AE List................................................................59
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................27
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................79
Appendix B
Responsibilities of the Investigator.....................................................................82
Appendix C
Elements of the Subject Informed Consent.........................................................84
Appendix D
Investigator Consent to Use of Personal Information..........................................87
Appendix E
Ambulatory Blood Pressure Monitoring.............................................................88
Appendix F
Detailed Description of Amendments to Text.....................................................90


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Asia, Pte. Ltd.
Compound:
TAK-491 (azilsartan medoxomil)
Title of Protocol: A Phase 3, Double-Blind, Randomized, 
Parallel-Group Study to Compare the Efficacy and Safety of 
TAK-491 with Valsartan in Chinese Subjects with Essential 
Hypertension
IND No.: Not Applicable
EudraCT No.:
Not Applicable
Study Number: TAK-491_305
Phase: 3
Study Design:
This is a phase 3, multicenter, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of 
TAK-491 compared with valsartan over an 8 week treatment period in Chinese subjects with essential hypertension 
(mean, sitting clinic systolic blood pressure (SBP) ≥150 and ≤180 mm Hg on Day 1).
A subgroup of approximately 60 subjects/arm from selected sites will undergo 24-hour ABPM 2 times during the 
study.
Primary Objective:
To evaluate the antihypertensive effect of TAK-491 compared with valsartan in Chinese subjects with essential 
hypertension.
Secondary Objective:
To evaluate safety and tolerability of TAK-491 compared with valsartan.
Subject Population: Subjects aged 18 and older with essential hypertension
Number of Subjects:
Estimated total: 600 randomized
200 subjects in each treatment arm
Number of Sites:
Approximately 20-25 sites in China
Dose Levels:
TAK-491 40 mg QD
TAK-491 80 mg QD
Valsartan 160 mg QD
Route of Administration:
Oral
Duration of Treatment:
8 week double-blind treatment period
Period of Evaluation:
7 to 14 day Screening period
14 day Single-Blind Run-in period
8 week Double-Blind Treatment period
14 day Follow-up period
Main Criteria for Inclusion:

The subject is treated with antihypertensive therapy and has a post-washout mean sitting clinic SBP ≥150 and 
≤180 mm Hg on Day 1; or the subject has not received antihypertensive treatment within 28 days prior to 
Screening and has a mean sitting clinic SBP ≥150 and ≤180 mm Hg at the Screening Visit and on Day 1.

The subject is a man or woman aged 18 years or older.

In the opinion of the investigator, the subject is capable of understanding and complying with protocol 
requirements.


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
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.

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 through 30 days after last study drug dose.

The subject has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) within 
the reference range for the testing laboratory or the investigator does not consider the results to be clinically 
significant.

The subject is willing to discontinue current antihypertensive medications on Day -21 or on Day -28 if the subject 
is on amlodipine or chlorthalidone.
Main Criteria for Exclusion:

The subject has a mean sitting, clinic diastolic blood pressure (DBP) greater than 110 mm Hg at Day 1(after 
placebo run in).

The subject is non-compliant (less than 70% or greater than 130%) with study medication during placebo run-in 
period.

The subject has secondary hypertension of any etiology (eg, renovascular disease documented as the cause of 
hypertension, pheochromocytoma, Cushing’s syndrome).

The subject has a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, 
percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient 
ischemic attack.

The subject has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick 
sinus syndrome).

The subject has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or 
hypertrophic obstructive cardiomyopathy.

The subject has severe renal dysfunction or disease (based on estimated glomerular filtration rate 
<30 mL/min/1.73 m2) at Screening.

Subject has known or suspected unilateral or bilateral renal artery stenosis.

The subject has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study 
drug. (This criterion does not apply to those subjects with basal cell or Stage 1 squamous cell carcinoma of the 
skin).

The subject has type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at 
Screening.

The subject has hyperkalemia (defined as serum potassium above the normal reference range of the central 
laboratory) at Screening.

The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of greater than 
2.5 times the upper limit of normal (ULN), active liver disease, or jaundice at Screening.

The subject has any other known serious disease or condition at Screening (or Randomization) that would 
compromise subject safety, might affect life expectancy, or make it difficult to successfully manage and follow 
the subject according to the protocol.

The subject has a history of hypersensitivity or allergies to hypersensitivity to TAK-491 (azilsartan medoxomil), 
any of its excipients or other angiotension II (AII) receptor blockers (ARBs).

If female, the subject is pregnant or lactating or intending to become pregnant during the participation in this 
study; or intending to donate ova during such time period.


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!
The subject currently is participating in another investigational study or is receiving or has received any 
investigational compound within 30 days prior to the first dose of the study medication.
Note: This criterion does not apply to subjects who participated in observational studies that lacked an 
intervention or invasive procedure.
!
The subject is an immediate family member, study site employee, or is in a dependant relationship with a study 
site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under 
duress.
!
The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within the 
past 2 years.
!
The subject is taking or expected to take an excluded medication listed in Section 7.3 of the protocol.
!
The subject works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]). (Only for subjects with 
ambulatory blood pressure monitoring (ABPM).
!
The subject has an upper arm circumference <24 cm or >42 cm. (Only for subjects with ABPM.)
Main Criteria for Evaluation and Analyses:
The primary endpoint is change from baseline to Week 8 in trough (approximately 24 hours after the previous dose) 
sitting clinic SBP.
Secondary endpoints are:
!
The change from baseline to Week 8 in trough sitting clinic DBP.
!
Percentage of responders at Week 8, as defined by the following:
a)
Clinic SBP <140 mm Hg and/or reduction of ≥20 mm Hg from baseline.
b)
Clinic DBP <90 mm Hg and/or reduction of ≥10 mm Hg from baseline.
c)
a and b.
!
Percentage of subjects achieving target blood pressure at Week 8, as defined by the following:
a)
Clinic SBP <140 mm Hg.
b)
Clinic DBP <90 mm Hg.
c)
Clinic SBP <140 mm Hg and DBP <90 mm Hg.
d)
Clinic SBP <130 mm Hg.
e)
Clinic DBP <80 mm Hg.
f)
Clinic SBP <130 mm Hg and DBP <80 mm Hg.
Additional endpoints are:
CCI


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Statistical Considerations:
Analysis Sets:
Safety Analysis Set: All subjects who receive at least 1 dose of double-blind study medication. Subjects will be 
analyzed according to the study medication they received.
Full Analysis Set (FAS): All randomized subjects who received at least 1 dose of study medication. Subjects will be 
analyzed according to the treatment group to which they were randomized.
Subjects who were randomized more than once will be excluded from both the safety analysis set and the FAS.
Efficacy Analysis:
Unless otherwise specified, efficacy analyses will be performed using the FAS and all statistical inference will use a 
2-sided 0.05 significance level. A subject will be included in the primary analyses only when there is both a baseline 
value and at least 1 value during the double-blind treatment period. Missing values will be imputed using last 
observation carried forward (LOCF) methodology. In the LOCF analysis data set, the last post-baseline double-blind 
observed value will be carried forward and used for all subsequent scheduled time points where data are missing (eg, 
the subject has missing data or has dropped out of the study).
The primary analysis will be based on an analysis of covariance (ANCOVA) model for change in clinic SBP from 
baseline to week 8. The model will include treatment as a fixed effect and baseline clinic SBP as a covariate. From the 
framework of the ANCOVA the following will be determined: treatment LS mean, LS mean for the difference 
between TAK-491 and valsartan, p-value and 2-sided 95% confidence intervals for the treatment difference. For the 
primary analysis the overall type 1 error rate of 0.05 will be controlled using the 4 step sequential test described below.

Step 1: A test for noninferiority of TAK-491 80 mg to valsartan 160 mg will be performed using a noninferiority 
margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the treatment difference (TAK-491 – valsartan) 
is not greater than 1.5 then proceed to Step 2.

Step 2: A test for noninferiority of TAK-491 40 mg to valsartan 160 mg will be performed using a noninferiority 
margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the treatment difference (TAK-491 – valsartan) 
is not greater than 1.5 then proceed to Step 3.

Step 3: A test for significant difference between TAK-491 80 mg versus valsartan 160 mg will be performed at the 
5% level. If the p-value is not greater than 0.05 then proceed to Step 4.

Step 4: A test for significant difference between TAK-491 40 mg versus valsartan 160 mg will be performed at the 
5% level.
Based on historical data, the observed placebo-corrected treatment effects on change from Baseline in clinic SBP for 
valsartan 160 mg once daily was -8.6 mm Hg. Therefore, the noninferiority margin was set conservatively at 
1.5 mm Hg, which is less than one-third of the valsartan treatment effect. Accordingly, TAK-491 will be considered 
noninferior to valsartan when the upper limit of the 2-sided 95% CI of the treatment difference 
(TAK-491-comparator) is ≤1.5 mm Hg. The secondary endpoint, change from baseline to Week 8 in trough sitting 
clinic DBP will be analyzed similar to the primary endpoint, excluding the sequential testing. Change from baseline 
for both SBP and DBP at other visits will be summarized similar to the primary endpoint.
Additionally, similar analyses will be performed for both SBP and DBP for selected subgroups where appropriate, eg, 
age, sex.
The categorical secondary efficacy endpoints, percentage of subjects responding to treatment and percentage of 
subjects reaching blood pressure target at Week 8 will be tabulated for each of the following definitions:

Response criteria.
a)
Clinic SBP <140 mm Hg and/or a reduction of 20 mm Hg from baseline.
b)
Clinic DBP <90 mm Hg and/or a reduction of 10 mm Hg from baseline.
c)
a and b (ie, joint criteria).

Target blood pressure.


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a) Clinic SBP <140 mm Hg.
b)
Clinic DBP <90 mm Hg.
c)
Clinic SBP<140 mm Hg and DBP<90 mm Hg.
d)
Clinic SBP<130 mm Hg.
e)
Clinic DBP<80 mm Hg.
f)
Clinic SBP<130 mm Hg and DBP<80 mm Hg.
A logistic model with treatment as fixed effect and baseline clinic SBP as a covariate will be used to analyze response 
for clinic SBP. The odds ratio and its 95% confidence will be estimated. Similarly, a logistic model with treatment as 
fixed and baseline clinic DBP as a covariate will be used to analyze the response for clinic DBP. The joint response for 
both clinic SBP and DBP will be analyzed using a logistic model with treatment as fixed effect and baseline clinic SBP 
as a covariate. A similar analysis and model will be used to analyze the percentage of subjects reaching target blood 
pressure at Week 8. The percentage of subjects responding to treatment, as well as reaching blood pressure target, will 
also be presented for other visits, using the above methods.
Subgroups (eg, age, sex) analyses may be performed if data permit.
Sensitivity analyses to be performed on the primary endpoint (and other endpoints where appropriate) include: 
multiple imputation for missing values; analyses using the per protocol set; and analyses using observed values only.
Safety Analysis:
All safety assessments, including AEs, clinical laboratory test results, vital sign measurements, and 12-lead ECG 
results will be presented in the data listings. Treatment-emergent AEs will be summarized by treatment group. 
Laboratory values, pulse rate, and 12-lead ECG results will be summarized with descriptive statistics and/or shift 
tables.
Sample Size Justification:
Assuming an SD of 17 mm Hg and a 10% dropout rate, a sample size of 200 subjects per treatment group (total of
600 subjects) is sufficient to achieve at least 90% power to detect a difference of 6 mm Hg between TAK-491 dose and 
valsartan by a 2-sample t-test on the mean change from baseline to Week 8 in mean sitting clinic SBP at 0.05 2-sided 
significance level. This sample size will also provide, for the above assumptions, at least 90% power for 
demonstrating noninferiority with a margin of 1.5 mm Hg between TAK-491 and valsartan.


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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
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
ABPM
ambulatory blood pressure monitoring
ACE
angiotensin-converting enzyme
AE
adverse event
AII
angiotensin II
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ARB
angiotensin II receptor blocker
AST
aspartate aminotransferase
AT1
angiotensin II type 1 receptor
AT2
angiotensin II type 2 receptor
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CCB
calcium channel blocker
CFDA
China Food and Drug Administration
COX-2
Cyclooxygenase-2
CPAP
continuous positive airway pressure
eCRF
case report form (electronic)
CRO
contract research organization
CYP
cytochrome P-450
DBP
diastolic blood pressure
ECG
Electrocardiogram
eGFR
estimated GFR
EMA
European Medicines Agency
ESRD
end-stage renal disease
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
-glutamyl transferase
HbA1c
Hemoglobin A1c
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein cholesterol
HOCM
hypertrophic obstructive cardiomyopathy
HTN
hypertension
ICH
International Conference on Harmonisation
IEC
independent ethics committee


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IRB
institutional review board
IVRS
interactive voice response system
IWRS
interactive web response system
JNC
Joint National Committee
LDL-C
low-density lipoprotein cholesterol
LFT
liver function test
LOCF
last observation carried forward
MAO
monamine oxidase
MedDRA
Medical Dictionary for Regulatory Activities
NSAIDs
nonsteroidal anti-inflammatory drugs
O/E
over-encapsulated
PDE5
phosphodiesterase type 5
PPS
per-protocol analysis set
PTE
pretreatment event
QD
once daily
RAAS
renin-angiotensin-aldosterone system
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SUSAR
suspected unexpected serious adverse reactions
t1/2z
terminal elimination half life
TAK-491
azilsartan medoxomil
TAK-536
azilsartan
TEAE
treatment-emergent adverse events
UACR
urinary albumin creatinine ratio
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
WBC
white blood cell
WHO
World Health Organization
3.4
Corporate Identification
TDC Asia
Takeda Development Center Asia, Pte. Ltd.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
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
According to the World Health Organization (WHO), hypertension is the most common 
attributable cause of preventable death in developed nations and is increasing in importance in 
developing countries [1], as uncontrolled hypertension greatly increases the risk of cardiovascular 
disease, cerebrovascular disease, and renal failure [2,3]. As the population ages, the prevalence of 
hypertension will continue to increase if broad and effective preventive and treatment measures 
are not implemented [2]. According to the current Chinese guideline for the management of 
hypertension, there are more than 200 million Chinese with hypertension. Despite the availability 
of antihypertensive agents, hypertension remains inadequately controlled. There is about 50% 
awareness of hypertension, the percentage of patients with hypertension receiving treatment is 
only 30% with only 10% with high BP controlled to below 140/90 mmHg in China [4].
Angiotensin Receptor Blockers (ARBs), such as olmesartan medoxomil and valsartan, are widely 
used for the treatment of hypertension and have well-established safety profiles [5]. ARBs 
modulate 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. Renin, an enzyme produced in the kidney, acts on angiotensinogen, to form 
angiotensin I, which is converted to angiotensin II (AII) in a reaction catalyzed by 
angiotensin-converting enzyme (ACE). AII is the principal pressor agent of the RAAS with effects 
on the cardiovascular system and electrolyte homeostasis [6]. Two receptor subtypes have been 
identified for AII, the angiotensin II type 1 receptor (AT1) and the angiotensin II type 2 receptor 
(AT2), which often have opposing actions when activated. Activation of the AT1 receptor results 
in vasoconstriction, hypertrophic proliferation, and inflammation, while activation of the 
AT2 receptor results in vasodilation and antiproliferative effects [7]. Blocking the AT1 receptor 
allows blood vessels to dilate, resulting in blood pressure (BP) reduction [8].
Drugs that modulate the RAAS are used globally for the treatment of hypertension (eg, ACE 
inhibitors, ARBs, and more recently the direct renin inhibitor, aliskiren) [8]. These and other 
antihypertensive agents are often effective, but many have side effects that limit their use. ACE 
inhibitors are associated with cough and, more rarely, with angioedema; β-blockers, with fatigue 
and erectile dysfunction; calcium-channel blockers (CCBs), with peripheral edema; and diuretics, 
with metabolic complications [9].
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 of ACE inhibitors [10]. 
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 which improve tolerability and efficacy for the treatment of 
hypertension and therefore, TAK-491 (azilsartan medoxomil), a prodrug that is rapidly hydrolyzed 


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to the active moiety, TAK-536 (azilsartan), 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 BP in rats and dogs after single or 
multiple daily dosing without tachycardia and without rebound hypertension after 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 (SBP), an observation consistent with the pharmacodynamic profile of the compound.
4.3
Summary of Clinical Data
After oral administration, TAK-491 is converted to the active moiety TAK-536 by ester hydrolysis 
in the gut and/or during the process of absorption. Conversion is rapid, as the salt free form of 
TAK-491 (TAK-491F) is undetectable in human plasma at the earliest time points examined 
(5 minutes following administration of single oral doses of TAK-491 at 40 and 80 mg and 
15 minutes following multiple oral doses of TAK-491 at 320 mg). TAK-536 undergoes extensive 
metabolism to TAK-536 M-I and TAK-536 M-II. Following both single and multiple dosing of 
TAK-491 tablets, dose proportionality was established for TAK-536 and TAK-536 M-II area 
under the plasma concentration-time curve and maximum observed plasma concentration values 
over the dose range of 20 to 320 mg.
TAK-491 has been evaluated in 17 phase 1 studies and 1 phase 2 study. The phase 3 program 
consisted of 5 randomized, controlled, monotherapy studies of 6 weeks or 6 months duration; 
2 randomized, controlled, 6-week studies in which TAK-491 was coadministered with the 
thiazide-like diuretic chlorthalidone or the calcium channel blocker (CCB) amlodipine; and 
2 open-label studies of up to 56 weeks duration.
Dose adjustment is not needed based on age, gender, or race.
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. Subjects with severe hepatic 
impairment were not studied. The increases in exposure to TAK-536 in the phase 1 hepatic 
impairment study 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. Therefore, TAK-491 dose reduction is not necessary for 
subjects with mild or moderate hepatic impairment, although subjects with any degree of hepatic 
impairment are excluded from the present study.
The single dose phase 1 study in renal impaired subjects showed that after 40 mg TAK-491 dosing, 
total exposure to TAK-536 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, or severe renal 


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impairment, and end-stage renal disease (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 (160 to 320 mg) study in healthy subjects (01-06-TL-491-017). The mean terminal 
elimination half-life (t1/2z) of TAK-536 was not substantially different in subjects with renal 
impairment than in healthy subjects. Therefore, no dose adjustment of TAK-491 is required for 
subjects with any degree of renal impairment or ESRD, although subjects with severe renal 
impairment (estimated glomerular filtration rate [eGFR] <30 (mL/min/1.73 m2) are excluded from 
this study.
No clinically significant interactions have been observed with drugs that are metabolized by 
cytochrome P-450 (CYP) isozymes (eg, pioglitazone, glyburide, caffeine, tolbutamide, 
midazolam, dextromethorphan, and warfarin), with the potent CYP inhibitors (ketoconazole and 
fluconazole), with drugs that are excreted unchanged in urine (metformin, digoxin, and 
chlorthalidone), or with the P-glycoprotein substrates (fexofenadine and digoxin). There was no 
clinically significant interaction between TAK-491 and an aluminum-magnesium hydroxide 
antacid. In a study evaluating the potential effects of TAK-491 on the QT interval, TAK-491 
320 mg was not associated with evidence of QT prolongation based on analyses of multiple QT 
interval correction formulae.
Results of the phase 3 program demonstrated that, relative to placebo, the TAK-491 20, 40, and 
80 mg doses produce clinically and statistically significant reductions in systolic blood pressure 
(SBP) and diastolic blood pressure (DBP), as assessed by both ambulatory blood pressure 
monitoring (ABPM) and clinic blood pressure measurements. The differences between doses were 
greater for subgroups of subjects characterized by more severe and/or resistant hypertension, 
including black subjects, subjects with renal impairment, and subjects with Grade 2 hypertension. 
In each study, most of the blood pressure-lowering effect of TAK-491 was observed within 
2 weeks of treatment; a plateau of effect was generally reached by week 4 and reductions were 
maintained through week 6 in short-term studies and over the long-term in two 6-month studies 
(and up to 1 year in open-label studies). In replicate studies, TAK-491 at 80 mg was shown to 
reduce systolic blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 
320 mg, the highest approved doses in the US.
In two controlled studies, coadministration of TAK-491 with chlorthalidone (491-009) and 
amlodipine (491-010) provided additional blood pressure reduction compared with chlorthalidone 
or amlodipine monotherapy. In open-label studies, addition of diuretic therapy to treatment with 
TAK-491 led to additional blood pressure reductions in subjects who did not reach blood pressure 
targets after initiation of TAK-491.
In clinical trials with hypertensive subjects, treatment with TAK-491 was well-tolerated with an 
overall incidence of adverse reactions and withdrawals due to adverse events similar to that of 
placebo. Generally, adverse reactions were mild, not dose related and similar regardless of age, 
gender and race. The safety and tolerability profile of TAK-491 was similar to that of other agents 
of the ARB class. Commonly reported adverse events included headache, dizziness, urinary tract 
infection (UTI), nasopharyngitis and dyslipidemia; diarrhea was reported more frequently with 
TAK-491 than placebo. As compared with other ARBs, a higher incidence of mechanism-based 


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side effects of dizziness and reversible serum creatinine elevations were observed with TAK-491, 
which is consistent with the greater antihypertensive effect of the drug.
In summary, TAK-491 was well tolerated at doses up to 320 mg in healthy subjects and up to 
80 mg in hypertensive subjects (maximal dose evaluated in this population). TAK-491 has been 
shown to have a strong antihypertensive effect, predictable pharmacokinetic and metabolic 
profiles, a prolonged duration of action, and good safety and tolerability profiles when 
administered as a monotherapy to hypertensive subjects. As of February 2016, TAK-491
(azilsartan medoxomil [Edarbi]) has been approved for the treatment of hypertension, either alone 
or in combination with other antihypertensive agents, in a total of 59 countries worldwide, 
including approval in the United States by the Food and Drug Administration (FDA) in February 
2011 and in the European Union by the European Medicines Agency (EMA) in December 2011.
Please refer to the TAK-491 monotherapy Investigator’s Brochure [11] and Edarbi package insert 
[12,13] for additional information.
4.4
Rationale for the Proposed Study
Phase 3 studies have demonstrated that TAK-491 treatment at a dose of 40 mg once daily and 
80 mg once daily are effective and safe in hypertensive subjects evaluated in the United States, 
Latin America, and Europe. This 8-week study is being conducted to compare the efficacy and 
safety profile of TAK-491 40 mg once daily and 80 mg once daily to that of valsartan 160 mg once 
daily in Chinese subjects with essential hypertension. Valsartan is a marketed, widely used ARB 
with well documented efficacy and safety in treatment of hypertension; the highest approved dose 
in China is 160 mg once daily (QD).


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To evaluate the antihypertensive effect of TAK-491 compared with valsartan in Chinese subjects 
with essential hypertension.
5.1.2
Secondary Objective
To evaluate safety and tolerability of TAK-491 compared with valsartan.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is change from baseline to Week 8 in trough (approximately 24 hours after 
the previous dose) sitting clinic SBP.
5.2.2
Secondary Endpoints
!
The change from baseline to Week 8 in trough sitting clinic DBP.
!
Percentage of responders at Week 8, as defined by the following:
a) Clinic SBP <140 mm Hg and/or reduction of ≥20 mm Hg from baseline.
b) Clinic DBP <90 mm Hg and/or reduction of ≥10 mm Hg from baseline.
c) a and b.
!
Percentage of subjects achieving target blood pressure at Week 8, as defined by the following:
a) Clinic SBP <140 mm Hg.
b) Clinic DBP <90 mm Hg.
c) Clinic SBP <140 mm Hg and DBP <90 mm Hg.
d) Clinic SBP <130 mm Hg.
e) Clinic DBP <80 mm Hg.
f)
Clinic SBP <130 mm Hg and DBP <80 mm Hg.
5.2.3
Additional Endpoints
Efficacy
!
CCI


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!
!
5.2.4
Safety
AEs, safety laboratory tests, 12-lead ECG findings and vital signs (including orthostatic vital 
signs).
CCI


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a phase 3, multicenter, randomized, double-blind, parallel-group study to evaluate the 
efficacy and safety of TAK-491 compared with valsartan over an 8 week treatment period in 
Chinese subjects with essential hypertension (trough, sitting clinic SBP ≥150 and ≤180 mm Hg on 
Day 1). This study will be conducted in China at approximately 20 to 25 sites and will include 
approximately 600 randomized subjects.
Before initiation of treatment, all subjects will participate in a 2-week, single-blind, placebo run-in 
period (Days -14 to -1). Subjects who have not received antihypertensive treatment within 28 days 
before screening can be entered into the run-in period as soon as all inclusion and exclusion 
criteria, including laboratory results, have been verified. Subjects taking previous antihypertensive 
agents will be required to participate in a 3-week washout/placebo run-in period (Days -21 to -1). 
If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then 
the washout/placebo run-in must be extended to 4 weeks (Days -28 to -1). Screening (Visit 1) will 
be scheduled before the washout/run-in period begins so that laboratory test results can be 
reviewed and subject eligibility can be confirmed before other treatments are stopped or placebo is 
initiated. At Day -14 (Visit 2), subjects will receive the first dose of single-blind placebo in clinic.
At Day 1 (Visit 5), eligible subjects will be randomly assigned to one of the following 3 groups 
with a 1:1:1 ratio:

TAK-491 40 mg QD.

TAK-491 80 mg QD.

Valsartan 160 mg QD.
Subjects will be given the first dose of randomized study drug in the clinic at Day 1 (Visit 5). The 
last dose of randomized study drug will be taken the day of Week 8 visit (Visit 9). End of study 
assessment will be taken at Week 8/Early Termination (Visit 9). All subjects who receive study 
drug (placebo or double-blind) will be required to have a follow-up telephone call at 
approximately 14 days after the last dose.
A schematic of the study design is included as Figure 6.a.


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Figure 6.a
Schematic of Study Design
Randomization
(n=200/arm)
TAK-491 40 mg QD (n=200)
TAK-491 80 mg QD (n=200)
Valsartan 160 mg QD (n=200)
Other
anti-HTN 
treatments 
stopped
1st dose 
of 
placebo 
(e)
Last 
dose
of 
placebo
First dose 
of double 
blind 
randomized 
study drug
Visit 6 
Wk 2
Visit 7 
Wk 4
Visit 8
Wk 6
Last dose 
of double 
blind (g)
Removal 
ABPM
Tele-
phone 
contact 
(h)
Visit 1 
(a)
N/A (b)
D -21(c) or 
D -28 (d)
Visit 2
D -14
(f)
Visit 3
D -7
Visit 4
D -1
(i)
Visit 5
D 1
Visit 9 
Final 
Visit/
ET 
Visit 10
(j)
N/A
Follow-
up
Single-Blind Placebo 
Run-In
Double-Blind Treatment
Post-treatment
Washout
Screening Visit
V=visit, N/A=not applicable, D=day, HTN=hypertension, Wk=week, ET=Early Termination.
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results can be reviewed 
and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated.
(b) Subjects may be notified by telephone to begin the washout period.
(c) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout/run-in period (Days -21 to -1).
(d) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout must be extended 
to 4 weeks (Days -28 to -1).
(e) The first dose of placebo will be taken at the clinic on Day -14 (Visit 2).
(f) Subjects who have not received antihypertensive treatment within 28 days prior to Screening can be entered into the run-in 
period as soon as all inclusion and exclusion criteria, including laboratory results, have been verified.
(g) Last dose of double-blind is the day of Week 8/Final clinic visit or ET (Visit 9). And, in subgroup of ABPM subjects will start 
24-hour ABPM measurement.
(h) The follow-up telephone contact should be made approximately 14 days after the last dose.
(i) Visit 4 only applies to ABPM subgroup subjects; start 24-hour ABPM measurement.
(j) Visit 10 only applies to ABPM subgroup subjects.
A schedule of assessments is provided in Appendix A.
6.2
Justification for Study Design, Dose, and Endpoints
TAK-491 is a prodrug that is rapidly hydrolyzed to the active moiety, TAK-536, which is a 
long-acting, angiotensin II AT1 receptor blocker (ARB). TAK-491 has been shown to have a 
strong antihypertensive effect, predictable pharmacokinetic and metabolic profiles, a prolonged 
duration of action, and good safety and tolerability profiles when administered as a monotherapy 
to hypertensive subjects. The phase 3 TAK-491 studies have shown that TAK-491 80 mg reduced 
blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 320 mg, the 
highest approved doses in the US. As of February 2016, TAK-491 has been approved for the 
treatment of hypertension, either alone or in combination with other antihypertensive agents, in a 
total of 59 countries worldwide, including approval in the United States by the Food and Drug 
Administration (FDA) in February 2011 and in the European Union by the European Medicines 
Agency (EMA) in December 2011.


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The objective of this phase 3, randomized, double-blind, parallel-group study of 8 weeks duration 
is to examine the efficacy and safety of TAK-491 compared to valsartan in Chinese subjects with 
mild to moderate essential hypertension. Since the intended registration doses for TAK-491 in 
China will be 40 mg and 80 mg, these were the TAK-491 doses selected for this study. Valsartan is 
a marketed, widely used ARB with known efficacy in mild to moderate essential hypertension and 
the highest approved dose in China is 160 mg, with 320 mg as the highest approved dose in other 
regions (United States, European Union, etc).In addition in Takeda’s global studies 
(TAK-491-019 and 301), TAK-491 40 mg and 80 mg were evaluated in comparison with 320 mg 
of valsartan. Based on these considerations, and to reflect standard of care practices in China, 
40 mg and 80 mg TAK-491 were selected for comparison with 160 mg of valsartan in this study.
The 8 week duration is sufficient to evaluate the efficacy because in all previous studies, a plateau 
in blood pressure reduction was observed after 4 weeks of treatment for both TAK-491 and 
valsartan. The study design employs a 3 to 4 week washout period to establish a true drug-free 
baseline blood pressure and to determine severity of hypertension in enrolled population at 
randomization. A coincident 2-week, single-blind, placebo run-in period is to evaluate study drug 
compliance. This short-term washout/placebo treatment period is not associated with increased 
risk of major irreversible cardiovascular events in a hypertensive population [14,15].
Frequent visits and withdrawal criteria for elevated BP during the study as defined in Section 7.5
will further ensure the safety of the study subjects.
The primary endpoint of this study is sitting, clinic SBP, which is a well-established measure for 
assessing antihypertensive effect and is a better predictor of cardiovascular outcomes than DBP. 
Clinic SBP is an appropriate primary endpoint because it is validated as a surrogate endpoint in 
observational and interventional clinical studies [16-18].
ABPM parameters will also be evaluated in a subset of approximately 60 patients per arm. ABPM 
parameters are clinically more predictive of cardiovascular outcome than clinic BP measurements, 
as demonstrated by numerous studies. In particular, mean 24-hour SBP is the best predictor of 
cardiovascular risk, even after adjustment for risk factors including clinic BP [19-21].
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.


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6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
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 Sites
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 randomization.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria:
1. The subject is treated with antihypertensive therapy and has a post-washout mean sitting clinic 
SBP ≥150 and ≤180 mm Hg on Day 1; or the subject has not received antihypertensive 
treatment within 28 days prior to Screening and has a mean sitting clinic SBP ≥150 and 
≤180 mm Hg at the Screening Visit and on Day 1.
2. The subject is a man or woman aged 18 years or older.
3. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
4. 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.
5. 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 
through 30 days after last study drug dose.
*Definitions and acceptable methods of contraception are provided in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and reporting 
responsibilities are defined in Section 9.1.10 Pregnancy.
6. The subject has clinical laboratory test results (clinical chemistry, hematology, and complete 
urinalysis) within the reference range for the testing laboratory or the investigator does not 
consider the results to be clinically significant.
7. The subject is willing to discontinue current antihypertensive medications on Day -21 or on 
Day -28 if the subject is on amlodipine or chlorthalidone.
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 a mean, sitting clinic DBP greater than 110 mm Hg at Day 1 (after placebo 
run in).
2. The subject is non-compliant (less than 70% or greater than 130%) with study medication 
during placebo run-in period.
3. The subject has secondary hypertension of any etiology (eg, renovascular disease documented 
as the cause of hypertension, pheochromocytoma, Cushing’s syndrome).


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4. The subject has a history of myocardial infarction, heart failure, unstable angina, coronary 
artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, 
cerebrovascular accident, or transient ischemic attack.
5. The subject has clinically significant cardiac conduction defects (eg, third-degree 
atrioventricular block, sick sinus syndrome).
6. The subject has hemodynamically significant left ventricular outflow obstruction due to aortic 
valvular disease and hypertrophic obstructive cardiomyopathy (HOCM).
7. The subject has severe renal dysfunction or disease (based on estimated glomerular filtration 
rate [GFR] <30 mL/min/1.73 m2) at Screening.
8. The subject has known or suspected unilateral or bilateral renal artery stenosis.
9. The subject has a history of cancer that has not been in remission for at least 5 years prior to the 
first dose of study drug. (This criterion does not apply to those subjects with basal cell or 
Stage 1 squamous cell carcinoma of the skin).
10. The subject has type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] 
>8.5%) at Screening.
11. The subject has hyperkalemia (defined as serum potassium above the normal reference range 
of the central laboratory) at Screening.
12. The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 
of greater than 2.5 times the upper limit of normal (ULN), active liver disease, or jaundice at 
Screening.
13. The subject has any other known serious disease or condition at Screening (or Randomization) 
that would compromise subject safety, might affect life expectancy, or make it difficult to 
successfully manage and follow the subject according to the protocol.
14. The subject has a history of hypersensitivity or allergies to TAK-491 (azilsartan medoxomil), 
any of its excipients or other angiotension II (AII) receptor blockers (ARBs).
15. 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.
16. The subject currently is participating in another investigational study or is receiving or has 
received any investigational compound within 30 days prior to the first dose of study 
medication.
Note: This criterion does not apply to subjects who participated in observational studies that 
lacked an intervention or invasive procedure.
17. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.


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18. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol 
abuse within the past 2 years.
19. The subject is taking or expected to take an excluded medication listed in Section 7.3 of the 
protocol.
20. The subject works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]). (Only for 
subjects with ABPM)
21. The subject has an upper arm circumference <24 cm or >42 cm. (Only for subjects with 
ABPM)
7.3
Excluded Medications and Treatments

Antihypertensive agents, including those used for treatment of other conditions, such as benign 
prostatic hyperplasia (-blockers) or edema (diuretics). Those used at screening must be 
discontinued for the washout/run-in period through the completion of final in-clinic 
procedures at Week 8/Early Termination (Visit 9). Amlodipine and chlorthalidone should be 
discontinued on Day -28, while all other antihypertensive medications should be discontinued 
on Day -21. If necessary, medications that need to be stopped gradually may be tapered in the 
first week of screening, but must be discontinued completely by Day -14.

Other agents that alter BP are excluded from the beginning of the run-in period through the 
remainder of the study. These include:

Tricyclic antidepressants.

Monoamine oxidase (MAO) inhibitors.

Central nervous system stimulants.

Amphetamines or their derivatives.

Dopamine agonists.

Atypical antipsychotic agents.

Trazodone.

Lithium.

Diet medications (except orlistat).

Nitrates.

Thiazolidinediones.

Conditionally excluded medications as specified:

Phosphodiesterase type 5 (PDE5) inhibitors within 72 hours of a clinic visit.


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
Chronically used (defined as more than 3 doses per week) common cold medications with 
pseudoephedrine or phenylephrine, or nonsteroidal anti-inflammatory drugs (NSAIDs), 
including aspirin >325 mg/day or cyclooxygenase-2 (COX-2) inhibitors.

Systemic use of corticosteroids (topical or inhaled is acceptable).

Subjects will be instructed not to take any medications, including over-the-counter products, 
without first consulting the investigator.
7.4
Diet, Fluid, Activity Control
Subjects should be encouraged to avoid foods high in sodium and avoid adding extra salt to food 
since excessive sodium consumption may elevate blood pressure in certain individuals. Otherwise, 
subjects should maintain their usual diet prior to, and during the study.
For a subject with signs of volume depletion, such as weight loss or orthostatic hypotension (BP 
decreases by 20 mm Hg systolic or 10 mm Hg diastolic after standing for 2 minutes), inquire 
about other sources of volume loss (eg, diarrhea, vomiting, poor oral intake). If there is evidence of 
volume depletion, consider temporarily liberalizing salt intake and encouraging increased 
hydration. If these measures do not alleviate the orthostatic hypotension, the case should be 
discussed with the medical monitor and the subject considered for withdrawal.
After informed consent is provided, subjects will be asked to fast prior to blood draws within the 
Screening Period, and will be instructed to fast for at least 8 hours prior to returning to the study 
site for Day 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9).
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 (electronic) (eCRF) using the following categories. For screen 
failure subjects, refer to Section 9.1.12.
1. Pretreatment event or adverse event (AE). The subject has experienced a pretreatment event 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 pretreatment 
event or AE.
2. Major protocol deviation. The discovery post randomization 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.
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 
(e)CRF.


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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 or lack of efficacy 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. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
investigational treatment; and, continued participation would pose an unacceptable risk to the 
subject.
Note: If the mean blood pressure exceeds 180 mm Hg systolic and/or 110 mm Hg diastolic at 
any time after screening or randomization, the blood pressure measurement should be repeated 
within 48 hours. If blood pressure remains elevated, the subject should be considered for 
withdrawal.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the (e)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 Early Termination 
Visit. Discontinued or withdrawn subjects will not be replaced.


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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
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to all or any of the drugs defined below.

TAK-491 40 mg and matching placebo tablets.

TAK-491 80 mg and matching placebo tablets.

Valsartan 80 mg and matching placebo capsules.
8.1.1.1
Investigational Drug
TAK-491 and Matching Placebo Tablets
TAK-491 study medication is manufactured by Takeda Pharmaceutical Company, Osaka, Japan 
and will be supplied as white, round 40 mg or 80 mg tablets with matching placebo tablets.
TAK-491 study medication will be foil/foil blistered and packaged in 20-day (2 week plus 
6 additional spare daily doses) child resistant, blister cards containing 40 tablets with 
40 desiccants. Each tablet is connected to a desiccant through a linked channel during the 
blistering process. Each blister card for the single blind treatment period will contain twenty 
placebo for TAK-491 40 mg tablets and twenty placebo for TAK-491 80 mg tablets. Each blister 
card for the blinded treatment periods will contain twenty TAK-491 40 mg, twenty TAK-491 
80 mg or matching placebo tablets. The daily dose will be 2 tablets.
Each blister card label will be compliant with requirements of the China Food and Drug 
Administration, P.R., China (CFDA).
Valsartan and Matching Placebo Capsules
Valsartan 80 mg capsules will be manufactured by Novartis Pharmaceuticals Corp., China
Valsartan capsules will be over-encapsulated (O/E) and placebo capsules will be manufactured by 
Fisher Clinical Services. The capsules will be Swedish Orange Opaque, Size AAeL, DBcaps. The 
capsules will be packaged in 120 cc wide-mouth, pharmaceutical-grade, round, white, 
high-density polyethylene bottles with a 38 mm child-resistant cap with 75M induction seal.
Each bottle for the single blind placebo run-in period will contain 40 placebo capsules. Each bottle 
for the treatment period will contain 40 O/E valsartan 80 mg or matching placebo capsules. The 
daily dose will be 2 capsules (160 mg) to support the study design.


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Each bottle label will be compliant with requirements of the China Food and Drug Administration, 
P.R, China (CFDA).
8.1.1.2
Sponsor-Supplied Drug
Sponsor-supplied drugs referenced in other sections of the protocol include the following:

TAK-491 40 mg and matching placebo tablets.

TAK-491 80 mg and matching placebo tablets.

Valsartan 80 mg and matching placebo capsules.
8.1.1.3
Ancillary Materials
ABPM devices will be supplied to the designated sites by the sponsor.
The investigator or designee must ensure that the sponsor-supplied device is used in accordance 
with the approved protocol and is dispensed only to subjects enrolled in the study. The investigator 
must maintain records of all sponsor-supplied device delivery to the site, site inventory, 
dispensation and use by each subject, and return to the sponsor or designee after the subjects 
complete the study.
8.1.2
Storage
TAK-491 investigational study drugs should be stored at 25°C (77°F); with excursions permitted 
to 15-30°C (59-86°F). Study medication is to remain stored in the original container until time of 
dosing.
Valsartan and matching placebo study drug should be stored at 25°C (77°F); with excursions 
permitted to 15-30°C (59-86°F). Protect from moisture.
All clinical trial material must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. All sponsor-supplied drugs 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
This is a phase 3, multicenter, randomized, double-blind, parallel-group, 8-week efficacy and 
safety study comparing TAK-491 and valsartan.
Subjects will be randomized to 1 of the following 3 therapy treatment groups as follows:

TAK-491 40 mg QD (N=200).

TAK-491 80 mg QD (N=200).

Valsartan 160 mg QD (N=200).
Study medication will be packaged in a manner to maintain the blind.


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Placebo Run-in Period (Day-14 [Visit 2] to Day -1)

Subjects will be dispensed one 2-week blister card and one bottle.

Subjects will receive single-blind placebo tablets and placebo capsules.

First dose will be given in-clinic at Day -14 (Visit 2).

The daily oral administered dose will be two tablets from a blister card and two capsules from 
the bottle.
Treatment Period (Day 1 [Visit 5] through Week 8 / Early Termination [Visit 9])

Subjects will receive blinded study medication and will be instructed to take their blinded 
study medication prior to their first meal of the day. Subjects will be dispensed one 2-week 
carton and one bottle at day 1 (Visit 5), at week 2 (Visit 6), week 4 (Visit 7), and week 6 
(Visit 8).

First dose will be given in-clinic at Day 1 (Visit 5).

The daily oral administered dose will be two tablets from a blister card and two capsules from 
the bottle.
Table 8.a describes the dose and tablet/capsule count that will be provided to each group.
Table 8.a
Sponsor-Supplied Drug
Treatment 
Group
Dose
Treatment Description
Active
Placebo
Run-in QD
Zero active tablets/capsules
One placebo for 40 mg TAK-491 tablet, one 
placebo for 80 mg TAK-491 tablet, two placebo 
for 80 mg valsartan capsules
A
40 mg TAK-491 
QD
One 40 mg TAK-491 tablet
One placebo for 80 mg TAK-491 tablet, two 
placebo for 80 mg valsartan capsules
B
80 mg TAK-491 
QD
One 80 mg TAK-491 tablet
One placebo for 40 mg TAK-491 tablet, two 
placebo for 80 mg valsartan capsules
C
160 mg valsartan 
QD
Two 80 mg valsartan O/E 
capsules
One placebo for 40 mg TAK-491 tablet, one 
placebo for 80 mg TAK-491 tablet
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 (e)CRF, in order to capture this important safety information consistently in 


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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. Hemodialysis does 
not significantly remove TAK-536 or M-II from the systemic circulation. Valsartan cannot be 
removed from plasma by hemodialysis [22].
8.2
Investigational drug Assignment and Dispensing Procedures
The investigator or investigator’s designee will access the interactive voice/web response system 
(IVRS/IWRS) at Screening (Visit 1) to obtain the subject study number. The IVRS/IWRS will be 
accessed at Day -14 (Visit 2) to enroll the subject into the single-blind run-in period of the study 
and to randomize the subject into the study at Day 1 (Visit 5). During each of these contacts, the 
investigator or designee will provide the necessary subject-identifying information, including the 
subject number assigned at screening. The medication identification (ID) number of the 
investigational drug and other sponsor-supplied drug(s) to be dispensed will then be provided by 
the IVRS/IWRS. If sponsor-supplied drug is lost or damaged, the site can request a replacement 
from IVRS/IWRS. (Refer to IVRS/IWRS manual provided separately.). The Medication ID 
number will be entered onto the (e)CRF. At subsequent drug-dispensing visits, the investigator or 
designee will again contact the IVRS/IWRS to request additional investigational drug and other 
sponsor-supplied drug(s) for a subject. The medication ID number of the investigational drug and 
other sponsor-supplied drug(s) to be dispensed will be provided by the IVRS/IWRS. The 
Medication ID number will be entered onto the (e)CRF.
8.3
Randomization Code Creation and Storage
Randomization personnel of the sponsor or designee will generate the randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel.
8.4
Investigational Drug Blind Maintenance
The investigational drug blind will be maintained using the IVRS/IWRS.
8.5
Unblinding Procedure
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. 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 the investigator, by 
accessing the IVRS/IWRS. The sponsor must be notified as soon as possible if the investigational 


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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.
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug (TAK-491 40 mg, 
TAK-491 80 mg and OE Valsartan 80 mg and matching placebo) is used in accordance with the 
approved protocol and is dispensed only to subjects enrolled in the study. To document appropriate 
use of sponsor-supplied drug, the investigator must maintain records of all sponsor-supplied drug 
delivery to the site, site inventory, dispensation and use by each subject, and return to the sponsor 
or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and is in 
good condition. If quantity and conditions are acceptable, investigator or designee should 
acknowledge the receipt of the shipment by recording in IVRS/IWRS. 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 sponsor-supplied drugs received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to:

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot (or Medication ID or job number) 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 sponsor-supplied 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 sponsor-supplied 
drugs, date and amount dispensed including initials of the person dispensing the drug, and the date 
and amount returned to the site by the subject, including the initials of the person receiving the 
sponsor-supplied drug. The log should include all required information as a separate entry for each 
subject to whom sponsor-supplied drug is dispensed.


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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. The investigator will retain a 
copy of the documentation regarding clinical study material accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
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, certificates of analyses, 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 (Visit 1).
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases (relevant to the disease under study) that stopped at or prior to signing of 
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 and efficacy/safety evaluation stopped at or within 28 days prior to signing of informed 
consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the pretreatment assessment immediately prior to the 
start of investigational drug) 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. All subsequent physical examinations should assess clinically 
significant changes from the baseline examination.
9.1.4
Weight, Height and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The body mass index (BMI) is calculated by Takeda or designee using metric units with the 
formula provided below:
BMI = weight (kg)/height (m)2


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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 be measured at the visits indicated in the Schedule of Study Procedures (see 
Appendix A), and will include sitting and standing BP and pulse, along with time of collection.
At each visit, 3 serial BP measurements should be taken while the subject is seated, with a 
semi-automated BP device, which will be provided by the sponsor. The measurements should be a 
minimum of 2 minutes apart with the cuff fully deflated between each reading [2,23]. A single 
sitting pulse measurement also should be taken manually. Prior to measuring sitting BP, the 
subject should be seated quietly in a chair, not an examination table, for at least 5 minutes with feet 
on the floor and arm supported at heart level. The time the subject began sitting should be recorded 
in the source documents. BP will be measured using an appropriately sized cuff (cuff bladder 
encircling at least 80% of the arm) that is applied on the upper non-dominant arm at heart level. 
The same arm should be used for each measurement at all visits. Every effort should be made to 
standardize the conditions of clinic BP measurements, and blood pressure levels are to be assessed 
by the same investigator or site personnel (whenever possible), with the same equipment [2]. All 
readings are entered into the source document and (e)CRF for all subjects.
BP levels should be measured in the morning approximately 24 hours after the previous day’s 
dosing but before blood collection and before the next dose of study drug is administered. The date 
and time of the dose prior to the clinic BP measurement should be captured in the subject source 
document and (e)CRF. If any of the 3 SBP measurements differ by more than 8 mm Hg or any of 
the 3 DBP measurements differ by more than 5 mm Hg, a second set of 3 BP measurements should 
be obtained. The second set of readings should be entered into the (e)CRF. Original and 
repeat readings all must be recorded in the source documents with an explanation. The mean of the 
3 serial blood pressure measurements will be used to determine subject eligibility.
Standing blood pressure will also be measured at each visit to evaluate orthostatic vital signs. After 
BP is measured in the seated position as described above, a single BP measurement will be 
obtained after 2 minutes of standing. Standing BP will be measured using the same equipment and 
the same (non-dominant) arm that was used for the seated measurements. For standing BP 
measurements, the arm should be supported and extended such that the cuff is at heart level. A 
single pulse measurement also should be taken while the subject is standing.
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 


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end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the (e)CRF.
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 screening examination. The condition 
(ie, diagnosis) should be described.
Data on medical conditions that require Continuous Positive Airway Pressure (CPAP) will be 
collected during the study. If CPAP is ongoing at the time of informed consent, the medical 
condition that required CPAP will be captured on the concurrent medical conditions (e)CRF. If 
CPAP is administered after first dose of study drug, then the medical condition will be captured as 
an AE.
9.1.8
Procedures for Clinical Laboratory Samples
9.1.8.1
Clinical Laboratory Tests
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 15 mL. The approximate total volume of 
blood for the study is 75 mL for male subjects, and 80 mL for female subjects (including an 
additional 5 mL of blood drawn for a serum pregnancy test on Day -14 [Visit 2]). After informed 
consent is provided, subjects will be asked to fast prior to blood draws within the Screening Period, 
and will be instructed to fast for at least 8 hours prior to blood draws on Day 1 (Visit 5), Week 2 
(Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9). Details of these procedures and required 
safety monitoring will be given in the laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hemoglobin
Hematocrit
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count with 
differential
Albumin
Alanine aminotransferase (ALT)
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bicarbonate
Bilirubin, total
Bilirubin, direct (only if total is about ULN)
Blood urea nitrogen (BUN)
Calcium
Chloride
Creatinine
Creatine kinase (CK)
γ-Glutamyl transferase (GGT)
Glucose
Magnesium
Potassium
Protein, total
Sodium
Uric Acid
High-density lipoprotein cholesterol (HDL-C)
Low-density lipoprotein cholesterol (LDL-C)
Total cholesterol
Triglycerides
Specific gravity
pH
Qualitative
Protein
Blood
Ketones
Bilirubin
Glucose
Microscopy
RBCs
WBCs
Other
HbA1c
Female subjects of childbearing potential only:
Serum human chorionic gonadotropin (hCG) for pregnancy
Urine hCG for pregnancy (a)
Urine albumin
Urine creatinine
Albumin:creatinine ratio (UACR)
eGFR
Plasma renin concentration and activity
Plasma and urine aldosterone
(a) Urine hCG will be performed at the site on Day 1 (Visit 5) prior to randomization.
The central laboratory will perform laboratory tests for hematology, serum chemistries, urinalysis, 
and other tests listed above. Estimated GFR will be calculated by the central laboratory using the 
Modification of Diet in Renal Disease equation [24,25]. Urinary albumin creatinine ratio (UACR) 
will also be calculated by the central laboratory. The urine pregnancy test on Day 1 (Visit 5) will 
be performed at the site. The results of laboratory tests will be sent to the investigator, who is 
responsible for reviewing and filing these results.
Clinical follow-up should take place (including repeat laboratory tests) until a subject’s laboratory 
profile has returned to normal/baseline status. If at any time during treatment the subject’s 
laboratory test meets the following criteria, the event must be reported as SAE:

ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN.


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The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
As a reminder, all abnormal laboratory results at final visit need to be followed until resolution to 
baseline levels or stabilization. Every effort should be made to obtain these follow-up tests from 
the central laboratory, and resolution or stabilization should be documented in the subject’s source 
documents.
9.1.8.2
Management, Withdrawal, and Follow-up of Subjects with Creatinine Elevations
Acute, reversible increases of creatinine have been described in patients receiving agents that 
block the RAAS, including ACE inhibitors and ARBs. This effect is caused by inhibition of 
AII-mediated vasoconstriction of efferent glomerular arterioles, resulting in decreased 
intraglomerular pressure, and thus an acute decrease of GFR. The acute creatinine increases 
observed with RAAS blockade may be exacerbated under certain conditions, such as 
hypovolemia. If elevations in serum creatinine are observed, potential causes for the elevation 
should be investigated. If there is evidence for volume depletion such as body weight reduction or 
orthostatic hypotension, evaluate for sources of volume loss such as diarrhea, vomiting, low fluid 
or food intake, exercise-related water loss, etc. If there is evidence of volume depletion, consider 
temporarily liberalizing salt intake and encouraging increased hydration. The use of concomitant 
medications may be assessed, in particular nonsteroidal anti-inflammatory drugs (NSAIDs), that 
may worsen renal function or decrease renal creatinine secretion. Such medications may be 
discontinued if appropriate. Possible underlying causes of decreased renal function, such as 
bilateral arterial disease or heart failure also should be considered [25-27].
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.


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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:
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.

Minipill.

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 
(Appendix A). In addition to a negative serum hCG pregnancy test at Screening (Visit 1), subjects 
also must have a negative serum hCG pregnancy test at Day -14 (Visit 2) and a negative urine 
pregnancy test on the day of first dose of study drug (Day 1 [Visit 5]). Negative urine pregnancy 
test must be confirmed prior to receiving any dose of active study medication. A serum hCG 
pregnancy test will also be performed on Day 1 (Visit 5), at Week 4 (Visit 7), and at Week 8/ET 
(Visit 9). At any time during the study, a subject with a positive serum or urine pregnancy test will 
be discontinued immediately.
9.1.10 Pregnancy
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued.
If the pregnancy occurs during administration of active study medication, for example, after Day 1 
(Visit 5) or within 30 days of the last dose of active study medication, the pregnancy should be 
reported immediately, using a pregnancy notification form, to the contact listed in Section 1.0.
Should the pregnancy occur during or after administration of blinded drug, the investigator must 
inform the subject of their right to receive treatment information. If the subject chooses to receive 
unblinded treatment information, the individual blind should be broken by the investigator.


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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. Results of the 
evaluation of the child after birth will also be collected.
9.1.11 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer 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 
following parameters will be recorded on the (e)CRF from the subject’s ECG trace: heart rate, 
PR interval, QT interval, QRS interval, and physician’s assessment. Corrected QT interval will be 
calculated by Takeda or designee and will not be recorded on the (e)CRF.
Note: ECG traces recorded on thermal paper should be photocopied to avoid degradation of trace 
over time.
9.1.12 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 (e)CRF. 
The IVRS/IWRS should be contacted as a notification of screen failure.
The primary reason for screen failure is recorded in the (e)CRF using the following categories:

Pretreatment event/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.
9.1.13 Documentation of Randomization and Run-In Failure
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. The IVRS/IWRS will be contacted for treatment 
assignment and this information should be captured on the appropriate (e)CRFs.


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If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable (e)CRF. If the subject has begun the single-blind 
placebo run-in study medication and they are found to not be eligible for randomization, they are 
considered a run-in failure. The investigator or designee should complete the appropriate (e)CRFs 
and register the subject as a run-in failure in the IVRS/IWRS.
9.1.14 Ambulatory Blood Pressure Monitoring (for subset patients)
Subjects should be instructed to withhold their dose of study medication on the morning when an 
ABPM recording is scheduled to begin, and that day’s dose of study medication will be 
administered in the clinic at 0800 (±2 hours).
The 24-hour ABPM reading will be started immediately after in-clinic dosing. ABPMs are 
performed only in a subset of subjects in selected sites at Baseline (Visit 4) and after the last dose 
of the double blind treatment (Visit 9).
An automated, portable ABPM device supplied by the sponsor will be used to record SBP and 
DBP over a 24-hour period on two occasions during the study; Baseline (Visit 4): 
Pre-randomization and Final (Visit 9): Week 8/Early termination visit. ABPM should be repeated 
within 3 days if pre defined quality control criteria are not met, as long as the subject has adequate 
supply of medication to stay on the current treatment.
The Baseline recording will begin on the last day of the single-blind placebo run-in period 
(Day -1), immediately after administration of the last dose of placebo.
The final ABPM will begin immediately after administration of the last dose of double-blind study 
drug at the Week 8 visit. If a subject wishes to withdraw early from the study and (a) has not been 
without study medication, (b) has completed at least 4 weeks of double-blind treatment, and (c) has 
not initiated other antihypertensive therapy, the site will attempt (safety permitting) to complete 
the final ABPM.
It is permitted for each scheduled ABPM to be repeated up to once only. In each instance, subjects 
will be instructed to return to the clinic on the morning after the device is fitted so that the ABPM 
measurement can be verified and the device removed.
See Appendix E for additional ABPM guidelines.
9.2
Monitoring Subject Treatment Compliance
Subjects will be required to bring study medication containers to each clinic visit, regardless of 
whether the study medication container is empty.
If a subject is persistently noncompliant with the study medication (<70% or >130% of the 
allocated medication for the period since the last visit), it may be appropriate to withdraw the 
subject from the study. All subjects should be reinstructed about the dosing requirement during 
study contacts. The authorized study personnel conducting the re-education must document the 
process in the subject source records.


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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).
Study days/weeks and visit windows should be calculated after randomization and should be 
calculated from the day of the first dose of treatment (Day 1[Visit 5]). Visit windows are listed in 
Appendix A.
9.3.1
Screening (Visit 1)
Subjects will be screened for enrollment prior to discontinuing previous antihypertensive 
treatment or initiating the placebo run-in in accordance with the predefined entrance criteria 
described in Section 7.0. See Section 9.1.12 for procedures for documenting screen failures. After 
informed consent is provided, subjects will be asked to fast prior to blood draws within the 
Screening Period.
Procedures to be completed at the Screening (Visit 1) include:

Informed consent.

Inclusion and exclusion criteria.

Demographics, medical history, and medication history.

Physical examination.

Vital signs (including standing measurements). For subjects who have not received 
antihypertensive medications within 28 days, determine the mean sitting SBP for subject 
eligibility.

Weight and height. BMI will be calculated during data analysis.

12-lead ECG.

Concomitant medications.

Concurrent medical conditions.

Clinical laboratory tests (hematology, chemistry, urinalysis) and HbA1c. Estimated GFR will 
be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Register subject in IVRS/IWRS to obtain subject number.

Pretreatment event (PTE) assessment.


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9.3.2
Washout, Day -28 or Day -21 through Day -1
If the subject is currently taking, or has taken antihypertensive medication within 28 days of 
screening, the subject will require washout. Subjects should not begin washout until all applicable 
inclusion and exclusion criteria, including laboratory results, have been verified.

The subject may be notified by telephone to begin washout of current antihypertensive 
medication (if applicable) by Day -21 at the latest.
Note: Subjects taking previous antihypertensive agents are required to participate in a 3-week 
washout period (Days -21 to -1). If the subject’s previous antihypertensive treatment includes 
amlodipine or chlorthalidone, then the washout must be extended to 4 weeks (Days -28 to -1). 
Subjects who have not received antihypertensive medications within 28 days before screening 
can be entered into the run-in period as soon as all inclusion/exclusion criteria, including 
laboratory parameters, have been checked.
9.3.3
Placebo Run-in, Day -14 through Day -1 (Visits 2 and 3)
For subjects who were previously taking antihypertensive agents, the placebo run-in will coincide 
with the last two weeks of the washout period. Subjects who have not received antihypertensive 
treatment for 28 days before screening may begin the placebo run-in period after all inclusion 
criteria, including laboratory results, have been verified. The start of the placebo run-in period 
should occur approximately 14 days prior to randomization; however, this can be extended as long 
as the subject has an adequate amount of single-blind study medication. Subjects should take 
single-blind study medication (placebo) for a minimum of 10 days prior to randomization. The 
run-in period will consist of the 2 following visits:
9.3.3.1
Placebo Run-in, Day -14 (Visit 2)
The following procedures will be performed and documented during placebo Run-in, Day -14 
(Visit 2):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Concomitant medications.

PTE/Adverse event (AE) assessment.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Serum pregnancy test (female subjects of childbearing potential only).

Access the IVRS/IWRS for single-blind placebo run-in study medication assignment.

Dispense single-blind placebo run-in study medication with dosing instructions.

In-clinic dose of single-blind placebo run-in study medication.


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If the subject fails to meet the inclusion and exclusion criteria after starting single-blind placebo 
run-in study medication, they are considered a run-in failure. The procedure for documenting 
run-in failures is provided in Section 9.1.13.
9.3.3.2
Placebo Run-in, Day -7 (Visit 3)
The Placebo Run-in Day -7 visit should occur approximately 7 days from the Day -14 visit. 
Reminder: subjects should be on placebo run-in no less than 10 days prior to randomization.
The following procedures will be performed and documented during Run-in, Day -7 (Visit 3):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Concomitant medications.

AE assessment.

Collect single-blind placebo run-in study medication and assess compliance, and counsel if on 
compliance if required.

In-clinic dose with single-blind placebo run-in study medication (from the returned medication 
supply).

Redispense single-blind placebo run-in study medication and instruct subject to withhold dose 
the morning of Day 1 (Visit 5). Last day of single-blind dosing is Day -1.

Remind subjects to fast 8 hours before Day 1 Visit.
If the subject fails to meet the inclusion and exclusion criteria after starting single-blind placebo 
run-in study medication, they are considered a run-in failure. The procedure for documenting 
run-in failures is provided in Section 9.1.13.
9.3.4
Day -1 (Visit 4)
This visit only applies to the ABPM subgroup. Day -1 visit will take place 1 day prior to Day 1 
visit. Reminder: the subject must be on placebo run-in medication a minimum of 10 days prior to 
randomization. The following procedures will be performed and documented during Visit 4:

Update eligibility status (inclusion and exclusion criteria).

Collect vital signs.

Document changes to concomitant medications.

Assess for AEs.


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
Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Collect single-blind study medication and assess subject compliance with dosing regimen.
Instruct subject to withhold dose the morning of the Day 1 (Randomization).

Single-blind clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start.

Start 24-hour ABPM.

Remind subjects to fast 8 hours before Day 1 Visit.
If the subject does not meet the inclusion and exclusion criteria, the subject should be discontinued 
from the study. The procedure for documenting run-in failures is provided in Section 9.1.13.
9.3.5
Randomization, Day 1 (Visit 5)
Study randomization will take place on Day 1. Subjects should fast for at least 8 hours before this 
visit. The following procedures will be performed and documented during study randomization:

Remove ABPM and ensure ABPM reading is successful (for subjects conduct ABPM only).
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current placebo treatment and ABPM should be repeated within 3 days.

Inclusion and exclusion criteria (before randomized to treatment).

Vital signs (including standing measurements) and weight. BP must meet inclusion #1 and 
must not meet exclusion #1.

Urine pregnancy test (female subjects of childbearing potential only). Analysis is performed at 
the site. Test must be negative for subject before subject can be randomized.

Collect single-blind placebo run-in study medication and assess subject compliance with 
dosing.

Concomitant medications.

AE assessment.

If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IVRS/IWRS system, as described 
in Section 9.1.13. If subject does not meet all of the inclusion and none of the exclusion 
criteria, document the subject as a run-in failure and record the primary reason for failure on 
the applicable (e)CRF. The procedure for documenting run-in failures is provided in 
Section 9.1.13.

Physical examination.

12-lead ECG.


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
Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, plasma renin 
concentration and activity, plasma and urine aldosterone, urine albumin, and urine creatinine. 
Estimated GFR and UACR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Dispense double-blind study medication with dosing instruction.

In-clinic first dose of double-blind study medication.

Instruct the subject to fast for at least 8 hours prior to Week 2 (Visit 6).
9.3.6
Treatment Visits, Week 2 through Week 6 (Visit 6 through Visit 8)
See Appendix A for windows for each visit. Subjects should fast for a minimum of 8 hours before 
Visits 6 and 7. The following procedures will be performed at these visits:

Vital signs (including standing measurements) and weight.

Laboratory tests: Clinical laboratory tests (hematology, chemistry, urinalysis) at Visits 6 and 7 
only; plasma renin concentration and activity, and plasma and urine aldosterone at Visit 7 only. 
Estimated GFR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only) at Visit 7 only.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen. If 
required, counsel subject on compliance.

Access the IVRS/IWRS and dispense double-blind study medication with dosing instructions.

In-clinic first dose of the newly assigned double-blind medication in the clinic.

Instruct subject to withhold dose of study medication the morning of all in-clinic study visits.

Instruct the subject at Week 2 (Visit 6) to fast for at least 8 hours prior to Week 4 (Visit 7) and 
at Week 6 (Visit 8) to fast for Week 8 (Visit 9).
9.3.7
Week 8/Final Visit or Early Termination (Visit 9)
Subjects should fast for 8 hours before this visit. Assessments scheduled for Week 8/ET (Visit 9) 
should be completed (safety permitting) for subjects who were randomized and withdraw early. 
The following procedures will be performed and documented:


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Clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start (in subgroup only).

Start 24-hour ABPM (in subgroup only).

Vital signs (including standing measurements) and weight.

Physical examination.

12-lead ECG.

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen.

Access the IVRS/IWRS to register subject completion/early termination.

Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, plasma renin 
concentration and activity, plasma and urine aldosterone, urine albumin and urine creatinine. 
Estimated GFR and UACR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).
9.3.8
ABPM Removal (Visit 10)
This visit only applies to the ABPM subgroup. Assessments scheduled for ABPM Removal Visit
(Visit 10) should be completed (safety permitting) for subjects. The following procedures will be 
performed:

Remove ABPM and ensure ABPM reading is successful.
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current treatment and ABPM should be repeated within 3 days

Vital signs (including standing measurements) and weight.

AE assessment.

Concomitant medications.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).
9.3.9
Follow-up

Subjects should receive a follow-up telephone call to assess any new or ongoing AEs and 
changes to concomitant medications 14 days after the last dose of study medication 
(single-blind placebo or double-blind). Female subjects of childbearing potential should be 


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counseled on avoidance of pregnancy, ova donation, and use of acceptable methods of 
contraception through 30 days after the last dose of study medication.

For all subjects receiving study medication, the investigator must complete the End of Study 
(e)CRF page.
9.3.10 Post Study Care
Study medication will not be available upon completion of the subject’s participation in the study. 
The subject should be returned to the care of a physician and standard therapies as required.


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Events
A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation subject who has signed informed consent to participate in a study but prior to 
administration of any study 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.
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 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation 
or monitoring of an abnormality is not considered an intervention.


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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.
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 


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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.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The principal investigator must make the distinction between exacerbation of 
pre-existing illness and lack of therapeutic efficacy.
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 (e)CRF. Any 
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of 
the (e)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
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizures
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome 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/serious 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/serious 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.

Dose interrupted – the dose was interrupted due to the particular AE.
10.1.12
Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the 
AE/serious 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/serious 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/serious PTE state remaining “Not 
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/serious 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.


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
Unknown – the course of the AE/serious PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study.
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 single-blind placebo 
run-in study medication (Day -14 [Visit 2]) or until screen failure. For subjects who discontinue 
prior to single-blind placebo run-in 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 single-blind 
placebo study medication (Day -14 [Visit 2]). Routine collection of AEs will continue until 
14 days after the last dose of study medication, at which time a follow-up phone call will be made 
to the subject to query for any new AEs. Spontaneous reporting of AEs and SAEs will be collected 
from through 14 or 30 days, respectively, after the final dose of study medication.
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 (e)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.

Severity.

Investigator’s opinion of the causal relationship between the event and administration of study 
medication(s) (yes or no) (not completed for PTEs).


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
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.
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 SAE eCRF must be completed, in English, in EDC 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 1.1.
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 (LFT)
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, a LFT Increases (e)CRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.2).


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10.3
Follow-up of SAEs
10.3.1 Safety Reporting of SAEs
If information not available at the time of the first report becomes available at a later date, the 
investigator should enter follow-up information via the SAE eCRF and/or provide other 
documentation (eg, ECGs, laboratory test results, diagnostic test results, discharge summary, 
death certificate, hospital notes etc.) and fax them immediately, within 24 hours of receipt to the 
contact provided (as per Section 1.1). 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, 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, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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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
CRFs (Electronic)
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. The sponsor 
will make arrangements to train appropriate site staff in the use of the (e)CRF. 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. Data are transcribed directly onto 
(e)CRFs.
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 change. Reasons for significant corrections should additionally be included.
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.
(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 
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. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 


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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 Clinical Study Site Agreement 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 subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
All randomized subjects will comprise the randomized set. Analysis sets to be used include the 
following:
Safety Analysis Set: All subjects who receive at least 1 dose of double-blind study medication. 
Subjects will be analyzed according to the study medication they received.
Full Analysis Set (FAS): All randomized subjects who received at least 1 dose of study 
medication. Subjects will be analyzed according to the treatment group to which they were 
randomized.
Per-Protocol Set (PPS): All subjects in the FAS, excluding any subjects who had major protocol 
violations. Major violations from the protocol leading to exclusion from the Per Protocol Set will 
be identified prior to unblinding of subject’s treatment assignment.
The FAS will be the primary data set used for efficacy analyses. Efficacy analysis based on the Per 
Protocol Set will also be performed where appropriate. All routine safety analysis will be based on 
the Safety Analysis Set.
All subjects who were randomized more than once will be excluded from the safety analysis set, 
the FAS, and the PPS.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics (eg, age, race, gender, height, weight) will be 
summarized using descriptive statistics for each treatment group and overall (eg, mean, standard 
deviation, median, minimum and maximum values, and the number and percent of subjects in 
specified categories).
13.1.3 Efficacy Analysis
Unless otherwise specified, efficacy analyses will be performed using the FAS and all statistical 
inference will use a 2-sided 0.05 significance level. A subject will be included in the primary 
analyses only when there is both a baseline value and at least 1 value during the double-blind 
treatment period. Missing values will be imputed using last observation carried forward (LOCF) 
methodology. In the LOCF analysis data set, the last post-baseline double-blind observed value is 


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carried forward and used for all subsequent scheduled time points where data are missing (eg, the 
subject has missing data or has dropped out of the study).
The primary analysis will be based on an analysis of covariance (ANCOVA) model for change in 
clinic SBP from baseline to week 8. The model will include treatment as a fixed effect and baseline 
clinic SBP as a covariate. From the framework of the ANCOVA the following will be determined: 
treatment LS mean, LS mean for the difference between TAK-491 and valsartan, p-value and 
2-sided 95% confidence intervals for the treatment difference. For the primary analysis the overall 
type 1 error rate of 0.05 will be controlled using the 4 step sequential test described below.

Step 1: A test for noninferiority of TAK-491 80 mg to valsartan 160 mg will be performed 
using a noninferiority margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the 
treatment difference (TAK-491 – valsartan) is not greater than 1.5 then proceed to Step 2.

Step 2: A test for noninferiority of TAK-491 40 mg to valsartan 160 mg will be performed 
using a noninferiority margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the 
treatment difference (TAK-491 – valsartan) is not greater than 1.5 then proceed to Step 3.

Step 3: A test for significant difference between TAK-491 80 mg versus valsartan 160 mg will 
be performed at the 5% level. If the p-value is not greater than 0.05 then proceed to Step 4.

Step 4: A test for significant difference between TAK-491 40 mg versus valsartan 160 mg will 
be performed at the 5% level.
Based on historical data, the observed placebo-corrected treatment effects on change from 
Baseline in clinic SBP for valsartan 160 mg once daily was -8.6 mm Hg [28]. Therefore, the 
noninferiority margin was set conservatively at 1.5 mm Hg, which is less than one-third of the 
valsartan treatment effect. Accordingly, TAK-491 will be considered noninferior to valsartan 
when the upper limit of the 2-sided 95% CI of the treatment difference (TAK 491 – comparator) is 
≤1.5 mm Hg.
The secondary endpoint, change from baseline to Week 8 in trough sitting clinic DBP will be 
analyzed similar to the primary endpoint, excluding the sequential testing. Change from baseline 
for both SBP and DBP at other visits will be summarized similar to the primary endpoint. 
Additionally, similar analyses will be performed for both SBP and DBP for selected subgroups, 
where appropriate, eg, age, sex.
The categorical secondary efficacy endpoints, percentage of subjects responding to treatment and 
percentage of subjects reaching blood pressure target at Week 8 will be tabulated for each of the 
following definitions:

Response criteria.
a) Clinic SBP <140 mm Hg and/or a reduction of 20 mm Hg from baseline.
b) Clinic DBP <90 mm Hg and/or a reduction of 10 mm Hg from baseline.
c) a and b (ie, joint criteria).


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
Target blood pressure.
a) Clinic SBP <140 mm Hg.
b) Clinic DBP <90 mm Hg.
c) Clinic SBP<140 mm Hg and DBP<90 mm Hg.
d) Clinic SBP<130 mm Hg.
e) Clinic DBP<80 mm Hg.
f)
Clinic SBP<130 mm Hg and DBP<80 mm Hg.
A logistic model with treatment as fixed effect and baseline clinic SBP as a covariate will be used 
to analyze response for clinic SBP. The odds ratio and its 95% confidence will be estimated. 
Similarly, a logistic model with treatment as fixed and baseline clinic DBP as a covariate will be 
used to analyze the response for clinic DBP. The joint response for both clinic SBP and DBP will 
be analyzed using a logistic model with treatment as fixed effect and baseline clinic SBP as a 
covariate. A similar analysis and model will be used to analyze the percentage of subjects reaching 
target blood pressure at Week 8. The percentage of subjects responding to treatment, as well as 
reaching blood pressure target, will also be presented for other visits, using the above methods.
Change from baseline to Week 8 24-hour mean SBP by ABPM will be analyzed using an 
ANCOVA model with treatment as a fixed effect and baseline 24-hour mean SBP by ABPM as a 
covariate. Similar analyses will be performed for other ABPM parameters for both SBP and DBP 
determined and descriptive statistics calculated.
The peak effect and trough-to-peak ratio will also be calculated and summarized.
Subgroup (eg, age, sex) analyses may be performed if data permit.
Sensitivity analyses to be performed on the primary endpoint (and other endpoints where 
appropriate) include: multiple imputation for missing values; analyses using the per protocol set; 
and analyses using observed values only.
13.1.4 Safety Analysis
Safety and tolerability will be accessed via treatment emergent adverse events, laboratory results, 
and other safety variables. Unless otherwise specified safety analyses will be performed using the 
safety analysis set, and presented by treatment group. Results presented by study visit will also 
include the final visit; where final visit is defined as the last observation (post-baseline) carried 
forward no later than 7 days after the last dose of study drug.
13.1.4.1 Adverse Events
Adverse events will be coded using MedDRA. Treatment-emergent adverse events (TEAE) will 
be defined as any AEs, regardless of relationship to study drug, that occur after the first dose of 
double-blind study drug, no later than 14 days after the last dose of study drug for AEs, and no later 
than 30 days after the last dose of study drug for SAEs. TEAEs will be tabulated by system organ


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class and preferred term. The TEAE summary tables will include count and percent of subjects 
reporting the event by treatment group. Therefore, if a subject experiences more than 1 episode of 
a particular AE, the subject will be counted only once for that event. 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. Similarly, if a subject has more than 1 AE within a system organ class, the subject will be 
counted only once in that system organ class. Adverse events with onset dates on or after the start 
of treatment and prior to 14 days (onset date – last date of dose &14) after the permanent 
discontinuation of the study medication, or continuing AEs diagnosed prior to the date of first dose 
of study medication and getting worse in severity or intensity after receiving study medication will 
be summarized.
Serious adverse events with onset dates on or after the start of treatment and prior to 30 days (onset 
date – last date of dose &30) after the last dose of study medication will be summarized. Specific 
decision will be made for inclusion of SAEs with onset dates 30 days after the final discontinuation 
of study medication.
TEAEs will also be presented by causality (relationship to study drug) and severity (mild, 
moderate, severe). Serious TEAEs, TEAEs leading to study drug discontinuation, and TEAEs 
leading to death will also be summarized using preferred term and system organ class.
13.1.4.2 Laboratory Analysis
Laboratory test variables will be summarized by treatment group and study visit using descriptive 
statistics for the observed and change from baseline values. Markedly abnormal laboratory values 
will be determined and listed by treatment group and study visit. The number and percentage of 
subjects with markedly abnormal laboratory values in each of the laboratory parameters will be 
presented. Shift tables displaying the change (number of subjects) relative to the normal range 
from Baseline to each study visit will also be presented by treatment for each laboratory test. 
Laboratory data collected more than 7 days after the last dose of study medication will be excluded 
from the summaries but will be listed.
13.1.4.3 Additional Safety Values
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
CCI


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13.3
Determination of Sample Size
Assuming an SD of 17 mm Hg and a 10% dropout rate, a sample size of 200 subjects per treatment 
group (total of 600 subjects) is sufficient to achieve at least 90% power to detect a difference of 
6 mm Hg between TAK-491 dose and valsartan by a 2-sample t-test on the mean change from 
baseline to Week 8 in mean sitting clinic SBP at 0.05 2-sided significance level. This sample size 
will also provide, for the above assumptions, at least 90% power for demonstrating noninferiority 
with a margin of 1.5 mm Hg between TAK-491 and valsartan.


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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 (contract research organization [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.
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 Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B.
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 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 notify site once the sponsor has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from competent authority to begin the trial. Until the site receives 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.


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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 
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.


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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.
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, FDA, Medicines and Healthcare products Regulatory Agency, 
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 [e]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 Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


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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 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov or 
other publicly accessible websites before trial initiation. Takeda contact information, along with 
investigator’s information, country, and recruiting status will be registered and available for public 
viewing.
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of this clinical trial, 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 Clinical Study Site 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
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report of the Joint National Committee on prevention, detection, evaluation, and treatment of 
high blood pressure: the JNC 7 report. JAMA 2003;289(19):2560-72.
3. World Health Organization. International Society of Hypertension Writing Group. 2003 World 
Health Organization (WHO)/International Society of Hypertension (ISH) statement on 
management of hypertension. J Hypertens 2003;21(11):1983-92.
4. Chinese Guidelines. Chinese guidelines for management of hypertension - 2010. Chinese 
Journal of Hypertension 2011;19(8):701-43.
5. Shusterman N. Risk-benefit assessment of angiotensin II receptor antagonists. Expert Opin 
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6. Appel GB, Appel AS. Angiotensin II receptor antagonists: role in hypertension, cardiovascular 
disease, and renoprotection. Prog Cardiovasc Dis 2004;47(2):105-15.
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8. Weber MA. The angiotensin II receptor blockers: opportunities across the spectrum of 
cardiovascular disease. Rev Cardiovasc Med 2002;3(4):183-91.
9. Graettinger WF. Systemic hypertension. In: Crawford MH, editor. Current Diagnosis & 
Treatment in Cardiology. 2nd ed. New York, NY: McGraw-Hill Professional; 2003, p. 167-78.
10. 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.
11. TAK-491 Global Investigator's Brochure. 10th Edition. Takeda Development Centre Europe 
Ltd., 22 April 2015.
12. Edarbi 20, 40, and 80 mg tablets. Summary of Product Characteristics. Taastrup, Denmark: 
Takeda Pharma A/S, Revised 09 September 2014.
13. Edarbi (azilsartan medoxomil) Tablets. Full Prescribing Information. Atlanta, GA: Arbor 
Pharmaceuticals, LLC, Revised May 2014.
14. DeFelice A, Willard J, Lawrence J, Hung J, Gordon MA, Karkowsky A, et al. The risks 
associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive 
meta-analysis. J Hum Hypertens 2008;22(10):659-68.
15. Al-Khatib SM, Califf RM, Hasselblad V, Alexander JH, McCrory DC, Sugarman J. Medicine. 
Placebo-controls in short-term clinical trials of hypertension. Science 2001;292(5524):2013-5.


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16. Williams B, Lindholm LH, Sever P. Systolic pressure is all that matters. Lancet 
2008;371(9631):2219-21.
17. Duprez DA. Systolic hypertension in the elderly: addressing an unmet need. Am J Med 
2008;121(3):179-84 e3.
18. Franklin SS, Jacobs MJ, Wong ND, L'Italien GJ, Lapuerta P. Predominance of isolated systolic 
hypertension among middle-aged and elderly US hypertensives: analysis based on National 
Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001;37(3):869-74.
19. Kikuya M, Hansen TW, Thijs L, Bjorklund-Bodegard K, Kuznetsova T, Ohkubo T, et al. 
Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year 
cardiovascular risk. Circulation 2007;115(16):2145-52.
20. Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, et al. 
Prognostic value of ambulatory blood-pressure recordings in patients with treated 
hypertension. N Engl J Med 2003;348(24):2407-15.
21. Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C. Ambulatory blood pressure 
monitoring and risk of cardiovascular disease: a population based study. Am J Hypertens 
2006;19(3):243-50.
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Milpharm Limited, Revised 09 August 2013.
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suggestions for measuring blood pressure to use in populations surveys. Rev Panam Salud 
Publica 2003;14(5):300-2, 3-5.
24. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study equation 
for estimating glomerular filtration rate. Ann Intern Med 2006;145(4):247-54.
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26. Thorp ML, Ditmer DG, Nash MK, Wise R, Jaderholm PL, Smith JD, et al. A study of the 
prevalence of significant increases in serum creatinine following angiotension-converting 
enzyme inhibitor administration. J Hum Hypertens 2005;19(5):389-92.
27. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in 
serum creatinine: is this a cause for concern? Arch Intern Med 2000;160(5):685-93.
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Appendix A
Schedule of Study Procedures
Study Day or Week:
Screening
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 (b)
or
D -28 (c)
Single-Blind Placebo Run-in
D -14 (d,e)
D -7
D -1 (v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
Removal 
Visit (w)
Tele-
phone 
Follow-
up (g)
Visit Window
N/A
N/A
N/A
N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
PTE assessment (h)
X
X
AE assessment (i,j,r)
X
X
X
X
X
X
X
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
X
X
Weight, height, and BMI (l)
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Clinical laboratory tests (m)
X
X
X
X
X
Urine albumin and creatinine and UACR (n)
X
X
HbA1c
X
X
X
Estimated GFR (n)
X
X
X
X
X
Serum hCG (o)
X
X
X
X
X
Urine pregnancy test (o,p)
X
Guidance on avoidance of pregnancy, ova donation, 
and acceptable methods of contraception
X
X
X
X
X
X
X
X
X
X
X
Notify subject to begin washout period (q)
X
Plasma renin concentration and activity, plasma and 
urine aldosterone
X
X
X
ABPM start (subgroup only)
X
X
ABPM removal (subgroup only)
X
X


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Study Day or Week:
Screening
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 (b)
or
D -28 (c)
Single-Blind Placebo Run-in
D -14 (d,e)
D -7
D -1 (v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
Removal 
Visit (w)
Tele-
phone 
Follow-
up (g)
Visit Window
N/A
N/A
N/A
N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Concurrent medical conditions (r)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Access IVRS/IWRS (s)
X
X
X
X
X
X
X
Dispense single-blind study placebo for run-in and 
dose in-clinic (t)
X
Redispense single-blind placebo for run-in
X
Last dose of single-blind placebo (u)
X
Dispense double blind study drug
X
X
X
X
Last dose of double blind study drug
X
Clinic dosing (u)
X
X
X
X
X
X
X
X
Compliance assessment
X
X
X
X
X
X
X
Footnotes for Appendix A are on the next page.


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Footnotes for Appendix A
D=Day, W=Week.
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results can be reviewed 
and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated.
(b) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout period (Days -21 to -1).
(c) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout must be extended 
to 4 weeks (Days -28 to -1).
(d) Subjects who have not received antihypertensive treatment within 28 days before screening can be entered into the run-in period 
as soon as all inclusion and exclusion criteria, including laboratory results, have been verified.
(e) At minimum, the run-in should be 10 days but can extend to as long as the subject has an adequate supply of single-blind placebo 
run-in study medication.
(f) Conduct Final Visit procedures for subjects who are randomized and discontinued early per Section 7.6.
(g) Telephone contact for the follow-up AE and concomitant medication assessments should be made approximately 14 days after 
the last dose (single-blind placebo or double-blind).
(h) Reports of pretreatment events should be solicited at each visit from the time that informed consent is acquired until the first 
dose of placebo run-in study medication.
(i) AEs should be solicited at each visit from the time that single-blind placebo run-in study medication is started through 14 days 
after the last dose (via the telephone follow-up AE assessment).
(j) Spontaneous reports of AEs and SAEs should be collected from the time of the first dose of single-blind placebo run-in 
medication through 14 or 30 days, respectively, after the last dose.
(k) Includes sitting and standing BP and pulse rate. Pulse rate will be taken manually while sitting and standing.
(l) Collect height at the Screening (Visit 1) only; BMI will be calculated during data analysis at Screening (Visit 1).
(m) Hematology, serum chemistry, and urinalysis tests (as listed in Table 9.a). After informed consent is provided, subjects will be 
asked to fast prior to blood draws within the Screening Period, and will be instructed to fast for at least 8 hours prior to blood draws 
on Day 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9).
(n) UACR and estimated GFR will be calculated by the central laboratory.
(o) Women of childbearing potential only.
(p) Urine pregnancy test is performed at the site and must be negative for subject prior to randomization on Day 1 (Visit 5).
(q) Subject can be notified by telephone to begin the washout period.
(r) Data on medical conditions that require Continuous Positive Airway Pressure (CPAP) will be collected during the study. If
CPAP is ongoing at the time of informed consent, the medical condition that required CPAP will be captured on the concurrent 
medical conditions (e)CRF. If CPAP is administered after first dose of study drug, then the medical condition will be captured as an 
AE.
(s) If a subject withdraws early, contact IVRS/IWRS to document the ET.
(t) Subjects to take the first dose of single-blind placebo run-in study medication in-clinic.
(u) Instruct subjects to withhold their dose of study drug, if applicable so they can be dosed in-clinic. For ABPM subgroup subjects, 
clinic dosing at 8:00 AM (±2 hours) for Visits 4 and 9.
(v) Visit 4 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the
subject must continue the current treatment and ABPM should be repeated within 3 days.
(w)Visit 10 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the 
subject must continue the current treatment and ABPM should be repeated within 3 days.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the 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 
eCRFs, 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/AESI, 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 which 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.


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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 
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. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, 
unless prevailing laws require the sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. 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


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e) that the subject’s identity will remain confidential in the event that study results are 
published.
25. 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. Regular pregnancy tests will be 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study medication will be discontinued and the investigator 
will offer the subject the choice to receive unblinded treatment information.
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov.


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Appendix D
Investigator Consent to Use of 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
Ambulatory Blood Pressure Monitoring
The ambulatory BP recording device provided by the sponsor has been validated independently by 
the American Association for the Advancement of Medical Instrumentation. The device is an
automatic, portable monitor that will be used to record BP and heart rate over a 24-hour period on 
two occasions during the study per the Schedule of Assessments, Appendix A.
The ABPM studies should be performed under similar circumstances (eg, a working weekday) if 
possible, and the device should be applied on the same day of the week and as close to the same 
time of day as feasible on each occasion. The non-dominant arm should be used for all ABPM 
readings. For each evaluation, the subject should report to the clinic for ABPM placement by 
0800 am (±2 hours). Calibration should be performed per the ABPM Training Manual.
The ABPM recorder will be manually initiated to indicate the beginning of the test and the start 
time will be recorded in the eCRF and source document. The time of the in-clinic dose of study 
medication will also be recorded in the eCRF and source document. The device will be set to 
obtain readings every 15 minutes during the interval of 0600 to 2200 (to coincide with the daytime, 
awake period) and every 20 minutes during the interval of 2200 to 0600 (to coincide with the night 
time, sleeping period). Refer to the ABPM Training Manual for specific set-up requirements.
The subject should engage in their usual physical activity levels, but should avoid strenuous 
exercise during the monitoring period. Additionally, sleeping during the daytime (eg, a siesta) 
should be avoided during the ABPM study period. During the actual BP measurements, the subject 
should be instructed to hold their arm still and remain in place once cuff inflation begins.
Following completion of the 24-hour collection period, subjects should be instructed to return to 
the clinic site to return the ABPM equipment. The data collected should be verified by the 
investigator or designee to ensure adequate data collection. An ABPM recording will be 
considered of sufficient quality (pass) if:

The “Beginning of Test” time is between 0600 and 1000.

The monitoring period is at least 24 hours in duration.

A minimum of 80% of the BP readings expected during the 24-hour period is recorded.

There are no more than 2 non-consecutive hours with less than 1 valid BP reading, and 
0 consecutive hours with less than 1 valid BP reading.
If any of the ABPM measurements do not pass these quality control criteria, they may be repeated 
once as long as the subject has an adequate supply of medication (placebo run-in /double-blind 
treatment) to resume treatment until the repeat measure can be taken.


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For the Baseline (pre-randomization) and Final (week 8/early termination) ABPM recordings it is 
preferable, but not mandatory, that recordings satisfy the predefined quality control criteria before 
moving on to the next study step. ABPM readings for the Baseline (pre-randomization) and Final 
(week 8/early termination) if repeated, must be completed within 3 days.
In all cases of repeat ABPM recordings, only 1 repeat is permitted. Clinic vital signs should be 
collected whenever repeat ABPM measurements are taken.


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Appendix F
Detailed Description of Amendments to Text
Page 2, Section 1.1: Contacts
Existing Text
Issue
China Contact
Serious adverse event and pregnancy reporting
Quintiles Integrated Safety Management
Lifecycle Safety
Contact details: See Study Reference Materials
Medical Monitor
(medical advice on protocol, compound, and medical 
management of subjects)
Quintiles Medical Services Department
Contact details: See Study Reference Materials
Responsible Medical Officer
(carries overall responsibility for the conduct of the study)
Revised Text
Issue
China Contact
Serious adverse event and pregnancy reporting
Quintiles Integrated Safety Management
Lifecycle Safety
Contact details: See Study Reference Materials
Medical Monitor
(medical advice on protocol, compound, and medical 
management of subjects)
Quintiles Medical Services Department
Contact details: See Study Reference Materials
Responsible Medical Officer
(carries overall responsibility for the conduct of the study)
Rational for Amendment
To update the name of and contact information for the Responsible Medical Officer.
PPD
PPD


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Page 3, Section 1.2: Approval
Existing Text
Date
Date
Date
Date
Date
Date
Revised Text
Date
Date
Date
Date
Rationale for Amendment
To update the names and titles for the Takeda signatories.
Page 14, Study Summary (paragraph 1)
Existing Text
The primary endpoint is change from baseline to Week 8 in trough (22-24 hour after the previous 
dose) sitting clinic SBP.
Revised Text
The primary endpoint is change from baseline to Week 8 in trough (approximately 24 hours after 
the previous dose) sitting clinic SBP.
Rationale for Amendment
To be consistent with the required timing of blood pressure measurements stated in Section 9.1.5
(Vital Sign Procedures).
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Page 14, Study Summary: Main Criteria for Evaluation and Analyses, Efficacy
Existing Text
Change from baseline in trough sitting clinic SBP and DBP; percentage of responders; and 
percentage of subjects achieving target blood pressure at other study visits.
Revised Text
Change from baseline in trough sitting clinic SBP and DBP; percentage of responders; and 
percentage of subjects achieving target blood pressure at other study visits.
Change from Baseline to Week 8 in the following ABPM parameters (in a subgroup): 
24 hour mean SBP and DBP; trough (22-24 hours after dosing) SBP and DBP; mean 
daytime (6 AM-10 PM) SBP and DBP; mean nighttime (12 AM-6 AM) SBP and DBP; mean 
SBP and DBP at 0-12 hours after dosing; peak (SBP and DBP) effect.
Trough-to-peak ratios (SBP and DBP) as determined by ABPM (in a subgroup).
Rationale for Amendment
For clarity.
Page 15, Study Summary: Statistical Considerations, Analysis Sets
Existing Text
Safety Analysis Set: All subjects who receive at least 1 dose of double-blind study medication. 
Subjects will be analyzed according to the study medication they received.
Full Analysis Set (FAS): All randomized subjects who received at least 1 dose of study 
medication. Subjects will be analyzed according to the treatment group to which they were 
randomized.
Revised Text
Safety Analysis Set: All subjects who receive at least 1 dose of double-blind study medication. 
Subjects will be analyzed according to the study medication they received.
Full Analysis Set (FAS): All randomized subjects who received at least 1 dose of study 
medication. Subjects will be analyzed according to the treatment group to which they were 
randomized.
Subjects who were randomized more than once will be excluded from both the safety 
analysis set and the FAS.
CCI


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Rational for Amendment
For clarity.
Page 21, Section 4.3: Summary of Clinical Data (paragraph 4)
Existing Text
TAK-491 dose reduction is not necessary for subjects with mild or moderate hepatic impairment, 
although such subjects are excluded from the present study.
Revised Text
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. Subjects with 
severe hepatic impairment were not studied. The increases in exposure to TAK-536 in the 
phase 1 hepatic impairment study 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. Therefore, TAK-491 dose 
reduction is not necessary for subjects with mild or moderate hepatic impairment, although 
subjects with any degree of hepatic impairment are excluded from the present study.
Rational for Amendment
To add clinical data from the phase 1 hepatic impairment study to support the addition of Week 2 
clinical laboratory tests.
Page 21, Section 4.3: Summary of Clinical Data (paragraph 5)
Existing Text
The single dose phase 1 study in renal impaired subjects showed that after 40 mg TAK-491 dosing, 
the total exposure to TAK-536 tended to be higher in subjects with renal impairment than in 
healthy subjects with increases of 30%, 25%, 96%, and 5% in subjects with mild, moderate, or 
severe renal impairment, and end-stage renal disease (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 (160 to 320 mg) study in healthy subjects. The mean terminal 
elimination half-life (T1/2) of TAK-536 was not substantially different in subjects with renal 
impairment than in healthy subjects. Therefore, no dose adjustment of TAK-491 is required for 
subjects with any degree of renal impairment or ESRD, although subjects with severe renal 
impairment (estimated glomerular filtration rate [eGFR] <30 (mL/min/1.73 m2) are excluded from 
this study.
Revised Text
The single dose phase 1 study in renal impaired subjects showed that after 40 mg TAK-491 dosing, 
the total exposure to TAK-536 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, or 
severe renal impairment, and end-stage renal disease (ESRD), respectively. These increases in 


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exposure to TAK-536 are not considered to be clinically meaningful, as TAK-491 was 
well-tolerated in a high-dose (160 to 320 mg) study in healthy subjects (01-06-TL-491-017). The 
mean terminal elimination half-life (t1/2z) of TAK-536 was not substantially different in subjects 
with renal impairment than in healthy subjects. Therefore, no dose adjustment of TAK-491 is 
required for subjects with any degree of renal impairment or ESRD, although subjects with severe 
renal impairment (estimated glomerular filtration rate [eGFR] <30 (mL/min/1.73 m2) are excluded 
from this study.
Rationale for Amendment
To report total exposure for subjects with renal impairment as AUCinstead of AUClast. The 
abbreviation for half-life was updated to the current Takeda standard.
Page 22, Section 4.3: Summary of Clinical Data (paragraph 7)
Existing Text
Results of the phase 3 program demonstrated that, relative to placebo, the TAK-491 20, 40, and 
80 mg doses produce clinically and statistically significant reductions in systolic blood pressure 
(SBP) and diastolic blood pressure (DBP), as assessed by both ambulatory blood pressure 
monitoring (ABPM) and clinic blood pressure measurements. The differences between doses were 
greater for subgroups of subjects characterized by more severe and/or resistant hypertension, 
including black subjects, subjects with renal impairment, and subjects with essential hypertension. 
In each study, most of the blood pressure-lowering effect of TAK-491 was observed within 
2 weeks of treatment; a plateau of effect was generally reached by week 4 and reductions were 
maintained through week 6 in short-term studies and over the long-term in two 6-month studies 
(and up to 1 year in open-label studies). In replicate studies, TAK-491 at 80 mg was shown to 
reduce systolic blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 
320 mg, the highest approved doses in the US.
Revised Text
Results of the phase 3 program demonstrated that, relative to placebo, the TAK-491 20, 40, and 
80 mg doses produce clinically and statistically significant reductions in systolic blood pressure 
(SBP) and diastolic blood pressure (DBP), as assessed by both ambulatory blood pressure 
monitoring (ABPM) and clinic blood pressure measurements. The differences between doses were 
greater for subgroups of subjects characterized by more severe and/or resistant hypertension, 
including black subjects, subjects with renal impairment, and subjects with Grade 2 hypertension. 
In each study, most of the blood pressure-lowering effect of TAK-491 was observed within 
2 weeks of treatment; a plateau of effect was generally reached by week 4 and reductions were 
maintained through week 6 in short-term studies and over the long-term in two 6-month studies 
(and up to 1 year in open-label studies). In replicate studies, TAK-491 at 80 mg was shown to 
reduce systolic blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 
320 mg, the highest approved doses in the US.


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Rationale for Amendment
To correct the text.
Page 23, Section 4.3: Summary of Clinical Data (paragraph 10)
Existing Text
In summary, TAK-491 was well tolerated at doses up to 320 mg in healthy subjects and up to 
80 mg in hypertensive subjects (maximal dose evaluated in this population). TAK-491 has been 
shown to have a strong antihypertensive effect, predictable pharmacokinetic and metabolic 
profiles, a prolonged duration of action, and good safety and tolerability profiles when 
administered as a monotherapy to hypertensive subjects. TAK-491 has recently been approved in 
the United States (US) by the Food and Drug Administration (FDA), by the European Medicines 
Agency (EMA) in the European Union, and in other countries such as Canada, Switzerland, 
Mexico, Philippines for the treatment of hypertension, either alone or in combination with other 
antihypertensive agents.
Revised Text
In summary, TAK-491 was well tolerated at doses up to 320 mg in healthy subjects and up to 
80 mg in hypertensive subjects (maximal dose evaluated in this population). TAK-491 has been 
shown to have a strong antihypertensive effect, predictable pharmacokinetic and metabolic 
profiles, a prolonged duration of action, and good safety and tolerability profiles when 
administered as a monotherapy to hypertensive subjects. As of February 2016, TAK-491 has 
been approved for the treatment of hypertension, either alone or in combination with other 
antihypertensive agents, in a total of 59 countries worldwide, including approval in the 
United States by the Food and Drug Administration (FDA) in February 2011 and in the 
European Union by the European Medicines Agency (EMA) in December 2011.
Rationale for Amendment
To present current registration information.
Page 24, Section 5.2.1: Primary Endpoint
Existing Text
The primary endpoint is change from baseline to Week 8 in trough (22-24 hour after the previous 
dose) sitting clinic SBP.
Revised Text
The primary endpoint is change from baseline to Week 8 in trough (approximately 24 hours after 
the previous dose) sitting clinic SBP.
Rationale for Amendment
To be consistent with the required timing of blood pressure measurements stated in Section 9.1.5
(Vital Sign Procedures).


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Page 27, Section 6.1: Figure 6.a Schematic of Study Design (footnote [i])
Existing Text
(i) In subgroup of ABPM subjects will start 24-hour ABPM measurement.
Revised Text
(i) Visit 4 only applies to ABPM subgroup subjects; start 24-hour ABPM measurement.
Rationale for Amendment
To clarify that this visit applies only to the ABPM subgroup of subjects.
Page 27, Section 6.2: Justification for Study Design, Dose, and Endpoints
Existing Text
TAK-491 is a prodrug that is rapidly hydrolyzed to the active moiety, TAK-536, which is a 
long-acting, angiotensin II AT1 receptor blocker (ARB). TAK-491 has been shown to have a 
strong antihypertensive effect, predictable pharmacokinetic and metabolic profiles, a prolonged 
duration of action, and good safety and tolerability profiles when administered as a monotherapy 
to hypertensive subjects. The phase 3 TAK-491 studies have shown that TAK-491 80 mg reduced 
blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 320 mg, the 
highest approved doses in the US. TAK-491 has recently been approved in the US by FDA, by the 
EMA in the European Union, and in other countries, such as Canada, Switzerland, Mexico, 
Philippines for the treatment of hypertension, either alone or in combination with other 
antihypertensive agents.
Revised Text
TAK-491 is a prodrug that is rapidly hydrolyzed to the active moiety, TAK-536, which is a 
long-acting, angiotensin II AT1 receptor blocker (ARB). TAK-491 has been shown to have a 
strong antihypertensive effect, predictable pharmacokinetic and metabolic profiles, a prolonged 
duration of action, and good safety and tolerability profiles when administered as a monotherapy 
to hypertensive subjects. The phase 3 TAK-491 studies have shown that TAK-491 80 mg reduced 
blood pressure more effectively than olmesartan medoxomil 40 mg and valsartan 320 mg, the 
highest approved doses in the US. As of February 2016, TAK-491 has been approved for the 
treatment of hypertension, either alone or in combination with other antihypertensive 
agents, in a total of 59 countries worldwide, including approval in the United States by the 
Food and Drug Administration (FDA) in February 2011 and in the European Union by the 
European Medicines Agency (EMA) in December 2011.
Rationale for Amendment
To present current registration information.


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Page 33, Section 7.4: Diet, Fluid, and Activity Control (paragraph 3)
Existing Text
Subjects will be instructed to fast for at least 8 hours prior to returning to the study site for Day 1 
(Visit 5), Week 4 (Visit 7), and Week 8/ET (Visit 9).
Revised Text
After informed consent is provided, subjects will be asked to fast prior to blood draws 
within the Screening Period and will be instructed to fast for at least 8 hours prior to returning to 
the study site for Day 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9).
Rationale for Amendment
To state that after informed consent is provided, that subjects will be asked to fast prior to blood 
draws within the Screening Period as certain serum chemistry test results are not accurate unless 
the subject has fasted.
To add a fasting requirement for Week 2 (Visit 6); the fasting requirement for Week 2 (Visit 6) is 
due to the addition of clinical laboratory tests at this Visit.
Page 37, Section 8.1.3: Dose and Regimen (paragraphs 4 and 5)
Existing Text
Placebo Run-in Period (Day -14 [Visit 2] to Day -1)

Subjects will be dispensed one 2-week blister card and one bottle.

Subjects will receive single-blind placebo tablets and placebo capsules.

First dose will be given in-clinic at Day -14 (Visit 2).

The daily oral administered dose will be one tablet from a blister card and two capsules from 
the bottle.
Treatment Period (Day 1 [Visit 5] through Week 8 / Early Termination [Visit 9])

Subjects will receive blinded study medication and will be instructed to take their blinded 
study medication prior to their first meal of the day. Subjects will be dispensed one 2-week 
carton and one bottle at day 1 (Visit 5), at week 2 (Visit 6), week 4 (Visit 7), and week 6 
(Visit 8).

First dose will be given in-clinic at Day 1 (Visit 5).

The daily oral administered dose will be one tablet from a blister card and two capsules from 
the bottle.
Revised Text
Placebo Run-in Period (Day-14 [Visit 2] to Day -1)

Subjects will be dispensed one 2-week blister card and one bottle.


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
Subjects will receive single-blind placebo tablets and placebo capsules.

First dose will be given in-clinic at Day -14 (Visit 2).

The daily oral administered dose will be two tablets from a blister card and two capsules from 
the bottle.
Treatment Period (Day 1 [Visit 5] through Week 8 / Early Termination [Visit 9])

Subjects will receive blinded study medication and will be instructed to take their blinded 
study medication prior to their first meal of the day. Subjects will be dispensed one 2-week 
carton and one bottle at day 1 (Visit 5), at week 2 (Visit 6), week 4 (Visit 7), and week 6 
(Visit 8).

First dose will be given in-clinic at Day 1 (Visit 5).

The daily oral administered dose will be two tablets from a blister card and two capsules from 
the bottle.
Rationale of Amendment
To correct typographical errors.
Page 38, Section 8.1.4: Overdose (paragraph 3)
Existing Text
In the event of drug overdose, the subject should be treated symptomatically. Elimination of 
TAK-491 by dialysis or hemoperfusion has not been examined. Valsartan cannot be removed from 
the plasma by hemodialysis [22].
Revised Text
In the event of drug overdose, the subject should be treated symptomatically. Hemodialysis does 
not significantly remove TAK-536 or M-II from the systemic circulation. Valsartan cannot be 
removed from plasma by hemodialysis [22].
Rationale for Amendment
To add results from the TAK-491 phase 1 renal impairment study.
Page 43, Section 9.1.7: Documentation of Concurrent Medical Conditions (paragraph 2)
Existing Text
Continuous Positive Airway Pressure (CPAP) data will be collected during the study. If CPAP is 
ongoing at the time of informed consent, this data will be captured on the concurrent medical 
conditions (e)CRF. If CPAP is administered after first dose of study drug administration, then this
will be captured as an AE.


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Revised Text
Data on medical conditions that require Continuous Positive Airway Pressure (CPAP) will be 
collected during the study. If CPAP is ongoing at the time of informed consent, the medical 
condition that required CPAP will be captured on the concurrent medical conditions (e)CRF. If 
CPAP is administered after first dose of study drug, then the medical condition will be captured 
as an AE.
Rationale for Amendment
For clarity.
Pages 43-44, Section 9.1.8: Procedures for Clinical Laboratory Samples (paragraph 1, 
Table 9.a and paragraph 2)
Existing Text
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 40 mL, and The approximate total volume of 
blood for the study is 185 mL. Subjects will be instructed to fast for at least 8 hours prior to blood 
draws on Day 1 (Visit 5), Week 4 (Visit 7), and Week 8/ET (Visit 9). Details of these procedures 
and required safety monitoring will be given in the laboratory manual.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hemoglobin
Hematocrit
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count with 
differential
Albumin
Alanine aminotransferase (ALT)
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bicarbonate
Bilirubin, total
Bilirubin, direct (only if total is about ULN)
Blood urea nitrogen (BUN)
Calcium
Chloride
Creatinine
Creatine kinase (CK)
γ-Glutamyl transferase (GGT)
Glucose (serum)
Magnesium
Potassium
Protein, total
Sodium
Uric Acid
Specific gravity
pH
Creatinine **
Albumin **
Albumin:creatinine 
ratio (UACR)**
Microscopy
RBCs
WBCs
Qualitative
Protein
Blood
Ketones
Bilirubin
Glucose
Other (Performed as indicated on Schedule of Study Procedures)
Lipid Panel
Other Screening/Safety
Other
High-density lipoprotein (HDL) 
cholesterol
Low-density lipoprotein (LDL) 
cholesterol
Total cholesterol
Triglycerides
HbA1c
Female subjects only
Serum human chorionic gonadotropin (hCG)--for 
pregnancy (female subjects of childbearing 
potential)
Urine hCG —for pregnancy (female subjects of 
childbearing potential)*
eGFR
Plasma renin 
concentration and 
activity
Plasma and urine 
aldosterone
*Urine hCG will be performed at the site at Day-7 (Visit 3) and Day 1 (Visit 5) prior to randomization.
** Performed as indicated on the Schedule of Study Procedures.
The central laboratory will perform laboratory tests for hematology, serum chemistries, urinalysis, 
lipid panel, other screening/safety parameters, and other tests listed above. Estimated GFR will be 
calculated by the central laboratory using the Modification of Diet in Renal Disease equation 
[24,25]. Urinary albumin creatinine ratio (UACR) will also be calculated by the central laboratory. 
The urine pregnancy test at Day -7 (Visit 3) and Day 1 (Visit 5) will be performed at the site. The 
results of laboratory tests will be returned to the investigator, who is responsible for reviewing and 
filing these results.
Revised Text
All samples will be collected in accordance with acceptable laboratory procedures. The maximum 
volume of blood at any single visit is approximately 15 mL. The approximate total volume of 
blood for the study is 75 mL for male subjects, and 80 mL for female subjects (including an 
additional 5 mL of blood drawn for a serum pregnancy test on Day -14 [Visit 2]). After 


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informed consent is provided, subjects will be asked to fast prior to blood draws within the 
Screening Period, and will be instructed to fast for at least 8 hours prior to blood draws on Day 1 
(Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9). Details of these procedures 
and required safety monitoring will be given in the laboratory manual.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hemoglobin
Hematocrit
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count with 
differential
Albumin
Alanine aminotransferase (ALT)
Alkaline phosphatase
Aspartate aminotransferase (AST)
Bicarbonate
Bilirubin, total
Bilirubin, direct (only if total is about ULN)
Blood urea nitrogen (BUN)
Calcium
Chloride
Creatinine
Creatine kinase (CK)
γ-Glutamyl transferase (GGT)
Glucose
Magnesium
Potassium
Protein, total
Sodium
Uric Acid
High-density lipoprotein cholesterol (HDL-C)
Low-density lipoprotein cholesterol (LDL-C)
Total cholesterol
Triglycerides
Specific gravity
pH
Qualitative
Protein
Blood
Ketones
Bilirubin
Glucose
Microscopy
RBCs
WBCs
Other
HbA1c
Female subjects of childbearing potential only:
Serum human chorionic gonadotropin (hCG) for pregnancy
Urine hCG for pregnancy (a)
Urine albumin
Urine creatinine
Albumin:creatinine ratio (UACR)
eGFR
Plasma renin concentration and activity
Plasma and urine aldosterone
(a) Urine hCG will be performed at the site on Day 1 (Visit 5) prior to randomization.
The central laboratory will perform laboratory tests for hematology, serum chemistries, urinalysis, 
and other tests listed above. Estimated GFR will be calculated by the central laboratory using the 
Modification of Diet in Renal Disease equation [24,25]. Urinary albumin creatinine ratio (UACR) 
will also be calculated by the central laboratory. The urine pregnancy test on Day 1 (Visit 5) will 
be performed at the site. The results of laboratory tests will be sent to the investigator, who is 
responsible for reviewing and filing these results.


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Rationale for Amendment
To update the amount of blood needed at any single visit and for the study based on central 
laboratory blood volume requirements, to add a fasting requirement for Week 2 (Visit 6) due to the 
addition of clinical laboratory tests at this Visit, to state that after informed consent is provided, 
that subjects will be asked to fast prior to blood draws within the Screening Period as certain serum 
chemistry test results are not accurate unless the subject has fasted, to remove the urine pregnancy 
test on Day -7 (Visit 3) (replaced with a serum pregnancy test on Day -14 [Visit 2] per the current 
Takeda standard), to update the abbreviations for high- and low-density lipoprotein cholesterol for 
clarity, and to update Table 9.a for clarity.
Page 45, Section 9.1.9: Contraception and Pregnancy Avoidance Procedure (paragraphs 2 
and 4)
Existing Text
*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).
During the course of the study, regular serum/urine 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 (Appendix A). In addition to a negative serum hCG pregnancy test at Screening 
(Visit 1), subjects also must have a negative urine hCG pregnancy test at Day -7 (Visit 3) and on 
the day of first dose of study drug (Day 1 [Visit 5]), prior to receiving any dose of active study 
medication. A serum hCG pregnancy test will also be performed at Day 1. The subject will start 
study drug based on a negative urine test, but will be contacted if the serum test is found to be 
positive.
Revised Text
*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).
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 
(Appendix A). In addition to a negative serum hCG pregnancy test at Screening (Visit 1), subjects 
also must have a negative serum hCG pregnancy test at Day -14 (Visit 2) and a negative urine 
pregnancy test on the day of first dose of study drug (Day 1 [Visit 5]). Negative urine pregnancy 
test must be confirmed prior to receiving any dose of active study medication. A serum hCG 
pregnancy test will also be performed on Day 1 (Visit 5), at Week 4 (Visit 7), and at Week 8/ET 
(Visit 9). At any time during the study, a subject with a positive serum or urine pregnancy 
test will be discontinued immediately.


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Rationale for Amendment
To update the definition of “postmenopausal” and the time points for serum and urine hCG tests to 
the current Takeda standard. To re-iterate that subjects with a positive pregnancy test will be 
immediately removed from the study.
Page 47, Section 9.1.10: Pregnancy (paragraph 4)
Existing Text
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. An evaluation 
after the birth of the child will also be conducted.
Revised Text
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. Results of the 
evaluation of the child after birth will also be collected.
Rationale for Amendment
The Sponsor will collect information from eligible subjects; however, does not provide this 
evaluation as part of the study.
Page 49, Section 9.3.1: Screening (Visit 1)
Existing Text
Subjects will be screened for enrollment prior to discontinuing previous antihypertensive 
treatment or initiating the placebo run-in in accordance with the predefined entrance criteria 
described in Section 7.0. See Section 9.1.12 for procedures for documenting screen failures.
Procedures to be completed at the Screening (Visit 1) include:

Informed consent.

Inclusion and exclusion criteria.

Demographics, medical history, and medication history.

Physical examination.

Vital signs (including standing measurements). For subjects who have not received 
antihypertensive medications within 28 days, determine the mean sitting SBP for subject 
eligibility.

Weight and height. BMI will be calculated during data analysis.

12-lead ECG.

Concomitant medications.

Concurrent medical conditions.


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
Clinical laboratory tests (hematology, chemistry, urinalysis), lipid panel, and HbA1c. 
Estimated GFR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.

Register subject in IVRS/IWRS to obtain subject number.

Pretreatment event (PTE) assessment.
Revised Text
Subjects will be screened for enrollment prior to discontinuing previous antihypertensive 
treatment or initiating the placebo run-in in accordance with the predefined entrance criteria 
described in Section 7.0. See Section 9.1.12 for procedures for documenting screen failures. After 
informed consent is provided, subjects will be asked to fast prior to blood draws within the 
Screening Period.
Procedures to be completed at the Screening (Visit 1) include:

Informed consent.

Inclusion and exclusion criteria.

Demographics, medical history, and medication history.

Physical examination.

Vital signs (including standing measurements). For subjects who have not received 
antihypertensive medications within 28 days, determine the mean sitting SBP for subject 
eligibility.

Weight and height. BMI will be calculated during data analysis.

12-lead ECG.

Concomitant medications.

Concurrent medical conditions.

Clinical laboratory tests (hematology, chemistry, urinalysis) and HbA1c. Estimated GFR will 
be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Register subject in IVRS/IWRS to obtain subject number.

Pretreatment event (PTE) assessment.


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Rationale for Amendment
To state the requirement for fasting prior to Screening (Visit 1), and to clarify study procedures as 
follows: “lipid panel” is now part of the list of serum chemistry tests so is no longer stated 
separately; guidance regarding “ova donation” was added to the avoidance of pregnancy and 
acceptable methods of contraception procedure for consistency with Appendix A and 
Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if applicable” was 
replaced with “female subjects of childbearing potential” for consistency with Section 9.1.9.
Page 50, Section 9.3.3.1: Placebo Run-in, Day -14 (Visit 2) (bullet points)
Existing Text
The following procedures will be performed and documented during placebo Run-in, Day -14 
(Visit 2):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Concomitant medications.

PTE/Adverse event (AE) assessment.

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.

Access the IVRS/IWRS for single-blind placebo run-in study medication assignment.

Dispense single-blind placebo run-in study medication with dosing instructions.

In-clinic dose of single-blind placebo run-in study medication.
Revised Text
The following procedures will be performed and documented during placebo Run-in, Day -14 
(Visit 2):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Concomitant medications.

PTE/Adverse event (AE) assessment.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Serum pregnancy test (female subjects of childbearing potential only).

Access the IVRS/IWRS for single-blind placebo run-in study medication assignment.

Dispense single-blind placebo run-in study medication with dosing instructions.


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
In-clinic dose of single-blind placebo run-in study medication.
Rationale for Amendment
To add a serum pregnancy test at Day -14 (Visit 2) for consistency with the current Takeda 
standard. To clarify study procedures as follows: guidance regarding “ova donation” was added to 
the avoidance of pregnancy and acceptable methods of contraception procedure for consistency 
with Appendix A and Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if 
applicable” was replaced with “female subjects of childbearing potential” for consistency with 
Section 9.1.9.
Page 51, Section 9.3.3.2: Placebo Run-in, Day -7 (Visit 3) (bullet points)
Existing Text
The following procedures will be performed and documented during Run-in, Day -7 (Visit 3):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Urine pregnancy test (female subjects of childbearing potential only). Analysis is performed at 
the site. Test must be negative for subject to continue.

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.

Concomitant medications.

AE assessment.

Collect single-blind placebo run-in study medication and assess compliance, and counsel if on 
compliance if required.

In-clinic dose with single-blind placebo run-in study medication (from the returned medication 
supply).

Redispense single-blind placebo run-in study medication and instruct subject to withhold dose 
the morning of Day 1 (Visit 5). Last day of single-blind dosing is Day -1.

Remind subjects to fast 8 hours before Day 1 Visit.
Revised Text
The following procedures will be performed and documented during Run-in, Day -7 (Visit 3):

Inclusion and exclusion criteria.

Vital signs (including standing measurements).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Concomitant medications.


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
AE assessment.

Collect single-blind placebo run-in study medication and assess compliance, and counsel if on 
compliance if required.

In-clinic dose with single-blind placebo run-in study medication (from the returned medication 
supply).

Redispense single-blind placebo run-in study medication and instruct subject to withhold dose 
the morning of Day 1 (Visit 5). Last day of single-blind dosing is Day -1.

Remind subjects to fast 8 hours before Day 1 Visit.
Rationale for Amendment
To remove urine pregnancy tests on Day -7 (Visit 3) to be consistent with the current Takeda 
standard. To clarify study procedures as follows: guidance regarding “ova donation” was added to 
the avoidance of pregnancy and acceptable methods of contraception procedure for consistency 
with Appendix A and Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if 
applicable” was replaced with “female subjects of childbearing potential” for consistency with 
Section 9.1.9.
Pages 51-52, Section 9.3.4: Day -1 (Visit 4) (bullet points)
Existing Text

Update eligibility status (inclusion and exclusion criteria).

Collect vital signs.

Document changes to concomitant medications.

Assess for AEs.

Guidance on avoidance of pregnancy and ova donation and acceptable methods of 
contraception, if applicable.

Collect single-blind study medication and assess subject compliance with dosing regimen.
Instruct subject to withhold dose the morning of the Day 1 (Randomization).

Single-blind clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start.

Start 24-hour ABPM.

Remind subjects to fast 8 hours before Day 1 Visit.
Revised Text

Update eligibility status (inclusion and exclusion criteria).

Collect vital signs.

Document changes to concomitant medications.


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
Assess for AEs.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Collect single-blind study medication and assess subject compliance with dosing regimen.
Instruct subject to withhold dose the morning of the Day 1 (Randomization).

Single-blind clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start.

Start 24-hour ABPM.

Remind subjects to fast 8 hours before Day 1 Visit.
Rationale for Amendment
To clarify study procedures as follows: “if applicable” was replaced with “female subjects of 
childbearing potential” for consistency with Section 9.1.9 (Contraception and Pregnancy 
Avoidance Procedure).
Pages 52-53, Section 9.3.5: Randomization, Day 1 (Visit 5) (bullet points)
Existing Text
Study randomization will take place on Day 1. Subjects should fast for at least 8 hours before this 
visit. The following procedures will be performed and documented during study randomization:

Remove ABPM and ensure ABPM reading is successful.(for subjects conduct ABPM only).
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current placebo treatment and ABPM should be repeated within 3 days.

Inclusion and exclusion criteria (before randomized to treatment).

Vital signs (including standing measurements) and weight. BP must meet inclusion #1 and 
must not meet exclusion #1.

Urine pregnancy test (female subjects of childbearing potential only). Analysis is performed at 
the site. Test must be negative for subject before subject can be randomized.

Collect single-blind placebo run-in study medication and assess subject compliance with 
dosing.

Concomitant medications.

AE assessment.

If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IVRS/IWRS system, as described 
in Section 9.1.13. If subject does not meet all of the inclusion and none of the exclusion 
criteria, document the subject as a run-in failure and record the primary reason for failure on 


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the applicable (e)CRF. The procedure for documenting run-in failures is provided in 
Section 9.1.13.

Physical examination.

12-lead ECG.

Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, lipid panel, renin, 
aldosterone, urine albumin, and urine creatinine. Estimated GFR and UACR will be calculated 
by the central laboratory.

Serum/urine pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.

Dispense double-blind study medication with dosing instruction.

In-clinic first dose of double-blind study medication.
Revised Text
Study randomization will take place on Day 1. Subjects should fast for at least 8 hours before this 
visit. The following procedures will be performed and documented during study randomization:

Remove ABPM and ensure ABPM reading is successful (for subjects conduct ABPM only).
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current placebo treatment and ABPM should be repeated within 3 days.

Inclusion and exclusion criteria (before randomized to treatment).

Vital signs (including standing measurements) and weight. BP must meet inclusion #1 and 
must not meet exclusion #1.

Urine pregnancy test (female subjects of childbearing potential only). Analysis is performed at 
the site. Test must be negative for subject before subject can be randomized.

Collect single-blind placebo run-in study medication and assess subject compliance with 
dosing.

Concomitant medications.

AE assessment.

If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized using the IVRS/IWRS system, as described 
in Section 9.1.13. If subject does not meet all of the inclusion and none of the exclusion 
criteria, document the subject as a run-in failure and record the primary reason for failure on 
the applicable (e)CRF. The procedure for documenting run-in failures is provided in 
Section 9.1.13.

Physical examination.


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CONFIDENTIAL

12-lead ECG.

Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, plasma renin 
concentration and activity, plasma and urine aldosterone, urine albumin, and urine 
creatinine. Estimated GFR and UACR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Dispense double-blind study medication with dosing instruction.

In-clinic first dose of double-blind study medication.

Instruct the subject to fast for at least 8 hours prior to Week 2 (Visit 6).
Rationale for Amendment
To clarify that renin concentration and activity, and plasma and urine aldosterone will be 
measured, to add a fasting requirement for Week 2 (Visit 6) due to the addition of clinical 
laboratory tests at this Visit, and to remove duplication of urine pregnancy test instruction.
To clarify study procedures as follows: “lipid panel” is now part of the list of serum chemistry tests 
so is no longer stated separately; guidance regarding “ova donation” was added to the avoidance of 
pregnancy and acceptable methods of contraception procedure for consistency with Appendix A
and Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if applicable” was 
replaced with “female subjects of childbearing potential” for consistency with Section 9.1.9.
Page 53, Section 9.3.6: Treatment Visits, Week 2 through Week 6 (Visit 6 through Visit 8) 
(bullet points)
Existing Text
See Appendix A for windows for each visit. Subjects should fast for a minimum of 8 hours before 
Visit 7. The following procedures will be performed at these visits:

Vital signs (including standing measurements) and weight.

Laboratory tests (Visit 7 only)—Clinical laboratory tests (hematology, chemistry, and 
urinalysis), renin, and aldosterone. Estimated GFR will be calculated by the central lab.

Serum/urine pregnancy test (female subjects of childbearing potential only) at Visit 7 only.

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen. If 
required, counsel subject on compliance.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
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
Access the IVRS/IWRS and dispense double-blind study medication with dosing instructions.

In-clinic first dose of the newly assigned double-blind medication in the clinic.

Instruct subject to withhold dose of study medication the morning of all in-clinic study visits.

Instruct the subject to fast for at least 8 hours prior to Week 4 (Visit 7).
Revised Text
See Appendix A for windows for each visit. Subjects should fast for a minimum of 8 hours before 
Visits 6 and 7. The following procedures will be performed at these visits:

Vital signs (including standing measurements) and weight.

Laboratory tests: Clinical laboratory tests (hematology, chemistry, and urinalysis) at Visits 
6 and 7 only; plasma renin concentration and activity, and plasma and urine aldosterone 
at Visit 7 only. Estimated GFR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only) at Visit 7 only.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen. If 
required, counsel subject on compliance.

Access the IVRS/IWRS and dispense double-blind study medication with dosing instructions.

In-clinic first dose of the newly assigned double-blind medication in the clinic.

Instruct subject to withhold dose of study medication the morning of all in-clinic study visits.

Instruct the subject at Week 2 (Visit 6) to fast for at least 8 hours prior to Week 4 (Visit 7) and 
at Week 6 (Visit 8) to fast for Week 8 (Visit 9).
Rationale for Amendment
To add clinical laboratory tests (clinical chemistry, hematology, and urinalysis) and eGFR at 
Week 2 (Visit 6) to be consistent with the current Takeda standard. Week 2 blood draw will allow 
full characterization of possible early postdose laboratory parameter changes that are considered 
relevant for monitoring with use of an ARB class of drug, including serum creatinine, electrolytes, 
liver enzyme tests, CPK, and hemoglobin. Mild ALT and AST elevations above ULN (but not 
exceeding 3×ULN) were observed in 7 of 16 subjects on Day 11 of a phase 1 study of TAK-491 in 
healthy Chinese subjects.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
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CONFIDENTIAL
To remove the urine pregnancy test from Week 4 (Visit 7) (replaced with a serum pregnancy test 
per current Takeda standard), to clarify that renin concentration and activity, and plasma and urine 
aldosterone will be measured, and to add a fasting requirement for Week 8 (Visit 9).
To clarify study procedures as follows: guidance regarding “ova donation” was added to the 
avoidance of pregnancy and acceptable methods of contraception procedure for consistency with 
Appendix A and Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if 
applicable” was replaced with “female subjects of childbearing potential” for consistency with 
Section 9.1.9.
Page 53-54, Section 9.3.7: Week 8/Final Visit or Early Termination (Visit 9) (bullet points)
Existing Text
Subjects should fast for 8 hours before this visit. Assessments scheduled for Week 8/ET (Visit 9) 
should be completed (safety permitting) for subjects who were randomized and withdraw early. 
The following procedures will be performed and documented:

Clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start. (in subgroup only).

Start 24-hour ABPM. (in subgroup only).

Vital signs (including standing measurements) and weight.

Physical examination.

12-lead ECG.

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen.

Access the IVRS/IWRS to register subject completion/early termination.

Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, lipid panel, renin, 
aldosterone, urine albumin and urine creatinine. Estimated GFR and UACR will be calculated 
by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy and acceptable methods of contraception, if applicable.
Revised Text
Subjects should fast for 8 hours before this visit. Assessments scheduled for Week 8/ET (Visit 9) 
should be completed (safety permitting) for subjects who were randomized and withdraw early. 
The following procedures will be performed and documented:

Clinic dosing at 8:00 AM (±2 hours) and immediately prior to ABPM start (in subgroup only).

Start 24-hour ABPM (in subgroup only).


TAK-491 (azilsartan medoxomil)
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CONFIDENTIAL

Vital signs (including standing measurements) and weight.

Physical examination.

12-lead ECG.

Concomitant medications.

AE assessment.

Collect double-blind study medication and assess subject compliance with dosing regimen.

Access the IVRS/IWRS to register subject completion/early termination.

Clinical laboratory tests (hematology, chemistry, and urinalysis), HbA1c, plasma renin 
concentration and activity, plasma and urine aldosterone, urine albumin and urine 
creatinine. Estimated GFR and UACR will be calculated by the central laboratory.

Serum pregnancy test (female subjects of childbearing potential only).

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of contraception 
(female subjects of childbearing potential only).
Rationale for Amendment
To clarify that renin concentration and activity, and plasma and urine aldosterone will be 
measured. To clarify study procedures as follows: “lipid panel” is now part of the list of serum 
chemistry tests so is no longer stated separately; guidance regarding “ova donation” was added to 
the avoidance of pregnancy and acceptable methods of contraception procedure for consistency 
with Appendix A and Section 9.1.9 (Contraception and Pregnancy Avoidance Procedure), and “if 
applicable” was replaced with “female subjects of childbearing potential” for consistency with 
Section 9.1.9.
Page 54, Section 9.3.8: ABPM Removal (Visit 10) (bullet points)
Existing Text
This visit only applies to the ABPM subgroup. Assessments scheduled for ABPM Removal Visit
(Visit 10) should be completed (safety permitting) for subjects. The following procedures will be 
performed:

Remove ABPM and ensure ABPM reading is successful.
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current treatment and ABPM should be repeated within 3 days

Vital signs (including standing measurements) and weight.

AE assessment.

Concomitant medications.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
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CONFIDENTIAL
Revised Text
This visit only applies to the ABPM subgroup. Assessments scheduled for ABPM Removal Visit
(Visit 10) should be completed (safety permitting) for subjects. The following procedures will be 
performed:

Remove ABPM and ensure ABPM reading is successful.
Reminder: If the ABPM measurement does not pass the predefined criteria (fails), the subject 
must continue the current treatment and ABPM should be repeated within 3 days

Vital signs (including standing measurements) and weight.

AE assessment.

Concomitant medications.

Guidance on avoidance of pregnancy, ova donation, and acceptable methods of 
contraception (female subjects of childbearing potential only).
Rationale for Amendment
To add guidance for avoidance of pregnancy, ova donation, and acceptable methods of 
contraception at this Visit to be consistent with the current Takeda standard.
Page 54, Section 9.3.9: Follow-up (bullet 1)
Existing Text

Subjects should receive a follow-up telephone call to assess any new or ongoing AEs and 
changes to concomitant medications 14 days after the last dose of study medication 
(single-blind placebo or double-blind). Female subjects of childbearing potential should be 
counseled on avoidance of pregnancy and use of acceptable methods of contraception through 
30 days after the last dose of study medication.
Revised Text

Subjects should receive a follow-up telephone call to assess any new or ongoing AEs and 
changes to concomitant medications 14 days after the last dose of study medication 
(single-blind placebo or double-blind). Female subjects of childbearing potential should be 
counseled on avoidance of pregnancy, ova donation, and use of acceptable methods of 
contraception through 30 days after the last dose of study medication.
Rationale for Amendment
The guidance regarding “ova donation” was added to the avoidance of pregnancy and acceptable 
methods of contraception procedure for consistency with Appendix A and Section 9.1.9
(Contraception and Pregnancy Avoidance Procedure).


TAK-491 (azilsartan medoxomil)
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Page 58, Section 10.1.4: SAEs
Existing Text
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
Revised Text
Is a CONGENITAL ANOMALY/BIRTH DEFECT.
Rationale for Amendment
To be consistent with ICH and USFDA definitions.
Page 67, Section 13.1.1: Analysis Sets (paragraphs 4 and 6)
Existing Text
Per-Protocol Set (PPS): All subjects in the FAS, excluding any subjects who had major protocol 
violations. Major deviations from the protocol leading to exclusion from the Per Protocol Set will 
be identified prior to unblinding of subject’s treatment assignment.
The FAS will be the primary data set used for efficacy analyses. Efficacy analysis based on the Per 
Protocol Set will also be performed where appropriate. All routine safety analysis will be based on 
the Safety Analysis Set.
Revised Text
Per-Protocol Set (PPS): All subjects in the FAS, excluding any subjects who had major protocol 
violations. Major violations from the protocol leading to exclusion from the Per Protocol Set will 
be identified prior to unblinding of subject’s treatment assignment.
The FAS will be the primary data set used for efficacy analyses. Efficacy analysis based on the Per 
Protocol Set will also be performed where appropriate. All routine safety analysis will be based on 
the Safety Analysis Set.
All subjects who were randomized more than once will be excluded from the safety analysis 
set, the FAS, and the PPS.
Rationale for Amendment
For clarity.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
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Pages 79-81, Appendix A: Schedule of Study Procedures
Existing Text
Study Day:
Screen-
ing
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 
(b)
or D 
-28 (c)
Single-Blind 
Placebo Run-in
D -1
4
(d,e) D -7
D -1
(v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
removal 
visit (w)
Tele-
phone 
Follow-
up (g)
Visit Windows
N/A
N/A
N/A N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
PTE assessment (h)
X
X
AE assessment (i,j,r)
X
X
X
X
X
X
X
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
X
X
Weight, height, and BMI (l)
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Clinical laboratory tests (m)
X
X
X
X
Urine albumin and creatinine 
and UACR (n)
X
X
Lipid panel
X
X
X
HbA1c
X
X
X
Estimated GFR (n)
X
X
X
X
Serum hCG (o)
X
X
X
X
Urine pregnancy test (o,p)
X
X
X
Guidance on avoidance of 
pregnancy and ova donation
X
X
X
X
X
X
X
X
X
X
Notify subject to begin 
washout period (q)
X
Plasma renin concentration 
and activity, Plasma and urine 
Aldosterone
X
X
X
ABPM start (subgroup only)
X
X
ABPM removal (subgroup 
only)
X
X
Concurrent medical 
conditions (r)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Access IVRS/IWRS (s)
X
X
X
X
X
X
X
Dispense single-blind study 
placebo for run-in and dose 
in-clinic (t)
X
Redispense single-blind 
placebo for run-in
X
Last dose of single-blind 
placebo (u)
X


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
Page 117 of 121
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CONFIDENTIAL
Study Day:
Screen-
ing
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 
(b)
or D 
-28 (c)
Single-Blind 
Placebo Run-in
D -1
4
(d,e) D -7
D -1
(v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
removal 
visit (w)
Tele-
phone 
Follow-
up (g)
Visit Windows
N/A
N/A
N/A N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Dispense double blind study 
drug
X
X
X
X
Last dose of double blind 
study drug
X
Clinic dosing (u)
X
X
X
X
X
X
X
X
Compliance assessment
X
X
X
X
X
X
X
-
Footnotes are on the last table page.
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results can be reviewed 
and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated.
(b) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout period (Days -21 to -1).
(c) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout must be extended 
to 4 weeks (Days -28 to -1).
(d) Subjects who have not received antihypertensive treatment within 28 days before screening can be entered into the run-in period 
as soon as all inclusion and exclusion criteria, including laboratory results, have been verified.
(e) At minimum, the run-in should be 10 days but can extend to as long as the subject has an adequate supply of single-blind placebo 
run-in study medication.
(f) Conduct Final Visit procedures for subjects who are randomized and discontinued early per Section 7.6.
(g) Telephone contact for the follow-up AE and concomitant medication assessments should be made approximately 14 days after 
the last dose (single-blind placebo or double-blind).
(h) Reports of pretreatment events should be solicited at each visit from the time that informed consent is acquired until the first 
dose of placebo run-in study medication.
(i)AEs should be solicited at each visit from the time that single-blind placebo run-in study medication is started through 14 days 
after the last dose (via the telephone follow-up AE assessment).
(j) Spontaneous reports of AEs and SAEs should be collected from the time of the first dose of single-blind placebo run-in 
medication through 14 or 30 days, respectively, after the last dose.
(k) Includes sitting and standing BP and pulse rate. Pulse rate will be taken manually while sitting and standing.
(l) Collect height at the Screening (Visit 1) only; BMI will be calculated during data analysis at Screening (Visit 1).
(m) Hematology, serum chemistry, and urinalysis tests (as listed in Table 9.a). Subjects should be fasted for at least 8 hrs prior to 
Visits 5, 7 and 9.
(n) UACR and estimated GFR will be calculated by the central laboratory.
(o) Women of childbearing potential only.
(p) Urine pregnancy test is performed at the site at Day -7 (Visit 3) and prior to randomization on Day 1 (Visit 5).
(q) Subject can be notified by telephone to begin the washout period.
(r) Continuous Positive Airway Pressure (CPAP) data will be collected during the study. If CPAP is ongoing at the time of informed 
consent, this data will be captured on the concurrent medical conditions (e)CRF. If CPAP is administered after first dose of study 
drug administration, then this will be captured as an AE.
(s) If a subject withdraws early, contact IVRS/IWRS to document the ET.
(t) Subjects to take the first dose of single-blind placebo run-in study medication in-clinic.
(u) Instruct subjects to withhold their dose of study drug, if applicable so they can be dosed in-clinic. For ABPM subgroup subjects, 
clinic dosing at 8:00AM((±2 hours) for visit 4 and 9.
(v) Visit 4 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the 
subject must continue the current treatment and ABPM should be repeated within 3 days.
(w)Visit 10 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the 
subject must continue the current treatment and ABPM should be repeated within 3 days.


TAK-491 (azilsartan medoxomil)
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CONFIDENTIAL
Revised Text
Study Day or Week:
Screening
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 (b)
or
D -28 (c)
Single-Blind Placebo Run-in
D -14 (d,e)
D -7
D -1 (v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
Removal 
Visit (w)
Tele-
phone 
Follow-
up (g)
Visit Window
N/A
N/A
N/A
N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
PTE assessment (h)
X
X
AE assessment (i,j,r)
X
X
X
X
X
X
X
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
X
X
Weight, height, and BMI (l)
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Clinical laboratory tests (m)
X
X
X
X
X
Urine albumin and creatinine and UACR (n)
X
X
HbA1c
X
X
X
Estimated GFR (n)
X
X
X
X
X
Serum hCG (o)
X
X
X
X
X
Urine pregnancy test (o,p)
X
Guidance on avoidance of pregnancy, ova 
donation, and acceptable methods of 
contraception
X
X
X
X
X
X
X
X
X
X
X
Notify subject to begin washout period (q)
X
Plasma renin concentration and activity, plasma and 
urine aldosterone
X
X
X
ABPM start (subgroup only)
X
X
ABPM removal (subgroup only)
X
X


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
Page 119 of 121
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CONFIDENTIAL
Study Day or Week:
Screening
Visit (a)
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
D -21 (b)
or
D -28 (c)
Single-Blind Placebo Run-in
D -14 (d,e)
D -7
D -1 (v)
D1
W2
W4
W6
Final 
clinic/
ET
W8
(f)
ABPM 
Removal 
Visit (w)
Tele-
phone 
Follow-
up (g)
Visit Window
N/A
N/A
N/A
N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Concurrent medical conditions (r)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Access IVRS/IWRS (s)
X
X
X
X
X
X
X
Dispense single-blind study placebo for run-in and 
dose in-clinic (t)
X
Redispense single-blind placebo for run-in
X
Last dose of single-blind placebo (u)
X
Dispense double blind study drug
X
X
X
X
Last dose of double blind study drug
X
Clinic dosing (u)
X
X
X
X
X
X
X
X
Compliance assessment
X
X
X
X
X
X
X
Footnotes for Appendix A are on the next page.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
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CONFIDENTIAL
Footnotes for Appendix A
D=Day, W=Week.
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results can be reviewed 
and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated.
(b) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout period (Days -21 to -1).
(c) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout must be extended 
to 4 weeks (Days -28 to -1).
(d) Subjects who have not received antihypertensive treatment within 28 days before screening can be entered into the run-in period 
as soon as all inclusion and exclusion criteria, including laboratory results, have been verified.
(e) At minimum, the run-in should be 10 days but can extend to as long as the subject has an adequate supply of single-blind placebo 
run-in study medication.
(f) Conduct Final Visit procedures for subjects who are randomized and discontinued early per Section 7.6.
(g) Telephone contact for the follow-up AE and concomitant medication assessments should be made approximately 14 days after 
the last dose (single-blind placebo or double-blind).
(h) Reports of pretreatment events should be solicited at each visit from the time that informed consent is acquired until the first 
dose of placebo run-in study medication.
(i)AEs should be solicited at each visit from the time that single-blind placebo run-in study medication is started through 14 days 
after the last dose (via the telephone follow-up AE assessment).
(j) Spontaneous reports of AEs and SAEs should be collected from the time of the first dose of single-blind placebo run-in 
medication through 14 or 30 days, respectively, after the last dose.
(k) Includes sitting and standing BP and pulse rate. Pulse rate will be taken manually while sitting and standing.
(l) Collect height at the Screening (Visit 1) only; BMI will be calculated during data analysis at Screening (Visit 1).
(m) Hematology, serum chemistry, and urinalysis tests (as listed in Table 9.a). After informed consent is provided, subjects will 
be asked to fast prior to blood draws within the Screening Period, and will be instructed to fast for at least 8 hours prior to 
blood draws on Day 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9).
(n) UACR and estimated GFR will be calculated by the central laboratory.
(o) Women of childbearing potential only.
(p) Urine pregnancy test is performed at the site and must be negative for subject prior to randomization on Day 1 (Visit 5).
(q) Subject can be notified by telephone to begin the washout period.
(r) Data on medical conditions that require Continuous Positive Airway Pressure (CPAP) will be collected during the study. 
If CPAP is ongoing at the time of informed consent, the medical condition that required CPAP will be captured on the 
concurrent medical conditions (e)CRF. If CPAP is administered after first dose of study drug, then the medical condition 
will be captured as an AE.
(s) If a subject withdraws early, contact IVRS/IWRS to document the ET.
(t) Subjects to take the first dose of single-blind placebo run-in study medication in-clinic.
(u) Instruct subjects to withhold their dose of study drug, if applicable so they can be dosed in-clinic. For ABPM subgroup subjects, 
clinic dosing at 8:00 AM (±2 hours) for Visits 4 and 9.
(v) Visit 4 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the
subject must continue the current treatment and ABPM should be repeated within 3 days.
(w)Visit 10 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined criteria (fails), the 
subject must continue the current treatment and ABPM should be repeated within 3 days.
Rationale for Amendment
To add clinical laboratory tests (clinical chemistry, hematology, and urinalysis) and eGFR at 
Week 2 (Visit 6) to be consistent with the current Takeda standard. Week 2 blood draw will allow 
full characterization of possible early postdose laboratory parameter changes that are considered 
relevant for monitoring with use of an ARB class of drug, including serum creatinine, electrolytes, 
liver enzyme tests, CPK, and hemoglobin. Mild ALT and AST elevations above ULN (but not 
exceeding 3×ULN) were observed in 7 of 16 subjects on Day 11 of a phase 1 study of TAK-491 in
healthy Chinese subjects.


TAK-491 (azilsartan medoxomil)
Study No. TAK-491_305
Page 121 of 121
Protocol Incorporating Amendment No. 4
09 May 2016
CONFIDENTIAL
To add a serum pregnancy test at Day -14 (Visit 2), remove urine pregnancy tests from Day -7 
(Visit 3) and Week 4 (Visit 7), and add guidance on avoidance of pregnancy and ova donation to 
Visit 10 to be consistent with the current Takeda standard. Footnote (r) modified for clarity.
The row for “lipid panel” was removed as it is now included in the list of serum chemistry tests in 
Table 9.a. To state that after informed consent is provided, that subjects will be asked to fast prior 
to blood draws within the Screening Period as certain serum chemistry test results are not accurate 
unless the subject has fasted. “Acceptable methods of contraception” was added to the procedure 
regarding guidance on avoidance of pregnancy and ova donation for consistency with Section 9.3
of the protocol.


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PPD

SAP_001.pdf: 
This may include, but is not limited to, redaction of the following: 


• 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 phase 3, double-blind, randomized, parallel-group study to compare the efficacy and safety 
of TAK-491 with valsartan in Chinese subjects with essential hypertension: an 8-week study 
NCT Number: NCT02480764
SAP Approve Date: 29 November 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 information or company confidential information. 
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.


STATISTICAL ANALYSIS PLAN
Study Number: TAK-491_305
A Phase 3, Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and 
Safety of TAK-491 with Valsartan in Chinese Subjects with Essential Hypertension
TAKEDA DEVELOPMENT CENTER ASIA, PTE. LTD.
Version: Final
Date: 29 November 2017
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.


Study No. TAK-491_305
Page 2 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
APPROVAL SIGNATURES
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
Prepared at Quintiles by:
Date
TDC Approvals:
Date
Date
Date
Date
PPD
PPD
PPD
PPD
PPD


Study No. TAK-491_305
Page 3 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
1.0
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
INTRODUCTION...........................................................................................................6
5.0
OBJECTIVES .................................................................................................................7
5.1
Primary Objective......................................................................................................7
5.2
Secondary Objective..................................................................................................7
5.3
Study Design .............................................................................................................7
6.0
ANALYSIS ENDPOINTS.............................................................................................11
6.1
Primary Endpoint.....................................................................................................11
6.2
Secondary Endpoints ...............................................................................................11
6.3
Additional Endpoints ...............................................................................................11
6.4
Safety Assessments..................................................................................................12
7.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
8.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
8.1
General Considerations............................................................................................14
8.1.1
Statistical Software ............................................................................................14
8.1.2
Summary Statistics and Precision.......................................................................14
8.1.3
Definition of Study Day and Baseline ................................................................14
8.1.4
Definitions of Study Visit Windows...................................................................15
8.2
Significant Protocol Deviations................................................................................15
8.3
Analysis Sets ...........................................................................................................16
8.4
Disposition of Subjects ............................................................................................17
8.5
Demographic and Baseline Efficacy Characteristics.................................................17
8.5.1
Demographic and Baseline Characteristics.........................................................17
8.5.2
Baseline Efficacy Parameters.............................................................................18
8.6
Medical History and Concurrent Medical Conditions...............................................18
8.7
Medication History and Concomitant Medications...................................................19
8.8
Study Drug Exposure and Compliance.....................................................................20
8.9
Efficacy Analysis.....................................................................................................21
8.9.1
Primary Efficacy Endpoint.................................................................................21
8.9.2
Secondary Efficacy Endpoints............................................................................22
8.9.3
Additional Efficacy Endpoints ...........................................................................23


Study No. TAK-491_305
Page 4 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
8.9.4
Efficacy Analysis for ABPM Subgroup Subjects................................................23
8.10
Safety Analysis........................................................................................................25
8.10.1 Adverse Events ..................................................................................................25
8.10.2 Clinical Laboratory Evaluations .........................................................................27
8.10.3 Vital Signs and Weight ......................................................................................29
8.10.4 12-Lead ECGs ...................................................................................................29
8.10.5 Physical Examinations .......................................................................................30
8.11
Interim Analysis ......................................................................................................30
8.12
Changes in the Statistical Analysis Plan From the Protocol Analysis Plan................30
9.0
REFERENCES..............................................................................................................31
LIST OF IN-TEXT TABLES
Table 5.a
Schedule of Study Procedures..............................................................................9
Table 8.a
Visit Analysis Windows for Efficacy and Safety Variables ................................15
Table 8.b
Clinical Laboratory Tests...................................................................................28
LIST OF IN-TEXT FIGURES
Figure 5.a
Schematic of Study Design ..................................................................................8
LIST OF APPENDIX
Appendix A.
Criteria for Identification of Markedly Abnormal Laboratory Values .................32


Study No. TAK-491_305
Page 5 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
2.0
LIST OF ABBREVIATIONS
ABPM
ambulatory blood pressure monitoring
AE
adverse event
ANCOVA
analysis of covariance
ANOVA
analysis of variance
BMI
body mass index
CI
confidence interval
DBP
diastolic blood pressure
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FAS
full analysis set
ICH
International Conference on Harmonization
LLN
lower limit of normal
LOCF
last observation carried forward
MAV
markedly abnormal values
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
OC
observed case
PE
physical examination
PPS
per protocol set
PT
preferred term
QD
once daily
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SE
standard error
SI
system International
SOC
system organ class
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHO
World Health Organization


Study No. TAK-491_305
Page 6 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
3.0
INTRODUCTION
This statistical analysis plan (SAP) describes the planned statistical analyses and data 
presentations for TAK-391_305, a phase 3, double-blind, randomized, parallel-group study to 
evaluate the efficacy and safety of TAK-491 compared with valsartan over an 8 week treatment 
period in Chinese subjects with essential hypertension (mean sitting clinic systolic blood 
pressure (SBP) ≥ 150 and ≤ 180 mm Hg on Day 1).
The purpose of this document is to ensure the credibility of the study findings by specifying the 
statistical approaches to the analysis of the double-blind data prior to database lock. This SAP 
was developed based on the International Conference on Harmonization (ICH) E3 and E9 
Guidelines and in reference to the following document:

Protocol TAK-491_305 Amendment No.4 dated 09 May 2016.
Any deviations during the analysis and reporting process from the current SAP will be described 
and justified in the final report. Analysis issues that suggest changes to the principal features 
stated in the protocol will be documented in a protocol amendment. Otherwise, the statistical 
analysis plan will be updated through an amendment with the changes in the analysis 
documented in the amendment.


Study No. TAK-491_305
Page 7 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
4.0
OBJECTIVES
4.1
Primary Objective
The primary objective of this study is to evaluate the antihypertensive effect of TAK-491 
compared with valsartan in Chinese subjects with essential hypertension.
4.2
Secondary Objective
The secondary objective is to evaluate the safety and tolerability of TAK-491 compared with 
valsartan.
4.3
Study Design
This is a phase 3, multicenter, randomized, double-blind, parallel-group study to evaluate the 
efficacy and safety of TAK-491 compared with valsartan over an 8 week treatment period in 
Chinese subjects with essential hypertension (mean sitting clinic SBP ≥150 and ≤180 mm Hg on 
Day 1). A subgroup of approximately 60 subjects/arm from selected sites will undergo 24-hour 
ambulatory blood pressure monitoring (ABPM) 2 times during the study.
This study will be conducted in China at approximately 20 to 25 sites and will include 
approximately 600 randomized subjects.
Before initiation of treatment, all subjects will participate in a 2-week, single-blind, placebo run-
in period (Days -14 to -1). Subjects who have not received antihypertensive treatment within 28 
days before screening can be entered into the run-in period as soon as all inclusion and exclusion 
criteria, including laboratory results, have been verified. Subjects taking previous 
antihypertensive agents will be required to participate in a 3-week washout/placebo run-in period 
(Days -21 to -1). If the subject’s previous antihypertensive treatment includes amlodipine or 
chlorthalidone, then the washout/placebo run-in must be extended to 4 weeks (Days -28 to -1). 
Screening (Visit 1) will be scheduled before the washout/run-in period begins so that laboratory 
test results can be reviewed and subject eligibility can be confirmed before other treatments are 
stopped or placebo is initiated. At Day -14 (Visit 2), subjects will receive the first dose of single-
blind placebo in clinic. 
At Day 1 (Visit 5), eligible subjects will be randomly assigned to one of the following 3 groups 
with a 1:1:1 ratio: 

TAK-491 40 mg QD. 

TAK-491 80 mg QD. 

Valsartan 160 mg QD. 
Subjects will be given the first dose of randomized study drug in the clinic at Day 1 (Visit 5). 
The last dose of randomized study drug will be taken the day of Week 8 visit (Visit 9). End of 
study assessment will be taken at Week 8/Early Termination (Visit 9). All subjects who receive 
study drug (placebo or double-blind) will be required to have a follow-up telephone call at 
approximately 14 days after the last dose.


Study No. TAK-491_305
Page 8 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
A schematic of the study design is included as Figure 4.a. A schedule of assessments is listed in
Table 4.a.
Figure 4.a
Schematic of Study Design
Randomization
(n=200/arm)
TAK-491 40 mg QD (n=200)
TAK-491 80 mg QD (n=200)
Valsartan 160 mg QD (n=200)
Other 
anti-HTN 
treatments 
stopped
1st dose 
of 
placebo 
(e)
Last 
dose 
of 
placebo
First dose 
of double 
blind 
randomized 
study drug
Visit 6 
Wk 2
Visit 7 
Wk 4
Visit 8
Wk 6
Last dose
of double 
blind (g)
Removal 
ABPM
Tele-
phone 
contact 
(h)
Visit 1
(a)
N/A (b)
D -21(c) or 
D -28 (d)
Visit 2
D -14
(f)
Visit 3
D -7
Visit 4
D -1
(i)
Visit 5
D 1
Visit 9 
Final 
Visit/
ET 
Visit10
(j)
N/A
Follow-
up
Single-Blind Placebo 
Run-In
Double-Blind Treatment
Post-treatment
Washout
Screening Visit
V=visit, N/A=not applicable, D=day, HTN=hypertension, Wk=week, ET=Early Termination. 
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results 
can be reviewed and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated. 
(b) Subjects may be notified by telephone to begin the washout period. 
(c) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout/run-in period 
(Days -21 to -1).
(d) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout 
must be extended to 4 weeks (Days -28 to -1). 
(e) The first dose of placebo will be taken at the clinic on Day -14 (Visit 2). 
(f) Subjects who have not received antihypertensive treatment within 28 days prior to Screening can be entered into 
the run-in period as soon as all inclusion and exclusion criteria, including laboratory results, have been verified. 
(g) Last dose of double-blind is the day of Week 8/Final clinic visit or ET (Visit 9). And, in subgroup of ABPM 
subjects will start 24-hour ABPM measurement. 
(h) The follow-up telephone contact should be made approximately 14 days after the last dose. 
(i) Visit 4 only applies to ABPM subgroup subjects; start 24-hour ABPM measurement. 
(j) Visit 10 only applies to ABPM subgroup subjects.


Study No. TAK-491_305
Page 9 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
Table 4.a
Schedule of Study Procedures
Washout
Double-Blind Treatment Period
Post-Treatment 
Period
Single-Blind 
Placebo Run-in
Study Day:
Screen-
ing 
Visit (a)
D -21 (b) 
or 
D -28 (c)
D -14
(d,e)
D -7
D -1
(v)
D1
W2
W4
W6
Final 
clinic/ET
W8
(f)
ABPM 
Removal 
Visit (w)
Telephone 
Follow- up 
(g)
Visit Windows
N/A
N/A
N/A
N/A
N/A
N/A
±2d
±2d
±2d
±2d 
N/A
N/A
Visit Number:
1
N/A
2
3
4
5
6
7
8
9
10
N/A
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics and medical 
history
X
Medication history
X
Physical examination
X
X
X
PTE assessment (h)
X
X
AE assessment (i,j,r)
X
X
X
X
X
X
X
X
X
X
Vital signs (k)
X
X
X
X
X
X
X
X
X
X
Weight, height, and BMI (l)
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Clinical laboratory tests (m)
X
X
X
X
X
Urine albumin and creatinine and 
UACR (n)
X
X
HbA1c
X
X
X
Estimated GFR (n)
X
X
X
X
X
Serum hCG (o)
X
X
X
X
X
Urine pregnancy test (o,p)
X
Guidance on avoidance of 
pregnancy, ova donation, and 
acceptable methods of 
contraception 
X
X
X
X
X
X
X
X
X
X
X
Notify subject to begin 
washout period (q)
X
Plasma renin concentration and 
activity, plasma and urine 
aldosterone
X
X
X
ABPM start (subgroup only)
X
X
ABPM removal (subgroup only)
X
X
Concurrent medical conditions (r)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Access IVRS/IWRS (s)
X
X
X
X
X
X
X
Dispense single-blind study 
placebo for run-in and dose in-
clinic (t)
X
Redispense single-blind placebo 
for run-in
X
Last dose of single-blind placebo
(u)
X
Dispense double blind study drug
X
X
X
X
Last dose of double blind study 
drug
X
Clinic dosing (u)
X
X
X
X
X
X
X
X
Compliance assessment
X
X
X
X
X
X
X
Footnotes for Table 5.a are on the next page.


Study No. TAK-491_305
Page 10 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
D=Day, W=Week. 
(a) The Screening Visit should be scheduled before the washout/run-in period begins so that laboratory tests results 
can be reviewed and subject eligibility can be confirmed before other treatments are stopped or placebo is initiated. 
(b) Subjects taking previous antihypertensive agents are required to participate in a 3-week washout period (Days -
21 to -1). 
(c) If the subject’s previous antihypertensive treatment includes amlodipine or chlorthalidone, then the washout must 
be extended to 4 weeks (Days -28 to -1). 
(d) Subjects who have not received antihypertensive treatment within 28 days before screening can be entered into 
the run-in period as soon as all inclusion and exclusion criteria, including laboratory results, have been verified. 
(e) At minimum, the run-in should be 10 days but can extend to as long as the subject has an adequate supply of 
single-blind placebo run-in study medication. 
(f) Conduct Final Visit procedures for subjects who are randomized and discontinued early per protocol Section 7.6
(g) Telephone contact for the follow-up AE and concomitant medication assessments should be made approximately 
14 days after the last dose (single-blind placebo or double-blind). 
(h) Reports of pretreatment events should be solicited at each visit from the time that informed consent is acquired 
until the first dose of placebo run-in study medication. 
(i) AEs should be solicited at each visit from the time that single-blind placebo run-in study medication is started 
through 14 days after the last dose (via the telephone follow-up AE assessment). 
(j) Spontaneous reports of AEs and SAEs should be collected from the time of the first dose of single-blind placebo 
run-in medication through 14 or 30 days, respectively, after the last dose. 
(k) Includes sitting and standing BP and pulse rate. Pulse rate will be taken manually while sitting and standing. 
(l) Collect height at the Screening (Visit 1) only; BMI will be calculated during data analysis at Screening (Visit 1). 
(m) Hematology, serum chemistry, and urinalysis tests. After informed consent is provided, subjects will be asked to 
fast prior to blood draws within the Screening Period, and will be instructed to fast for at least 8 hours prior to blood 
draws on Day 1 (Visit 5), Week 2 (Visit 6), Week 4 (Visit 7), and Week 8/ET (Visit 9). 
(n) UACR and estimated GFR will be calculated by the central laboratory. 
(o) Women of childbearing potential only. 
(p) Urine pregnancy test is performed at the site and must be negative for subject prior to randomization on Day 1 
(Visit 5). 
(q) Subject can be notified by telephone to begin the washout period. 
(r) Data on medical conditions that require Continuous Positive Airway Pressure (CPAP) will be collected during 
the study. If CPAP is ongoing at the time of informed consent, the medical condition that required CPAP will be 
captured on the concurrent medical conditions (e)CRF. If CPAP is administered after first dose of study drug, then 
the medical condition will be captured as an AE. 
(s) If a subject withdraws early, contact IVRS/IWRS to document the ET. 
(t) Subjects to take the first dose of single-blind placebo run-in study medication in-clinic. 
(u) Instruct subjects to withhold their dose of study drug, if applicable so they can be dosed in-clinic. For ABPM 
subgroup subjects, clinic dosing at 8:00 AM (±2 hours) for Visits 4 and 9. 
(v) Visit 4 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined 
criteria (fails), the subject must continue the current treatment and ABPM should be repeated within 3 days. 
(w) Visit 10 is only applied to ABPM subgroup subjects; if the ABPM measurement does not pass the predefined 
criteria (fails), the subject must continue the current treatment and ABPM should be repeated within 3 days.


Study No. TAK-491_305
Page 11 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is change from baseline to Week 8 in trough (approximately 24 hours after 
the previous dose) sitting clinic SBP. 
5.2
Secondary Endpoints
The secondary endpoints are as follows:
!
The change from baseline to Week 8 in trough sitting clinic DBP.
!
Percentage of responders at Week 8, as defined by the following:
a) Clinic SBP <140 mm Hg and/or reduction of ≥20 mm Hg from baseline.
b) Clinic DBP <90 mm Hg and/or reduction of ≥10 mm Hg from baseline.
c) a and b.
!
Percentage of subjects achieving target blood pressure at Week 8, as defined by the 
following:
a) Clinic SBP <140 mm Hg.
b) Clinic DBP <90 mm Hg.
c) Clinic SBP <140 mm Hg and DBP <90 mm Hg.
d) Clinic SBP <130 mm Hg.
e) Clinic DBP <80 mm Hg.
f)
Clinic SBP <130 mm Hg and DBP <80 mm Hg.
5.3
Additional Endpoints
Additional endpoints for efficacy are as follows:
CCI


Study No. TAK-491_305
Page 12 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
5.4
Safety Assessments
Safety will be assessed via adverse events (AEs), laboratory tests, 12-lead electrocardiogram 
(ECG) findings and vital signs (including orthostatic vital signs).


Study No. TAK-491_305
Page 13 of 33
Statistical Analysis Plan, Final
29 November 2017
CONFIDENTIAL
6.0
DETERMINATION OF SAMPLE SIZE
Assuming a standard deviation (SD) of 17 mm Hg and a 10% drop-out rate, a sample size of 
200 subjects per treatment group (total of 600 subjects) is sufficient to achieve at least 90% 
power to detect a difference of 6 mm Hg between TAK-491 dose and valsartan by a 2 sample 
t-test on the mean change from baseline to Week 8 in mean sitting clinic SBP at 0.05 2-sided 
significance level. This sample size will also provide, for the above assumptions, at least 90% 
power for demonstrating non-inferiority with a margin of 1.5 mm Hg between TAK-491 and 
valsartan.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Considerations
7.1.1
Statistical Software
Statistical analysis will be performed using the SAS System®, Version 9.2 or higher, on a 
Windows platform.
7.1.2
Summary Statistics and Precision
All tabulations of analysis results will include summaries for the following treatment groups: 
TAK-491 40 mg once daily (QD), TAK-491 80 mg QD and valsartan 160 mg QD.
Unless otherwise specified, confidence intervals (CIs), statistical tests, and resulting p-values 
will be reported as 2-sided and will be assessed at the 5% significance level. P-values will be 
rounded to 3 decimal places prior to assessment of statistical significance.
For continuous variables, descriptive statistics will include the number of subjects (n), mean, SD
or standard error (SE) as appropriate, minimum, median, and maximum. In general, the number 
of decimal places displayed for each statistic will be determined as follows:

Mean and median: 1 more than the number of decimal places allotted in the raw data 
received from data management.

SD and SE: 2 more than the number of decimal places allotted in the raw data.

Minimum and maximum: equal to the number of decimal places allotted in the raw data.

CIs will be presented using the same number of decimal places as SD or SE.
Exceptions to the above may be made for derived data. The specific precisions for each derived 
variables will be included in the derived dataset specifications. For categorical data, frequency 
counts and percentages will be presented. Percentages will be reported to 1 decimal place.
When applicable, data listings will be accompanied by individual subject data listings sorted by 
treatment, study centre and subject identifier. The actual day relative to the start of treatment will 
be determined and included in the listings. All ABPM subjects will be marked in the listings.
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 datasets 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.
7.1.3
Definition of Study Day and Baseline
Study Day 1 is defined as the date on which a subject took the first dose of double-blind study 
medication, as recorded on the electronic case report form (eCRF). Other study days are defined 
relative to Study Day 1 with Day -1 being the day prior to Study Day 1. If the date of an event is 


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on or after the date of first dose then Study Day = date of event – date of first dose + 1. If the 
date of an event is prior to the date of first dose then Study Day = date of event – date of first 
dose.
The baseline value for a variable is defined as the last non-missing observation collected before 
first dose on Day 1 (including a screening value or unscheduled assessment, if necessary). Time 
of first dose is collected, so baseline value will be determined based on both date and time when 
the time of the measurement is also available. In the case where the last non-missing 
measurement (except AE and concomitant medications) and the first dose on Day 1 coincide at 
the same time, or the same date if time of the measurement is not collected, that measurement 
will be considered as baseline value.
7.1.4
Definitions of Study Visit Windows
For each visit, a window will be defined; this window will establish a time interval around which 
data will be considered for the analysis of the scheduled visit pertaining to that window. The 
lower and upper bounds of each window are the approximate midpoints between the scheduled 
days for the current visit and its adjacent scheduled visits, with the exception of the Week 2 visit. 
The value used in analysis for by-visit summaries is the value within the specified window that is 
closest to the scheduled study day. If two observations are equidistant from the scheduled visit 
date, the observation with a later date will be used. The visit windows and applicable study day 
ranges are presented in Table 7.a. Cut-off days for inclusion in the window (number of days 
following the date of the last dose of double-blind study drug) are provided.
Table 7.a
Visit Analysis Windows for Efficacy and Safety Variables
Visit
Scheduled 
Visit Day
Visit Window (Days)
Variables
Scheduled 
at Week 2, 
Week 4, 
Week 6, 
Week 8
Variables
Scheduled
at Week 2, 
Week 4, 
Week 6
Variables 
Scheduled 
at Week 2, 
Week 4,
Week 8
Variables 
Scheduled 
at Week 8
Variables 
Scheduled 
at Week 4, 
Week 8
Safety 
Variables 
Summarized 
by Visit
Baseline 
1
≤1
≤1
≤1
≤1
≤1
≤1
Week 2
14
2 - 21
2 - 21
2 - 21
2 - 21
Week 4
28
22 - 35
22 - 35
22 - 42
2 - 42
22 - 35
Week 6
42
36 - 49
36 - Last 
Dose + 7
36 - 49
Week 8
56
50 - Last 
Dose + 7
43 - Last 
Dose + 7
2 - Last 
Dose + 7
43 - Last 
Dose + 7
50 - Last Dose 
+ Safety 
Cutoff
Note: Any value collected on Day 1 but after the administration of first dose will be grouped under Week 2.
7.2
Significant Protocol Deviations
Significant protocol deviations collected on the eCRF will be summarized by treatment group
and overall. Significant protocol deviations will also be listed.


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7.3
Analysis Sets
The following analysis sets will be used for analysis and presentation of the study data:
The Randomized Set will consist of all subjects who were randomized. For subjects who were 
randomized more than once, only the first randomization is used.
The Safety Analysis Set will consist of all subjects who received at least one dose of double-
blind study medication. Subjects will be analyzed according to the study medication they 
received. Subjects who were randomized more than once are excluded from the Safety Analysis 
Set.
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least one
dose of double-blind study medication. A subject in FAS will be included in the analyses of a 
specific variable only when there is both a baseline value and at least one value during the 
double-blind treatment period. Subjects will be analyzed according to the treatment group to 
which they were randomized. Subjects who were randomized more than once are excluded from 
the Full Analysis Set.
The Per Protocol Set (PPS) will consist of all subjects in the FAS, excluding those who meet 
following criteria: 
1. Subjects with SBP <150 mm Hg on Day 1.
2. Subjects who take study drug of a different treatment from the one randomized.
3. Subjects who are randomized more than once.
4. Subjects with a significant protocol deviation impacting baseline blood pressure.
5. Subjects with compliance outside of the range 70%-130%.
6. Subjects that took a prohibited medication potentially impacting baseline or Week 8 blood 
pressure.
Additional criteria may be identified prior to unblinding. If so, the additional criteria will be 
finalized and documented prior to database lock. Subjects who are included in the FAS but 
excluded from the PPS will be summarized for each criterion by treatment groups and overall. 
These subjects will also be presented in the listings.
The Ambulatory Blood Pressure Monitoring Set (ABPM Set) will consist of the subset of 
FAS subjects who received an ABPM recording at baseline. Subjects who have ABPM endpoints 
at both baseline and at least one post dose value will be included in all ABPM related summaries 
and analyses. Subjects who were randomized more than once are excluded from the ABPM Set.
The FAS will be the primary data set used for efficacy analyses. Efficacy analysis based on the 
PPS will also be performed where appropriate. All routine safety analyses will be based on the 
Safety Analysis Set. 


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7.4
Disposition of Subjects
Disposition of all screened subjects will be tabulated (count and percent); there will be no 
inferential analysis of subject disposition data. 
Disposition of non-randomized subjects will be tabulated according to screen failure and run-in 
failure, including primary reason for screen or run-in failure (pretreatment event/adverse event, 
major protocol deviation, lost to follow-up, voluntary withdrawal, study termination, did not 
meet entrance criteria or other) as entered on the eCRF.
Disposition of all randomized subjects will be tabulated by randomized treatment. For subjects 
who were randomized more than once, only the first randomization is used in the summary. The 
categories will include:

Randomized subjects.

Subjects who were randomized but not treated with double-blind study drug.

Subjects who completed double-blind study drug.

Subjects who prematurely (permanently) discontinued double-blind study drug.

Subjects unblinded by the investigator (inadvertently or for safety reasons).
The primary reason for discontinuation of study drug and/or study visits (pretreatment 
event/adverse event, major protocol deviation, lost to follow-up, voluntary withdrawal, study 
termination, pregnancy, lack of efficacy and other), as entered on the eCRF, will be tabulated for 
all randomized subjects.
The above summaries will also be performed for ABPM subgroup subjects.
Double-blind treatment group, date of first double-blind dose, date of last double-blind dose, 
duration of treatment (study day of last dose) and the reason for premature discontinuation of 
study drug/study visit will be listed for each randomized subject in the listings. Subjects in 
ABPM subgroup will be flagged. A listing of inclusion/exclusion criteria responses by subject 
will also be provided.
7.5
Demographic and Baseline Efficacy Characteristics
7.5.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics, including age (years) at the date of informed consent, 
gender, race, height (cm), weight (kg), body mass index (BMI) (kg/m2), smoking classification, 
female reproductive status, estimated glomerular filtration rate (eGFR) (mL/min/1.73m2) and 
baseline HbA1c (%) will be summarized for each treatment group and overall using the Safety 
Analysis Set. Demographic and baseline characteristics for the ABPM subgroup will also be 
summarized.


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Age is computed as the difference in years between date of birth and informed consent date; one
decimal will be kept for age in derived data. Age will be summarized as a continuous variable 
and will also be tabulated using the following categories: <45 years, 45 to 64 years, <65 years, 
≥65 years and ≥75 years.
Race will be recorded on the eCRF as American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific Islander and White. Subjects who identify 
themselves as more than one race on the eCRF will be classified as Multiracial for tabulation, 
and will be included only in the Multiracial category.
Baseline BMI is derived as: BMI (kg/m2) = (baseline weight in kg)/((height in cm)/100)2; one 
decimal will be kept for baseline BMI in derived data. BMI will be summarized as a continuous 
variable and will also be tabulated using the following categories: <27 kg/m2 and ≥27 kg/m2.
Baseline eGFR will be summarized as a continuous variable and will also be tabulated using the 
following categories: <30 mL/min/1.73m2, 30 to <60 mL/min/1.73m2, 60 to <90 mL/min/1.73m2
and ≥90 mL/min/1.73m2. 
There will be no inferential analysis of these demographic and baseline characteristics. 
All individual demographic and baseline characteristics will be listed by treatment, study centre
and subject number. The demographic data listing will include subject identifier, treatment, date 
of informed consent, date of birth, age at date of informed consent, gender, race, height, baseline 
weight and baseline BMI. Smoking classification, female reproductive status, baseline HbA1c 
level, baseline clinic measures of SBP and DBP and baseline eGFR will also be presented in a
data listing. 
7.5.2
Baseline Efficacy Parameters 
Baseline values of continuous efficacy endpoints will be summarized and analyzed using an 
analysis of variance (ANOVA) with treatment as a fixed factor. These endpoints include 
calculated mean sitting SBP and DBP. For ABPM subgroup subjects, the endpoints include all 
ABPM parameters.
Baseline calculated mean sitting SBP and DBP will be summarized as continuous variables. 
Further, baseline calculated mean sitting SBP will be tabulated using the following categories:
140 to <160 mm Hg, 160 to <180 mm Hg and ≥180 mm Hg. A separate tabulation will be 
completed for the following categories: <median baseline calculated mean sitting SBP and 
≥median baseline calculated mean sitting SBP. Baseline calculated mean sitting DBP will be 
tabulated using the following categories: <90 mm Hg and ≥90 mm Hg.
The baseline efficacy parameters will also be listed.
7.6
Medical History and Concurrent Medical Conditions
Summaries of medical history (significant conditions or diseases that stopped at or prior to the 
time of informed consent) and concurrent medical conditions (significant ongoing conditions or 


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diseases present at the time of informed consent) will be based on the Safety Analysis Set. No 
inferential statistics will be presented. 
Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA), Version 20.0 MIXED coding system. 
Medical history and concurrent medical conditions will be summarized by system organ class
(SOC) and preferred term (PT) for each treatment group. The tables will be sorted in alphabetic 
order by SOC and in decreasing frequency based on the total number of subjects in each PT. The 
number and percentage of subjects with any significant medical history and concurrent medical 
conditions will be summarized for each SOC and PT. The denominator used for calculating the 
percentages will be the total number of subjects included in each treatment group. For the tables, 
if a subject reports the same PT multiple times, then that PT will be counted only once for that 
subject. Similarly, if a subject reports multiple conditions within the same SOC, then that SOC 
will be counted only once for that subject.
A similar summary table will be provided for the ABPM subgroup.
All medical history and concurrent medical condition data will be listed.
7.7
Medication History and Concomitant Medications
Summaries of medication history and concomitant medications will be based on the Safety 
Analysis Set. No inferential statistics will be presented. 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and efficacy/safety evaluation 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 01March2015 Enhanced coding system. 
Medication history and concomitant medications will be summarized by treatment and preferred 
medication name. Preferred medication names will be sorted by decreasing frequency based on 
the total number of subjects.
Concomitant medications will be summarized separately according to the following subgroups:

Concomitant medications that started and stopped prior to baseline. This includes any 
medication that was stopped after the time of informed consent and prior to the first dose of 
double-blind study medication. 

Concomitant medications that started prior to and were ongoing at baseline. This includes 
any medication that started before and was not stopped prior to the first dose of double-blind 
study medication. 


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
Concomitant medications that started after baseline. This includes any medication that started 
at or after the first dose of double-blind study medication.

Concomitant medications that were ongoing at baseline and those that started after baseline. 
This includes any medication that started before and was not stopped prior to the first dose of 
double-blind study drug as well as any medication that started at or after the first dose of 
double-blind study medication.
Similar summaries will be provided for the ABPM subgroup.
Separate listings for medication history and concomitant medications will be presented by site 
and subject number. 
7.8
Study Drug Exposure and Compliance
The duration of exposure to double-blind study medication is defined as date of last dose of 
double-blind study drug - date of first dose double-blind study drug + 1. The date of last double-
blind dose will be obtained from the eCRF. In the event that the date of last dose is missing, the 
last dose date will be estimated as the later date between the last drug dispense date plus the 
number of days in the dosing interval (dispense date + next visit day – last visit day + 1) and the 
last study visit day for analysis and summary purposes.
The duration of exposure to double-blind treatment will be summarized by treatment group as a 
continuous variable and tabulated using following categories: 1 to 7 days, 8 to 14 days, 15 to 21
days, 22 to 28 days, 29 to 35 days, 36 to 42 days, 43 to 49 days, 50 to 56 days, 57 to 63 days and 
64 days or more.
Subjects are to take 2 tablets for TAK-491 (40mg/80mg) and matching placebo or 2 capsules for 
valsartan and matching placebo each day. Overall percent study drug compliance for the double-
blind treatment period will be calculated as: 100 × [(number of tablets dispensed – number of 
tablets returned) / (expected number of tablets to be taken)], where the expected number of 
tablets to be taken = [4*(date of last dose of medication – date of first dose of medication + 1)].
Compliance will be presented to 1 decimal place in the derived dataset.
Overall double-blind study drug compliance will be summarized using descriptive statistics and 
by the number of subjects in each of the following compliance categories: <70%, 70 to 130%, 
>130%. A missing category will also be included, if applicable. 
The summary of study drug exposure and compliance will be based on the Safety Analysis Set. 
No inferential statistics will be presented.
The above tables will also be provided for the ABPM subgroup. A compliance for ABPM 
procedure will be provided. The number and percentage of subjects with qualified ABPM 
recordings will be summarized by treatment group and overall at baseline and Week 8.
All study drug administration (single-blind placebo and double-blind study drug) and 
accountability data will be listed by site and subject number. 


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7.9
Efficacy Analysis
Unless otherwise specified, efficacy analyses will be performed using the FAS and all statistical 
inference will use a 2-sided 0.05 significance level. Efficacy analyses based on the PPS will also 
be performed, if appropriate.
The trough sitting clinic SBP/DBP will consist of an average (arithmetic mean) of the non-
missing SBP/DBP measurements performed at each visit that satisfy the trough requirements.
Post-baseline clinic BP measurements qualify as trough if they are obtained 20-28 hours 
(inclusive) after the previous study drug dose. Baseline clinic BP measurements are considered 
trough by default as no double-blind study drug has yet to be taken by subjects.
For the clinic sitting SBP and DBP, missing values will be handled using last observation carried
forward (LOCF) methodology. In the LOCF analysis data set, the last observed post-baseline 
double-blind value will be carried forward and used for all subsequent scheduled time points 
where data are missing (e.g., the subject has missing data or has dropped out of the study). The 
efficacy analysis for the response criteria will also be based on the LOCF data set.
7.9.1
Primary Efficacy Endpoint
The primary efficacy endpoint, change from Baseline to Week 8 in trough sitting clinic SBP, will 
be analyzed using an analysis of covariance (ANCOVA) model, with treatment group as a fixed 
effect and baseline sitting clinic SBP as a continuous covariate. Estimates of treatment LS mean,
differences in LS means between TAK-491 treatment groups and valsartan, p-value and 2-sided 
95% CIs for the treatment difference will be determined from the framework of the ANCOVA 
model. For the primary analysis, the overall type 1 error rate of 0.05 will be controlled using the 
4-step sequential test described below. 

Step 1: A test for non-inferiority of TAK-491 80 mg to valsartan 160 mg will be performed 
using a non-inferiority margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the 
treatment difference (TAK-491 – valsartan) is not greater than 1.5 then proceed to Step 2.

Step 2: A test for non-inferiority of TAK-491 40 mg to valsartan 160 mg will be performed 
using a non-inferiority margin of 1.5 mm Hg. If the upper limit of the 2-sided 95% CI of the 
treatment difference (TAK-491 – valsartan) is not greater than 1.5 then proceed to Step 3.

Step 3: A test for significant difference between TAK-491 80 mg versus valsartan 160 mg 
will be performed at the 5% level. If the p-value is not greater than 0.05 then proceed to 
Step 4.

Step 4: A test for significant difference between TAK-491 40 mg versus valsartan 160 mg 
will be performed at the 5% level.
Based on historical data, the observed placebo-corrected treatment effects on change from 
Baseline in clinic SBP for valsartan 160 mg once daily was -8.6 mm Hg [4]. Therefore, the non-
inferiority margin was set conservatively at 1.5 mm Hg, which is less than one-third of the 
valsartan treatment effect. Accordingly, TAK-491 will be considered non-inferior to valsartan 


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when the upper limit of the 2-sided 95% CI of the treatment difference (TAK 491- comparator) 
is ≤1.5 mm Hg. 
The following sensitivity analyses will be performed for the primary endpoint (change from 
Baseline in trough sitting clinic SBP at Week 8): 

Conduct the described primary analysis in the PPS to explore the robustness of the primary 
efficacy result.

A multiple imputation (MI) procedure to assess the impact of missing data and drop-outs for 
the FAS and PPS. The analysis based on MI assumes the data to be missing at random 
stratified within each treatment group while retaining consistency for each subject across 
various visits. 

ANCOVA method which is identical to the primary efficacy analysis, using only the 
observed case (OC) data for the FAS and PPS. 
In addition, the following subgroup analyses will be performed for the primary endpoint where 
appropriate. Only LOCF data for the FAS will be used: 

gender (males and females).

age (<45 years, 45 to 64 years, <65 years, ≥65 years and ≥75 years ).

baseline BMI(<27 kg/m2 and ≥27 kg/m2).

baseline sitting SBP(140 to <160mm Hg,160 to <180mm Hg and ≥180mm Hg ).

baseline sitting SBP (<baseline median and ≥baseline median).

baseline sitting DBP (<90 mm Hg and ≥90 mm Hg).
7.9.2
Secondary Efficacy Endpoints
Change from Baseline in trough clinic sitting DBP at Week 8 will be analyzed using the 
ANCOVA model described for the primary endpoint in Section 7.9.1, excluding the sequential 
testing. Baseline sitting clinic DBP will be the continuous covariate in the ANCOVA model. 
Subgroup analyses and OC sensitivity analyses described for the primary endpoint will also be 
performed for trough clinic sitting DBP secondary endpoints. 
The percentage of subjects responding to treatment and percentage of subjects reaching the 
target blood pressure at Week 8 will be tabulated for each of the following definitions:

Response criteria.
a) Clinic SBP <140 mm Hg and/or a reduction of ≥20 mm Hg from baseline.
b) Clinic DBP <90 mm Hg and/or a reduction of ≥10 mm Hg from baseline.
c) a and b (e.g., joint criteria).


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!
Target blood pressure: 
a) Clinic SBP <140 mm Hg.
b) Clinic DBP <90 mm Hg.
c) Clinic SBP <140 mm Hg and DBP <90 mm Hg.
d) Clinic SBP <130 mm Hg.
e) Clinic DBP <80 mm Hg.
f)
Clinic SBP <130 mm Hg and DBP <80 mm Hg.
Response criteria for clinic sitting SBP at Week 8 will be analyzed using a logistic model with 
treatment group as fixed effect and baseline clinic sitting SBP as a covariate. The odds ratio and 
its 95% CI will be estimated from the framework of the logistic model. Similarly, a logistic 
model with treatment as a fixed effect and baseline clinic sitting DBP as a covariate will be used 
to analyze the response criteria for sitting clinic DBP. The joint response criteria for both clinic 
sitting SBP and DBP will be analyzed using a logistic model with treatment as a fixed effect and 
baseline clinic sitting SBP as a covariate. A similar analysis and model will be used to analyze 
the percentage of subjects reaching target blood pressure at Week 8. The efficacy analysis for the 
response criteria will be based on the LOCF data set.
7.9.3
Additional Efficacy Endpoints
7.9.4
Efficacy Analysis for ABPM Subgroup Subjects
All ABPM related summaries and analyses will be based on OC data for the ABPM Set. 
The average and change from baseline ABPM values will be calculated by hour and 2-hour over 
the entire duration of the ABPM measurements. The following comparisons will be presented in 
figures:
!
Average baseline ABPM values by hour for the 0- to 24-hour interval, final ABPM values by 
hour for the 0- to 24-hour interval, and change from baseline in ABPM values by hour for the 
0- to 24-hour interval.
CCI


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
Average baseline ABPM values by hour for the 0- to 12-hour interval, final ABPM values by 
hour for the 0- to 12-hour interval, and change from baseline in ABPM values by hour for the 
0- to 12-hour interval.
The analysis of ABPM will be based on the following variables that are obtained by 
summarizing the individual ABPM measurements, namely, 0- to 24-hour mean ABPM, 0- to 
12-hour mean ABPM, daytime mean ABPM, nighttime mean ABPM, peak effect, 22- to 24-hour 
trough ABPM and trough-to-peak ratios.
The baseline 0- to 24-hour mean ABPM will consist of the average (arithmetic mean) of ABPM
measurements over the time period beginning with the first ABPM observation and including all
observations recorded over the subsequent 24 hours (any observations that are recorded 
≥24 hours after the first observation will be excluded). 
The final 0- to 24-hour mean ABPM will consist of the average of ABPM measurements over 
the time period beginning with the final study medication dose and including all observations 
recorded over the 24-hour period following that dose.
The baseline 0- to 12-hour mean ABPM will consist of the average (arithmetic mean) of ABPM
measurements over the time period beginning with the first ABPM observation and including all
observations recorded over the subsequent 12 hours (any observations that are recorded 
≥12 hours after the first observation will be excluded). The final 0- to 12-hour mean ABPM will
consist of the average of ABPM measurements over the time period beginning with the final
study medication dose and including all observations recorded over the 12-hour period following
that dose.
The daytime mean ABPM will consist of the average of those ABPM measurements that were
included in the respective 24-hour mean ABPM calculations and were also recorded between the
hours of 6 AM (inclusive) and 10 PM (exclusive).
The nighttime mean ABPM will consist of the average of those ABPM measurements that were
included in the respective 24-hour mean ABPM calculations and were also recorded between the
hours of 12 AM (inclusive) and 6 AM (exclusive).
The baseline 22- to 24-hour trough ABPM will consist of the average (arithmetic mean) of
ABPM measurements over the time period beginning 22 hours (inclusive) after the first ABPM
observation and ending 24 hours (exclusive) after the first ABPM observation. 
The final 22- to 24-hour trough ABPM will consist of the average of ABPM measurements over 
the time period beginning 22 hours (inclusive) after the final study medication dose and ending 
24 hours (exclusive) after the final study medication dose.
The peak effect interval was determined for each subject as the 2-hour interval during the 
24 hours after dosing in which the maximum decrease from baseline was observed for SBP. Peak 
effect is defined as the change from baseline to Week 8 in BP values by ABPM during the peak 
effect interval. 


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Trough-to-Peak Ratio was calculated as mean trough response divided by peak effect, where 
trough response is defined as the change from baseline in the mean trough (22- to 24 hour) 
ABPM to Week 8. 
The variables based on ABPM will be presented in summary tables by descriptive statistics 
(including mean, SD, median, minimum, and maximum). Change from Baseline for the ABPM 
variables will also be summarized in this fashion.
Change from baseline to Week 8 24-hour mean SBP by ABPM will be analyzed using an 
ANCOVA model with treatment as a fixed effect and baseline 24-hour mean SBP by ABPM as a 
covariate for ABPM Set. This analysis will be performed separately for DBP. Similar analyses 
will be performed for other ABPM parameters:

24-hour mean SBP and DBP.

Trough (22-24h) SBP and DBP. 

Mean daytime (6 AM to 10 PM) SBP and DBP. 

Mean nighttime (12 AM to 6 AM) SBP and DBP. 

Mean SBP and DBP at 0 to 12 hours after dosing.

Peak SBP and DBP effect
Only observed data will be used for the summary and analyses of ABPM parameters. No 
imputation will be performed for missing data.
ABPM parameters and ABPM related data collected on the eCRF will be included in the data 
listings. Raw 24-hour ABPM recordings will not be presented in a listing.
7.10
Safety Analysis
All safety summaries will be based on the Safety Analysis Set. The safety analysis will use OC 
data and be restricted to descriptive statistics unless otherwise specified.
7.10.1 Adverse Events
An AE is defined as any untoward medical occurrence in a clinical investigation subject that has 
been administered a pharmaceutical product, including placebo. It does not necessarily have to 
have a causal relationship with this treatment. AEs will be coded using MedDRA Version 20.0
MIXED. 
A pretreatment event is defined as any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study that occurs prior to 
administration of any study medication. It does not necessarily have to have a causal relationship 
with study participation. Pretreatment events will be summarized by SOC and PT.
Run-in AEs are defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study, which occurred on or after the first 


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dose of run-in placebo and prior to administration of double-blind study drug. Run-in AEs will 
be summarized by SOC and PT.
A treatment-emergent adverse event (TEAE) will be defined as any AE, regardless of 
relationship to study drug, that occurs after the first dose of double-blind study drug and no later 
than 14 days after the last dose of study drug for AEs, and no later than 30 days after the last 
dose of study drug for serious AEs. TEAEs will be summarized by SOC and PT.
AEs are recorded in the eCRF as being related or not related to study drug and study procedure. 
TEAEs that are recorded as related to study drug and/or study procedure will be summarized 
separately. TEAEs will also be summarized by intensity/severity (mild, moderate, severe). 
Serious TEAEs, TEAEs leading to study drug discontinuation and TEAEs leading to death will 
also be summarized.
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 PT subject-count summary levels. For 
the intensity summaries, if a subject reports multiple TEAEs coded to the same SOC or PT, then 
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 then the TEAE 
related to study drug will be included in the summary. If a TEAE is missing causality and/or 
intensity, then it will be assumed that the TEAE is related and/or severe in summary tables.
TEAEs will be summarized by treatment group, which will include the number and percentage 
of subjects as follows:

Overview of Treatment-Emergent Adverse Events.

Treatment-Emergent Adverse Events by SOC and PT (Overall and by Age groups: <45 
years-old; 45-64 years old, inclusive; <65 years old; ≥65 years old; ≥75 years old).

Treatment-Emergent Adverse Events by SOC.

Treatment-Emergent Adverse Events by PT.

Most Frequent (≥5% in any treatment arm) Treatment Emergent Adverse Events by SOC and 
PT (Overall and by Age groups: <45 years-old; 45-64 years old, inclusive; <65 years old; 
≥65 years old; ≥75 years old).

Most Frequent (≥5% in any treatment arm) Non-Serious Treatment Emergent Adverse 
Events by SOC and PT.

Drug-Related Treatment-Emergent Adverse Events by SOC and PT (Overall and by Age 
groups: <45 years-old; 45-64 years old, inclusive; <65 years old; ≥65 years old; ≥75 years 
old).

Intensity of Treatment-Emergent Adverse Events by SOC and PT


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
Intensity of Drug-Related Treatment-Emergent Adverse Events by SOC and PT.

Procedure-Related Treatment-Emergent Adverse Events by SOC and PT

Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by SOC and 
PT.

Serious Treatment-Emergent Adverse Events by SOC and PT.

Pretreatment Adverse Events by SOC and PT.

Run-in Adverse Events by SOC and PT.
Subject mappings will be presented by SOC and PT for the summary of TEAEs, serious TEAEs
and TEAEs leading to the discontinuation of study drug.
All AEs will be listed by site and subject number.
7.10.2 Clinical Laboratory Evaluations
Clinical laboratory tests will be assessed using the Safety Analysis Set and will be presented 
using System International (SI) units unless otherwise stated. Refer to Table 4.a for the schedule 
of measurements for clinical laboratory tests and to Table 7.b for a list of all clinical laboratory 
tests. Clinical laboratory data will be presented by subject and no inferential statistics will be 
presented. 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
lipid panel, other screening/safety parameters and other tests listed in Table 7.b. Only data 
obtained within 7 days of the last dose of study drug will be included in the summaries. All data 
will be presented in the listings.


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Table 7.b
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hemoglobin
Hematocrit
Platelet count
Red blood cell count
White blood cell count with 
differential
Albumin
Alanine aminotransferase 
Alkaline phosphatase
Aspartate aminotransferase
Bicarbonate
Bilirubin, total
Bilirubin, direct (only if total is above ULN)
Blood urea nitrogen
Calcium
Chloride
Creatinine
Creatine kinase
γ-Glutamyl transferase
Glucose (serum)
Magnesium
Potassium
Protein, total
Sodium
Uric Acid
High-density lipoprotein cholesterol 
Low-density lipoprotein cholesterol 
Total cholesterol
Triglycerides
Specific gravity
pH
Qualitative
Protein
Blood
Ketones
Bilirubin
Glucose
Microscopy
Red Blood Cells
White Blood Cells
Other 
HbA1c
Female subjects of childbearing potential only:
Serum human chorionic gonadotropin for pregnancy
Urine hCG for pregnancy (a)
Urine albumin
Urine creatinine
Albumin: creatinine ratio
eGFR
Plasma renin concentration and activity
Plasma and urine aldosterone
(a) Urine hCG will be performed at the site on Day 1 (Visit 5) prior to randomization.
The following summaries of hematology, serum chemistry, urinalysis lab tests, lipid panel, and
other will be presented for each scheduled time point (each visit and final visit):
Descriptive statistics (n, mean, SD, median, minimum, and maximum) by treatment group for the 
observed and change from baseline laboratory test values will be based on a single data value 
selected according to the window convention described in Table 7.a. Note that qualitative
urinalysis parameters will only be listed.
Shifts in laboratory test values will be presented as cross-tabulations (baseline versus each post-
baseline visit) of numbers of subjects with low, normal and high values relative to the normal 
range used at the central laboratory. Marginal totals will be provided for the baseline visit (e.g. 
total number of subjects with low, normal and high values at baseline) for each treatment group. 
Shifts from normal at baseline to high at visit (as well as normal to low) will be supplemented 
with the percentage (n in shift category/total normal at baseline). This classification will be based 
on the low, normal and high alert flags reported by the central laboratory. If a subject has 


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multiple values within a particular visit window, the most abnormal result will be used for 
summary. All clinical laboratory tests with reference ranges will be included in the shift 
summary.
Subjects with markedly abnormal values (MAV), identified by the criteria in Appendix A, for 
laboratory tests will be tabulated. If a subject has multiple values within a particular visit 
window, the most abnormal result will be used for summary. MAV tables will include all 
laboratory parameters with available MAV criteria.
The number and percentage of subjects with one or more post-baseline serum creatinine level 
≥1.3 × baseline AND >upper limit of normal (ULN) (e.g., 30% creatinine elevation) and ≥1.5 ×
baseline AND >ULN (e.g., 50% creatinine elevation) will be summarized by visit. Subjects 
meeting these criteria at any post dose visits and remain elevated at the final visit will also be 
summarized and listed. The number and percentage of subjects with consecutive elevations will 
also be determined. The relationship between the change of creatinine and change of clinic BP 
may be assessed.
Listings of all clinical safety laboratory data will be provided by site and subject number. 
Listings will be produced for hematology, serum chemistry and urinalysis categories separately. 
Laboratory data outside of the normal reference ranges will be indicated in the listings. A listing 
of subjects with MAVs will be provided.
7.10.3 Vital Signs and Weight
Refer to Table 4.a for scheduled measurements of Vital Signs and weight. Trough sitting clinic 
SBP/DBP are efficacy endpoints in Section 7.9 and therefore will not be included in this section. 
Vital signs (including sitting and standing pulse rate, weight and standing BP) at each scheduled 
visit and changes from baseline will be summarized using descriptive statistics for the Safety 
Analysis Set. 
Orthostatic vital signs will be calculated as the decrease in BP from sitting (the one that is two 
minutes after standing and the closest to standing BP in terms of the time of the measurement) to 
standing (e.g., standing BP – sitting BP). The number and percentage of subjects with one or 
more decreases in BP meeting the criteria of orthostatic hypotension (SBP decreases ≥20 mm Hg 
or DBP decreases ≥10 mm Hg after standing for 2 minutes) will be summarized by treatment and 
visit. A listing of the orthostatic vital signs for such subjects will also be provided. Only the 
values meeting the criteria will be included in the listing. No inferential statistics will be 
presented. 
Only data obtained within 7 days of the last dose of study drug will be included in vital signs
summaries. All data will be presented in the listings.
7.10.4 12-Lead ECGs
ECG data will be summarized using the Safety Analysis Set. The ECG endpoints include Heart 
Rate (beats/minute), RR interval (msec), PR interval (msec), QT interval (msec) and QRS 
interval (msec). Missing values of RR will be imputed as RR(msec) = 1000*(60/). The 


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corrected QT interval will be computed using both Bazett’s (QTcB = QT/RR1/2) and Fridericia’s 
(QTcF = QT/RR1/3) formulas, where RR is presented in seconds. The QTc intervals computed 
by both methods will be summarized along with other vital signs parameters. No decimal place 
will be presented in the derived dataset and TLF outputs.
Descriptive statistics (n, mean, SD, median, minimum and maximum values) will be used to 
summarize 12-lead ECG values at Baseline, Week 8 or final visit and change from Baseline to 
Week 8 or final visit by treatment group. 
The number and percentage of subjects with an increase ≥30 and ≥60 msec from Baseline in QTc 
interval will be tabulated as well as a tabulation of subjects with a post-baseline value >500 msec 
and an increase ≥60 msec from baseline.
Overall ECG interpretation category (normal, not clinically significant abnormal, clinically 
significant abnormal) will be collected on the 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). Marginal totals will be 
provided for the baseline visit (e.g. total number of subjects in each category at baseline) for each 
treatment group. Percentage will also be provided.
Shifts in QTc intervals between Baseline and Week 8 will also be tabulated based on the value 
categories listed below:

Females: ≤450, >450 to 470, >470 to 500 and >500 msec.

Males: ≤430, >430 to 450, >450 to 500 and >500 msec.
Only data obtained within 7 days of the last dose of study drug will be included in the 
summaries. No inferential statistics will be presented. All ECG data will be presented in the data 
listings.
7.10.5 Physical Examinations
All physical examination findings will be listed by treatment, study centre and subject number.
7.11
Interim Analysis
Not applicable.
7.12
Changes in the Statistical Analysis Plan From the Protocol Analysis Plan
Not applicable.


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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 Phase 3, Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and 
Safety of TAK-491 with Valsartan in Chinese Subjects with Essential Hypertension, Takeda 
Development Center Asia, Pte. Ltd., Protocol No. TAK-491_305, Amendment Number 4, 09 
May 2016.
4. Pool J, Oparil S, Hedner T, Glazer R, Oddou-Stock P, Hester A. Dose-Responsive 
Antihypertensive Efficacy of Valsartan, a New Angiotensin II-Receptor Blocker. Clinical 
Therapeutics 1998; 20:1106-14. 


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Appendix A. Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology
Parameter
Low Abnormal
High Abnormal
Hemoglobin
<0.8 × LLN
>1.2 × ULN
Hematocrit
<0.8 × LLN
>1.2 × ULN
RBC count
<0.8 × LLN
>1.2 × ULN
WBC count
<0.5 × LLN
>1.5 × ULN
Platelet count
<75 × 109/L
>600 × 109/L 
LLN=lower limit of normal, ULN=upper limit of normal, RBC=red blood cell, WBC=white blood cell.
Chemistry
Parameter
Low Abnormal
High Abnormal
ALT
--
>3 × ULN
ALT
--
>5 × ULN
ALT
--
>10 × ULN
AST
--
>3 × ULN
AST
--
>5 × ULN
AST
--
>10 × ULN
GGT
--
>3 × ULN
Alkaline phosphatase
--
>3 × ULN
Total bilirubin
--
>34.2 µmol/L 
ALT and Total Bilirubin
--
ALT>3 × ULN and TB>2 × ULN
AST and Total Bilirubin
--
AST>3 × ULN and TB>2 × ULN
Albumin
<25 g/L
--
Total protein
<0.8 × LLN
>1.2 × ULN
Creatinine
--
> 177 µmol/L
Sodium
<130 mmol/L
>150 mmol/L
Potassium
<3.0 mmol/L
>6.0 mmol/L
Blood Urea Nitrogen
--
>10.7 mmol/L
Calcium
<1.75 mmol/L
>2.88 mmol/L
Creatine kinase
--
>5 × ULN
Uric Acid
--
>773 µmol/L
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=γ-glutamyl transferase, LLN=lower limit of 
normal, ULN=upper limit of normal, TB=total bilirubin.


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Urinalysis
Parameter
Low Abnormal
High Abnormal
Blood
--
≥1+
Glucose
--
≥1+
Ketones
--
≥2+
Casts
--
Any
Microscopic RBCs*
--
≥5/hpf
Microscopic WBC
--
≥20/hpf
pH
≤4
≥8
Protein
--
≥1+
Specific Gravity
--
--
Hpf=high power field, RBC=red blood cell, WBC=white blood cell.
* Markedly abnormal if repeated values both meet the criteria; e.g., if two values are greater than or equal to 5/hpf 
within 30 days of one another.


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